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Sample records for agonist quinolinic acid

  1. Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

    PubMed Central

    Lugo-Huitrón, Rafael; Ugalde Muñiz, Perla; Pineda, Benjamin; Pedraza-Chaverrí, José; Ríos, Camilo; Pérez-de la Cruz, Verónica

    2013-01-01

    Quinolinic acid (QUIN), a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF) and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA) receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death. PMID:24089628

  2. Interactions of amino acids, carboxylic acids, and mineral acids with different quinoline derivatives

    NASA Astrophysics Data System (ADS)

    Kalita, Dipjyoti; Deka, Himangshu; Samanta, Shyam Sundar; Guchait, Subrata; Baruah, Jubaraj B.

    2011-03-01

    A series of quinoline containing receptors having amide and ester bonds are synthesized and characterised. The relative binding abilities of these receptors with various amino acids, carboxylic acids and mineral acids are determined by monitoring the changes in fluorescence intensity. Among the receptors bis(2-(quinolin-8-yloxy)ethyl) isophthalate shows fluorescence enhancement on addition of amino acids whereas the other receptors shows fluorescence quenching on addition of amino acids. The receptor N-(quinolin-8-yl)-2-(quinolin-8-yloxy) propanamide has higher binding affinity for amino acids. However, the receptor N-(quinolin-8-yl)-2-(quinolin-8-yloxy)acetamide having similar structure do not bind to amino acids. This is attributed to the concave structure of the former which is favoured due to the presence of methyl substituent. The receptor bis(2-(quinolin-8-yloxy)ethyl) isophthalate do not bind to hydroxy carboxylic acids, but is a good receptor for dicarboxylic acids. The crystal structure of bromide and perchlorate salts of receptor 2-bromo-N-(quinolin-8-yl)-propanamide are determined. In both the cases the amide groups are not in the plane of quinoline ring. The structure of N-(quinolin-8-yl)-2-(quinolin-8-yloxy)acetamide, N-(2-methoxyphenethyl)-2-(quinolin-8-yloxy)acetamide and their salts with maleic acid as well as fumaric acid are determined. It is observed that the solid state structures are governed by the double bond geometry of these two acid. Maleic acid forms salt in both the cases, whereas fumaric acid forms either salt or co-crystals.

  3. Quinoline

    Integrated Risk Information System (IRIS)

    Quinoline ; CASRN 91 - 22 - 5 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Effects

  4. Structure of Quinolinate Synthase from Pyrococcus horikoshii in the Presence of Its Product, Quinolinic Acid.

    PubMed

    Esakova, Olga A; Silakov, Alexey; Grove, Tyler L; Saunders, Allison H; McLaughlin, Martin I; Yennawar, Neela H; Booker, Squire J

    2016-06-15

    Quinolinic acid (QA) is a common intermediate in the biosynthesis of nicotinamide adenine dinucleotide (NAD(+)) and its derivatives in all organisms that synthesize the molecule de novo. In most prokaryotes, it is formed from the condensation of dihydroxyacetone phosphate (DHAP) and aspartate-enamine by the action of quinolinate synthase (NadA). NadA contains a [4Fe-4S] cluster cofactor with a unique, non-cysteinyl-ligated, iron ion (Fea), which is proposed to bind the hydroxyl group of a postulated intermediate in the last step of the reaction to facilitate a dehydration. However, direct evidence for this role in catalysis has yet to be provided. Herein, we present the structure of NadA in the presence of the product of its reaction, QA. We find that N1 and the C7 carboxylate group of QA ligate to Fea in a bidentate fashion, which is confirmed by Hyperfine Sublevel Correlation (HYSCORE) spectroscopy. This binding mode would place the C5 hydroxyl group of the postulated final intermediate distal to Fea and virtually incapable of coordinating to it. The structure shows that three strictly conserved amino acids, Glu198, Tyr109, and Tyr23, are in close proximity to the bound product. Substitution of these amino acids with Gln, Phe, and Phe, respectively, leads to complete loss of activity. PMID:27224840

  5. True Niacin Deficiency in Quinolinic Acid Phosphoribosyltransferase (QPRT) Knockout Mice.

    PubMed

    Shibata, Katsumi

    2015-01-01

    Pyridine nucleotide coenzymes (PNCs) are involved in over 500 enzyme reactions. PNCs are biosynthesized from the amino acid L-tryptophan (L-Trp), as well as the vitamin niacin. Hence, "true" niacin-deficient animals cannot be "created" using nutritional techniques. We wanted to establish a truly niacin-deficient model animal using a protocol that did not involve manipulating dietary L-Trp. We generated mice that are missing the quinolinic acid phosphoribosyltransferase (QPRT) gene. QPRT activity was not detected in qprt(-/-)mice. The qprt(+/+), qprt(+/-) or qprt(-/-) mice (8 wk old) were fed a complete diet containing 30 mg nicotinic acid (NiA) and 2.3 g L-Trp/kg diet or an NiA-free diet containing 2.3 g L-Trp/kg diet for 23 d. When qprt(-/-)mice were fed a complete diet, food intake and body weight gain did not differ from those of the qprt(+/+) and the qprt(+/-) mice. On the other hand, in the qprt(-/-) mice fed the NiA-free diet, food intake and body weight were reduced to 60% (p<0.01) and 70% (p<0.05) of the corresponding values for the qprt(-/-) mice fed the complete diet at day 23, respectively. The nutritional levels of niacin such as blood and liver NAD concentrations were also lower in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice. Urinary excretion of quinolinic acid was greater in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice (p<0.01). These data suggest that we generated truly niacin-deficient mice. PMID:26598832

  6. True Niacin Deficiency in Quinolinic Acid Phosphoribosyltransferase (QPRT) Knockout Mice.

    PubMed

    Shibata, Katsumi

    2015-01-01

    Pyridine nucleotide coenzymes (PNCs) are involved in over 500 enzyme reactions. PNCs are biosynthesized from the amino acid L-tryptophan (L-Trp), as well as the vitamin niacin. Hence, "true" niacin-deficient animals cannot be "created" using nutritional techniques. We wanted to establish a truly niacin-deficient model animal using a protocol that did not involve manipulating dietary L-Trp. We generated mice that are missing the quinolinic acid phosphoribosyltransferase (QPRT) gene. QPRT activity was not detected in qprt(-/-)mice. The qprt(+/+), qprt(+/-) or qprt(-/-) mice (8 wk old) were fed a complete diet containing 30 mg nicotinic acid (NiA) and 2.3 g L-Trp/kg diet or an NiA-free diet containing 2.3 g L-Trp/kg diet for 23 d. When qprt(-/-)mice were fed a complete diet, food intake and body weight gain did not differ from those of the qprt(+/+) and the qprt(+/-) mice. On the other hand, in the qprt(-/-) mice fed the NiA-free diet, food intake and body weight were reduced to 60% (p<0.01) and 70% (p<0.05) of the corresponding values for the qprt(-/-) mice fed the complete diet at day 23, respectively. The nutritional levels of niacin such as blood and liver NAD concentrations were also lower in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice. Urinary excretion of quinolinic acid was greater in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice (p<0.01). These data suggest that we generated truly niacin-deficient mice.

  7. Copper blocks quinolinic acid neurotoxicity in rats: contribution of antioxidant systems.

    PubMed

    Santamaría, Abel; Flores-Escartín, Abigail; Martínez, Juan Carlos; Osorio, Laura; Galván-Arzate, Sonia; Pedraza-Chaverrí, José; Chaverrí, José Pedraza; Maldonado, Perla D; Medina-Campos, Omar N; Jiménez-Capdeville, María E; Manjarrez, Joaquín; Ríos, Camilo

    2003-08-15

    Reactive oxygen species and oxidative stress are involved in quinolinic acid (QUIN)-induced neurotoxicity. QUIN, a N-methyl-D-aspartate receptor (NMDAr) agonist and prooxidant molecule, produces NMDAr overactivation, excitotoxic events, and direct reactive oxygen species formation. Copper is an essential metal exhibiting both modulatory effects on neuronal excitatory activity and antioxidant properties. To investigate whether this metal is able to counteract the neurotoxic and oxidative actions of QUIN, we administered copper (as CuSO(4)) intraperitoneally to rats (2.5, 5.0, 7.5, and 10.0 mg/kg) 30 min before the striatal infusion of 1 microliter of QUIN (240 nmol). A 5.0 mg/kg CuSO(4) dose significantly increased the copper content in the striatum, reduced the neurotoxicity measured both as circling behavior and striatal gamma-aminobutyric acid (GABA) depletion, and blocked the oxidative injury evaluated as striatal lipid peroxidation (LP). In addition, copper reduced the QUIN-induced decreased striatal activity of Cu,Zn-dependent superoxide dismutase, and increased the ferroxidase activity of ceruloplasmin in cerebrospinal fluid from QUIN-treated rats. However, copper also produced significant increases of plasma lactate dehydrogenase activity and mortality at the highest doses employed (7.5 and 10.0 mg/kg). These results show that at low doses, copper exerts a protective effect on in vivo QUIN neurotoxicity.

  8. Comparative neuroprotective profile of statins in quinolinic acid induced neurotoxicity in rats.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-01-01

    A possible neuroprotective role has been recently suggested for 3H3MGCoA reductase inhibitors (statins). Here, we sought to determine neuroprotective effect of statins in quinolinic acid induced neurotoxicity in rats. Rats were surgically administered quinolinic acid and treated with Atorvastatin (10, 20 mg/kg), simvastatin (15, 30 mg/kg) and fluvastatin (5, 10 mg/kg) once daily up to 3 weeks. Atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) treatment significantly attenuated the quinolinic acid induced behavioral (locomotor activity, rotarod performance and beam walk test), biochemical (lipid peroxidation, nitrite concentration, SOD and catalase), mitochondrial enzyme complex alterations in rats suggesting their free radical scavenging potential. Additionally, atorvastatin (10, 20 mg/kg), simvastatin (30 mg/kg) and fluvastatin (10 mg/kg) significantly decrease the TNF-α level and striatal lesion volume in quinolinic acid treated animals indicating their anti-inflammatory effects. In comparing the protective effect of different statins, atorvastatin is effective at both the doses while simvastatin and fluvastatins at respective lower doses were not able to produce the protective effect in quinolinic acid treated animals. These modulations can account, at least partly, for the beneficial effect of statins in our rodent model of striatal degeneration. Our findings show that statins could be explored as possible neuroprotective agents for neurodegenerative disorders such as HD. PMID:20696189

  9. The phosphorylation status and cytoskeletal remodeling of striatal astrocytes treated with quinolinic acid

    SciTech Connect

    Pierozan, Paula; Ferreira, Fernanda; Ortiz de Lima, Bárbara; Gonçalves Fernandes, Carolina; Totarelli Monteforte, Priscila; Castro Medaglia, Natalia de; Bincoletto, Claudia; Soubhi Smaili, Soraya; Pessoa-Pureur, Regina

    2014-04-01

    Quinolinic acid (QUIN) is a glutamate agonist which markedly enhances the vulnerability of neural cells to excitotoxicity. QUIN is produced from the amino acid tryptophan through the kynurenine pathway (KP). Dysregulation of this pathway is associated with neurodegenerative conditions. In this study we treated striatal astrocytes in culture with QUIN and assayed the endogenous phosphorylating system associated with glial fibrillary acidic protein (GFAP) and vimentin as well as cytoskeletal remodeling. After 24 h incubation with 100 µM QUIN, cells were exposed to {sup 32}P-orthophosphate and/or protein kinase A (PKA), protein kinase dependent of Ca{sup 2+}/calmodulin II (PKCaMII) or protein kinase C (PKC) inhibitors, H89 (20 μM), KN93 (10 μM) and staurosporin (10 nM), respectively. Results showed that hyperphosphorylation was abrogated by PKA and PKC inhibitors but not by the PKCaMII inhibitor. The specific antagonists to ionotropic NMDA and non-NMDA (50 µM DL-AP5 and CNQX, respectively) glutamate receptors as well as to metabotropic glutamate receptor (mGLUR; 50 µM MCPG), mGLUR1 (100 µM MPEP) and mGLUR5 (10 µM 4C3HPG) prevented the hyperphosphorylation provoked by QUIN. Also, intra and extracellular Ca{sup 2+} quelators (1 mM EGTA; 10 µM BAPTA-AM, respectively) prevented QUIN-mediated effect, while Ca{sup 2+} influx through voltage-dependent Ca{sup 2+} channel type L (L-VDCC) (blocker: 10 µM verapamil) is not implicated in this effect. Morphological analysis showed dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork, supporting misregulation of actin cytoskeleton. Both hyperphosphorylation and cytoskeletal remodeling were reversed 24 h after QUIN removal. Astrocytes are highly plastic cells and the vulnerability of astrocyte cytoskeleton may have important implications for understanding the neurotoxicity of QUIN in neurodegenerative

  10. Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D3 receptor-selective full agonist ligand

    PubMed Central

    Clark, Alia H.; McCorvy, John D.; Conley, Jason M.; Williams, Whitney K.; Bekkam, Markondaiah; Watts, Val J.

    2012-01-01

    This work describes the identification of a novel class of octahydrobenzo[f]quinolines as dopamine D3-selective full agonists. We developed a facile method that utilizes Suzuki coupling for easy incorporations of various substituted pendant rings into the scaffold. A small focused library of octahydrobenzo[f]quinolines 5 was synthesized, and these compounds demonstrated at least 14-fold D2-like selectivity over D1 in native porcine striatal tissue. Furthermore, n-propyl analog 5f was found to be a high affinity (ki = 1.1 nM) D3 dopamine full agonist with 145-fold selectivity over the D2 receptor and about 840-fold selectivity over the D1 receptor. 1. PMID:23018094

  11. 40 CFR 180.426 - 2-[4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinoline carboxylic acid...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 24 2014-07-01 2014-07-01 false 2- -3-quinoline carboxylic acid... Tolerances § 180.426 2- -3-quinoline carboxylic acid; tolerance for residues. A tolerance is established for residues of the herbicide 2- -3-quinoline carboxylic acid, in or on the raw agricultural commodity...

  12. 40 CFR 180.426 - 2-[4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinoline carboxylic acid...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 25 2013-07-01 2013-07-01 false 2- -3-quinoline carboxylic acid... Tolerances § 180.426 2- -3-quinoline carboxylic acid; tolerance for residues. A tolerance is established for residues of the herbicide 2- -3-quinoline carboxylic acid, in or on the raw agricultural commodity...

  13. 40 CFR 180.426 - 2-[4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinoline carboxylic acid...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 25 2012-07-01 2012-07-01 false 2- -3-quinoline carboxylic acid... Tolerances § 180.426 2- -3-quinoline carboxylic acid; tolerance for residues. A tolerance is established for residues of the herbicide 2- -3-quinoline carboxylic acid, in or on the raw agricultural commodity...

  14. 40 CFR 180.426 - 2-[4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinoline carboxylic acid...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false 2- -3-quinoline carboxylic acid... Tolerances § 180.426 2- -3-quinoline carboxylic acid; tolerance for residues. A tolerance is established for residues of the herbicide 2- -3-quinoline carboxylic acid, in or on the raw agricultural commodity...

  15. 40 CFR 180.426 - 2-[4,5-Dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinoline carboxylic acid...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 24 2011-07-01 2011-07-01 false 2- -3-quinoline carboxylic acid... Tolerances § 180.426 2- -3-quinoline carboxylic acid; tolerance for residues. A tolerance is established for residues of the herbicide 2- -3-quinoline carboxylic acid, in or on the raw agricultural commodity...

  16. Noncovalent-bonded 1D-3D supramolecular architectures from 2-methylquinoline/quinoline with monocarboxylic acid and dicarboxylic acid

    NASA Astrophysics Data System (ADS)

    Gao, Xingjun; Jin, Shouwen; Jin, Li; Ye, XiangHang; Zheng, Lu; Li, JingWen; Jin, BinPeng; Wang, Daqi

    2014-10-01

    Studies concentrating on noncovalent weak interactions between the organic base of 2-methylquinoline/quinoline, and carboxylic acid derivatives have led to an increased understanding of the role 2-methylquinoline/quinoline have in binding with carboxylic acids. Here anhydrous multicomponent organic acid-base adducts of 2-methylquinoline/quinoline have been prepared with carboxylic acids that ranged from monocarboxylic acid to dicarboxylic acid such as p-nitrobenzoic acid, (4-chloro-phenoxy)-acetic acid, 4-hydroxy-benzoic acid, 5-bromosalicylic acid, 2,4-dihydroxybenzoic acid, α-ketoglutaric acid, and 4-nitrophthalic acid. The seven crystalline complexes were characterized by X-ray diffraction analysis, IR, m.p., and elemental analysis. These structures adopted the hetero supramolecular synthons. Analysis of the crystal packing of 1-7 suggests that there are Nsbnd H⋯O, Osbnd H⋯N, and Osbnd H⋯O hydrogen bonds (charge assisted or neutral) between the acid and quinoline moieties in the studied compounds. Except the classical hydrogen bonding interactions, the secondary propagating interactions also play important roles in structure extension. These weak interactions combined, these compounds displayed 1D-3D framework structure.

  17. Licofelone attenuates quinolinic acid induced Huntington like symptoms: possible behavioral, biochemical and cellular alterations.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-03-30

    Cyclo-oxygenase and lipoxygenase enzymes are involved in arachidonic acid metabolism. Emerging evidence indicates that cyclo-oxygenase and lipoxygenase inhibitors prevent neurodegenerative processes and related complications. Therefore, the present study has been designed to explore the neuroprotective potential of licofelone (dual COX-2/5-LOX inhibitor) against quinolinic acid induced Huntington like symptom in rats. Intrastriatal administration of quinolinic acid significantly caused reduction in body weight and motor function (locomotor activity, rotarod performance and beam walk test), oxidative defense (as evidenced by increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidant enzymes), alteration in mitochondrial enzyme complex (I, II and IV) activities, raised TNF-α level and striatal lesion volume as compared to sham treated animals. Licofelone (2.5, 5 and 10 mg/kg) treatment significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, mitochondrial enzyme complex activities and attenuated TNF-α level and striatal lesion as compared to control (quinolinic acid). The present study highlights that licofelone attenuates behavioral, biochemical and cellular alterations against quinolinic acid induced neurotoxicity and this could be an important therapeutic avenue to ameliorate the Huntington like symptoms. PMID:21237233

  18. Anxiogenic activity of quinolinic acid and kynurenine in the social interaction test in mice.

    PubMed

    Lapin, I P; Mutovkina, L G; Ryzov, I V; Mirzaev, S

    1996-01-01

    Quinolinic acid, a metabolite of tryptophan on the kynurenine pathway, shortened the duration of social contacts (sniffings) in C57BL/6 mice which had been previously isolated for 24 h. This effect was observed at the following time intervals after i.c.v. administration: 2-6, 22-26 and 32-36 min. Locomotion was significantly less inhibited and only during the first interval. L-Kynurenine sulphate was less active. It shortened the duration of contacts only during the 32-36 min interval after i.c.v. administration. Grooming was significantly reduced by quinolinic acid at 7-11, 12-16 and 17-21 min after administration. These effects of quinolinic acid in the social interaction test are similar to those of standard anxiogens and suggest that quinolinic acid belongs to the putative endogenous anxiogens (and not only to the endogenous convulsants). The same assumption about L-kynurenine based on data in other models of anxiety has been made previously.

  19. [Antimicrobial effect of hydrazides and ilidenhydrazides of (quinoline-2-ilthio)carboxylic acids].

    PubMed

    Brazhko, O A

    2005-01-01

    Antimicrobial activity of hydrazides and ilidenhydrazides of (quinoline-2-ilthio) carboxylic acids has been studied. It was shown, that the majority of compounds had moderate antimicrobial activity. It was established that beta-(5-nitrofuryl-2)allylidenhydrazides (4-methylquinoline-2-ilthio)acetic acid showed the expressed antibacterial activity with respect to gram-positive bacterial and Candida albicans; it also suppresses the growth of similar yeast fungus. PMID:15765883

  20. Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-02-01

    Huntington disease is a neurodegenerative disease with complex pathophysiology. Recently, role of neuroinflammation and interplay between various other cellular cascades have been suggested to be involved in pathophysiology of Huntington disease. Involvement of calcium overload mediated oxidative damage and excitotoxicity have been suggested to play a central role in quinolinic acid induced Huntington like symptoms. The present study has been carried out to investigate the neuroprotective effect of calcium channel blockers (verapamil and diltiazem) against quinolinic acid induced dysfunction in motor, biochemical and neuroinflammatory signaling in rats. Intrastriatal quinolinic acid administration leads to significant motor [locomotor (72% reduction), rotarod (55% reduction), balance beam walk performance] dysfunction coupled with the marked oxidative damage and increased neuroinflammatory markers [TNF-α (140%), IL-6 (115%), caspase-3(75%)] levels in striatum as compared to the sham treatment. Verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) drug treatment for 21days resulted in a significant improvement in the motor function (improvement in locomotor activity, rotarod and balance beam walk performance). Further, verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) treatment significantly attenuated oxidative damage, level of proinflammatory mediators (TNF-α IL-6 and caspase-3) in quinolinic acid treated animals. Results of the present study demonstrate that protective effect of these calcium channel blockers (verapamil, diltiazem) might be due to their inhibitory action on different neuroinflammatory pathways against quinolinic acid induced Huntington disease like symptoms in rats. PMID:21112316

  1. [Changes in cat behavior as affected by intracerebral microinjections of kynurenine and quinolinic acid].

    PubMed

    Dutov, A A; Tolpyshev, B A

    1986-10-01

    Behavioural changes induced by microinjections of neuroactive tryptophan metabolites: L-kynurenine sulfate (KYN, 50-1,000 micrograms) and quinolinic acid (QA, 20-1,000 micrograms) were studied in chronic experiments on cats with cannulas implanted into nuclei caudati. Unlike KYN, whose effects were scarce and nonspecific, QA (500 and 1,000 micrograms) produced marked motor and emotional shifts. The effects were manifested in contralateral rotatory movements, limb hyperkinesis, emotional strain, malice, fear, aggression with snarling and hissing, attack on provocation. It is suggested that kynurenines and QA can participate in the generation of emotional disorders peculiar for epilepsy. PMID:3768511

  2. Post-Bariatric Surgery Changes in Quinolinic and Xanthurenic Acid Concentrations Are Associated with Glucose Homeostasis

    PubMed Central

    Pigeyre, Marie; Caiazzo, Robert; Raverdy, Violeta; Verkindt, Hélène; Leloire, Audrey; Guillemin, Gilles J.; Yengo, Loïc; Allorge, Delphine; Froguel, Philippe; Pattou, François

    2016-01-01

    Background An increase of plasma kynurenine concentrations, potentially bioactive metabolites of tryptophan, was found in subjects with obesity, resulting from low-grade inflammation of the white adipose tissue. Bariatric surgery decreases low-grade inflammation associated with obesity and improves glucose control. Objective Our goal was to determine the concentrations of all kynurenine metabolites after bariatric surgery and whether they were correlated with glucose control improvement. Design Kynurenine metabolite concentrations, analysed by liquid or gas chromatography coupled with tandem mass spectrometry, circulating inflammatory markers, metabolic traits, and BMI were measured before and one year after bariatric surgery in 44 normoglycemic and 47 diabetic women with obesity. Associations between changes in kynurenine metabolites concentrations and in glucose control and metabolic traits were analysed between baseline and twelve months after surgery. Results Tryptophan and kynurenine metabolite concentrations were significantly decreased one year after bariatric surgery and were correlated with the decrease of the usCRP in both groups. Among all the kynurenine metabolites evaluated, only quinolinic acid and xanthurenic acid were significantly associated with glucose control improvement. The one year delta of quinolinic acid concentrations was negatively associated with the delta of fasting glucose (p = 0.019) and HbA1c (p = 0.014), whereas the delta of xanthurenic acid was positively associated with the delta of insulin sensitivity index (p = 0.0018). Conclusion Bariatric surgery has induced a global down-regulation of kynurenine metabolites, associated with weight loss. Our results suggest that, since kynurenine monoxygenase diverts the kynurenine pathway toward the synthesis of xanthurenic acid, its inhibition may also contribute to glucose homeostasis. PMID:27327770

  3. Synthesis of sterically encumbered C10-arylated benzo[h]quinolines using ortho-substituted aryl boronic acids.

    PubMed

    Weimar, Marko; Fuchter, Matthew J

    2013-01-01

    The challenging coupling of 10-halobenzo[h]quinolines with ortho-substituted aryl boronic acids has been achieved using Pd(OAc)(2)/P(O)Ph(3) as the catalytic system. High yields were obtained for diversely functionalised substrates under mild reaction conditions. PMID:23069777

  4. Episodic barrel rotations induced by intrastriatal injection of quinolinic acid in rats. Inhibition by anticonvulsants.

    PubMed

    Marrannes, R; Wauquier, A

    1988-09-01

    Unilateral intrastriatal injection of quinolinic acid (2,3 pyridine dicarboxylate; QUIN) in the rat produces episodic barrel rotations and tonic-clonic forepaw movements, lasting for several hours. We investigated whether intraperitoneal posttreatment with anticonvulsants could abolish this phenomenon when it is already fully developed, and whether their potency ratio was similar in models of epilepsy. All 8 tested antiepileptics, namely carbamazepine, clonazepam, diazepam, diphenylhydantoin, ethosuximide, flunarizine, phenobarbital and sodium valproate decreased this behaviour in a dose-dependent way. Six other drugs with anticonvulsant properties were also effective: DL-2-amino-7-phosphonoheptanoic acid, desipramine, etomidate, ketamine, meprobamate and sabeluzole. The ED50-values for halving the frequency of the episodes of barrel rotation correlated well with published ED50-values for inhibition of tonic hindpaw extension in the maximal metrazol seizure test (rs = .95, p less than 0.001) and with the ED50-values for halving the duration of the forepaw clonus in the rat-kindling model (rs = .93, p less than 0.001). This quinolinic acid test allows visualization of the onset of action of anticonvulsants, with each animal as its own control. In order to assess whether this test is also sensitive to drugs influencing the symptoms of Huntington's disease, the effect of the dopamine antagonists haloperidol and pimozide, the acetylcholinesterase inhibitor physostigmine and the anticholinergics atropine and dexetimide were investigated as well. The experiments suggested that the barrel rotations and clonic forepaw movements, only 3-6 hours after intrastriatal injection of QUIN respond to anticonvulsants, but are not specifically sensitive to drugs used in the symptomatic treatment of Huntington's disease. PMID:2978064

  5. SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity

    PubMed Central

    2013-01-01

    It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein, we report structure–activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogues of brequinar. PMID:23930152

  6. Quinolinic Acid Responses during Interferon-α-Induced Depressive Symptomatology in Patients with Chronic Hepatitis C Infection - A Novel Aspect for Depression and Inflammatory Hypothesis

    PubMed Central

    Baranyi, Andreas; Meinitzer, Andreas; Breitenecker, Robert J.; Amouzadeh-Ghadikolai, Omid; Stauber, Rudolf; Rothenhäusler, Hans-Bernd

    2015-01-01

    Background The aim of this exploratory study is to gain for the first time a more comprehensive picture of the impact of changes of quinolinic acid concentrations on depressive symptomatology during and after IFN-α therapy. Methods The quinolinic acid concentrations of 35 HCV patients are examined in a prospective survey over the entire period of IFN-α treatment as well as three months later at six different times (baseline, one, three, six and nine months after the beginning of IFN-α treatment, and after the end of treatment). Results During IFN-α treatment Hamilton Depression Rating Scale scores rise significantly. At the same time there is greater activity of indoleamine 2,3-dioxygenase, with a resulting increase in plasma kynurenine concentrations. Compared to baseline values quinolinic acid concentrations increase significantly during therapy, reflecting an increased neurotoxic challenge. In addition, patients with higher scores in the Hamilton Depression Rating Scale at six and nine months after starting therapy show significantly higher levels of quinolinic acid concentration. Conclusions The increase of quinolinic acid during IFN-α therapy might contribute to depressive symptomatology through the neurotoxic challenge caused by quinolinic acid. Subsequently, our exploratory study results support the inflammatory hypothesis of depression. The awareness of relevant risk factors of IFN-α treatment-induced depression is essential to develop preventative treatment strategies. PMID:26368809

  7. Spectral investigation and theoretical study of zwitterionic and neutral forms of quinolinic acid

    NASA Astrophysics Data System (ADS)

    Karabacak, M.; Sinha, L.; Prasad, O.; Bilgili, S.; Sachan, Alok K.; Asiri, A. M.; Atac, A.

    2015-09-01

    In this study, molecular structure and vibrational analysis of quinolinic acid (2,3-pyridinedicarboxylic acid), in zwitterionic and neutral forms, were presented using FT-IR, FT-Raman, NMR, UV experimental techniques and quantum chemical calculations. FT-IR and FT-Raman spectra of 2,3-pyridinedicarboxylic acid (2,3-PDCA) in the solid phase were recorded in the region 4000-400 cm-1 and 3500-0 cm-1, respectively. The geometrical parameters and energies were obtained for zwitter and neutral forms by using density functional theory (DFT) at B3LYP/6-311++G(d,p) level of theory. 3D potential energy scan was performed by varying the selected dihedral angles using M06-2X and B3LYP functionals at 6-31G(d) level of theory and thus the most stable conformer of the title compound was determined. The most stable conformer was further optimized at higher level and vibrational wavenumbers were calculated. Theoretical vibrational assignment of 2,3-PDCA, using percentage potential energy distribution (PED) was done with MOLVIB program. 13C and 1H NMR spectra were recorded in DMSO. Chemical shifts were calculated at the same level of theory. The UV absorption spectra of the studied compound in ethanol and water were recorded in the range of 200-400 nm. The optimized geometric parameters were compared with experimental data.

  8. In vivo hydroxyl radical formation after quinolinic acid infusion into rat corpus striatum.

    PubMed

    Santamaría, A; Jiménez-Capdeville, M E; Camacho, A; Rodríguez-Martínez, E; Flores, A; Galván-Arzate, S

    2001-08-28

    We studied the effect of an acute infusion of quinolinic acid (QUIN) on in vivo hydroxyl radical (.OH) formation in the striatum of awake rats. Using the microdialysis technique, the generation of.OH was assessed through electrochemical detection of the salicylate hydroxylation product 2,3-dihydroxybenzoic acid (2,3-DHBA). The .OH extracellular levels increased up to 30 times over basal levels after QUIN infusion (240 nmol/microl), returning to the baseline 2 h later. This response was attenuated, but not abolished, by pretreatment with the NMDA receptor antagonist MK-801 (10 mg/kg, i.p.) 60 min before QUIN infusion. The mitochondrial toxin 3-nitropropionic acid (3-NPA, 500 nmol/microl) had stronger effects than QUIN on .OH generation, as well as on other markers of oxidative stress explored as potential consequences of .OH increased levels. These results support the hypothesis that early .OH generation contributes to the pattern of toxicity elicited by QUIN. The partial protection by MK-801 suggests that QUIN neurotoxicity is not completely explained through NMDA receptor overactivation, but it may also involve intrinsic QUIN oxidative properties.

  9. Atorvastatin Prevents Glutamate Uptake Reduction Induced by Quinolinic Acid Via MAPKs Signaling.

    PubMed

    Vandresen-Filho, S; Martins, W C; Bertoldo, D B; Rieger, D K; Maestri, M; Leal, R B; Tasca, C I

    2016-08-01

    Statins have been shown to promote neuroprotection in a wide range of neurological disorders. However, the mechanisms involved in such effects of statins are not fully understood. Quinolinic acid (QA) is a neurotoxin that induces seizures when infused in vivo and promotes glutamatergic excitotoxicity in the central nervous system. The aim of this study was to evaluate the putative glutamatergic mechanisms and the intracellular signaling pathways involved in the atorvastatin neuroprotective effects against QA toxicity. Atorvastatin (10 mg/kg) treatment for 7 days prevented the QA-induced decrease in glutamate uptake, but had no effect on increased glutamate release induced by QA. Moreover, atorvastatin treatment increased the phosphorylation of ERK1 and prevented the decrease in Akt phosphorylation induced by QA. Neither atorvastatin treatment nor QA infusion altered glutamine synthetase activity or the levels of phosphorylation of p38(MAPK) or JNK1/2 during the evaluation. Inhibition of MEK/ERK signaling pathway, but not PI3K/Akt signaling, abolished the neuroprotective effect of atorvastatin against QA-induced decrease in glutamate uptake. Our data suggest that atorvastatin protective effects against QA toxicity are related to modulation of glutamate transporters via MAPK/ERK signaling pathway.

  10. Quinolinic Acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms.

    PubMed

    Pérez-De La Cruz, Verónica; Carrillo-Mora, Paul; Santamaría, Abel

    2012-01-01

    Quinolinic acid (QUIN), an endogenous metabolite of the kynurenine pathway, is involved in several neurological disorders, including Huntington's disease, Alzheimer's disease, schizophrenia, HIV associated dementia (HAD) etc. QUIN toxicity involves several mechanisms which trigger various metabolic pathways and transcription factors. The primary mechanism exerted by this excitotoxin in the central nervous system (CNS) has been largely related with the overactivation of N-methyl-D-aspartate receptors and increased cytosolic Ca(2+) concentrations, followed by mitochondrial dysfunction, cytochrome c release, ATP exhaustion, free radical formation and oxidative damage. As a result, this toxic pattern is responsible for selective loss of middle size striatal spiny GABAergic neurons and motor alterations in lesioned animals. This toxin has recently gained attention in biomedical research as, in addition to its proven excitotoxic profile, a considerable amount of evidence suggests that oxidative stress and energetic disturbances are major constituents of its toxic pattern in the CNS. Hence, this profile has changed our perception of how QUIN-related disorders combine different toxic mechanisms resulting in brain damage. This review will focus on the description and integration of recent evidence supporting old and suggesting new mechanisms to explain QUIN toxicity.

  11. On the early toxic effect of quinolinic acid: involvement of RAGE.

    PubMed

    Cuevas, Elvis; Lantz, Susan; Newport, Glenn; Divine, Becky; Wu, Qiangen; Paule, Merle G; Tobón-Velasco, J César; Ali, Syed F; Santamaría, Abel

    2010-04-26

    Quinolinic acid (QUIN)-induced toxicity is characterized by N-methyl-d-aspartate receptors over-activation, excitotoxicity and oxidative damage. The characterization of toxic cascades produced by QUIN during the first hours after its striatal infusion is relevant for understanding toxic mechanisms. The role of the receptor-for-advanced-glycation-end-products (RAGE) in the early toxic pattern induced by QUIN was evaluated. RAGE expression - assessed by Western blot analysis and immunofluorescence - was enhanced in the striata of QUIN-lesioned rats at 2h post-lesion. QUIN-induced RAGE up-regulation was accompanied by expression of a RAGE target molecule, nuclear factor kappa B (NF-kappaB), and genes encoding for different enzymes. Other toxic markers linked to RAGE activation were increased by QUIN, including NO formation, premature glial response, lactate dehydrogenase leakage, mitochondrial dysfunction and nuclear condensation. Our results suggest that RAGE up-regulation may play a role in the early stages of QUIN toxicity.

  12. Sulforaphane reduces the alterations induced by quinolinic acid: modulation of glutathione levels.

    PubMed

    Santana-Martínez, R A; Galván-Arzáte, S; Hernández-Pando, R; Chánez-Cárdenas, M E; Avila-Chávez, E; López-Acosta, G; Pedraza-Chaverrí, J; Santamaría, A; Maldonado, P D

    2014-07-11

    Glutamate-induced excitotoxicity involves a state of acute oxidative stress, which is a crucial event during neuronal degeneration and is part of the physiopathology of neurodegenerative diseases. In this work, we evaluated the ability of sulforaphane (SULF), a natural dietary isothiocyanate, to induce the activation of transcription factor Nrf2 (a master regulator of redox state in the cell) in a model of striatal degeneration in rats infused with quinolinic acid (QUIN). Male Wistar rats received SULF (5mg/kg, i.p.) 24h and 5min before the intrastriatal infusion of QUIN. SULF increased the reduced glutathione (GSH) levels 4h after QUIN infusion, which was associated with its ability to increase the activity of glutathione reductase (GR), an antioxidant enzyme capable to regenerate GSH levels at 24h. Moreover, SULF treatment increased glutathione peroxidase (GPx) activity, while no changes were observed in γ-glutamyl cysteine ligase (GCL) activity. SULF treatment also prevented QUIN-induced oxidative stress (measured by oxidized proteins levels), the histological damage and the circling behavior. These results suggest that the protective effect of SULF could be related to its ability to preserve GSH levels and increase GPx and GR activities.

  13. Quinolinic Acid, an Endogenous Molecule Combining Excitotoxicity, Oxidative Stress and Other Toxic Mechanisms

    PubMed Central

    Pérez-De La Cruz, Verónica; Carrillo-Mora, Paul; Santamaría, Abel

    2012-01-01

    Quinolinic acid (QUIN), an endogenous metabolite of the kynurenine pathway, is involved in several neurological disorders, including Huntington’s disease, Alzheimer’s disease, schizophrenia, HIV associated dementia (HAD) etc. QUIN toxicity involves several mechanisms which trigger various metabolic pathways and transcription factors. The primary mechanism exerted by this excitotoxin in the central nervous system (CNS) has been largely related with the overactivation of N-methyl-D-aspartate receptors and increased cytosolic Ca2+ concentrations, followed by mitochondrial dysfunction, cytochrome c release, ATP exhaustion, free radical formation and oxidative damage. As a result, this toxic pattern is responsible for selective loss of middle size striatal spiny GABAergic neurons and motor alterations in lesioned animals. This toxin has recently gained attention in biomedical research as, in addition to its proven excitotoxic profile, a considerable amount of evidence suggests that oxidative stress and energetic disturbances are major constituents of its toxic pattern in the CNS. Hence, this profile has changed our perception of how QUIN-related disorders combine different toxic mechanisms resulting in brain damage. This review will focus on the description and integration of recent evidence supporting old and suggesting new mechanisms to explain QUIN toxicity. PMID:22408367

  14. Establishment of true niacin deficiency in quinolinic acid phosphoribosyltransferase knockout mice.

    PubMed

    Terakata, Miki; Fukuwatari, Tsutomu; Sano, Mitsue; Nakao, Natsuki; Sasaki, Ryuzo; Fukuoka, Shin-Ichi; Shibata, Katsumi

    2012-12-01

    Pyridine nucleotide coenzymes are involved in >500 enzyme reactions and are biosynthesized from the amino acid L-tryptophan (L-Trp) as well as the vitamin niacin. Hence, "true" niacin-deficient animals cannot be "created" using nutritional techniques. We wanted to establish a truly niacin-deficient model animal using a protocol that did not involve manipulating dietary L-Trp. We generated mice that are missing the quinolinic acid (QA) phosphoribosyltransferase (QPRT) gene. QPRT activity was not detected in qprt(-/-)mice. The qprt(+/+), qprt(+/-), or qprt(-/-) mice (8 wk old) were fed a complete diet containing 30 mg nicotinic acid (NiA) and 2.3 g L-Trp/kg diet or an NiA-free diet containing 2.3 g L-Trp/kg diet for 23 d. When qprt(-/-)mice were fed a complete diet, food intake and body weight gain did not differ from those of the qprt(+/+) and qprt(+/-) mice. On the contrary, in the qprt(-/-) mice fed the NiA-free diet, food intake and body weight were reduced to 60% (P < 0.01) and 70% (P < 0.05) of the corresponding values for the qprt(-/-) mice fed the complete diet at d 23, respectively. The nutritional levels of niacin, such as blood and liver NAD concentrations, were also lower in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice. Urinary excretion of QA was greater in the qprt(-/-) mice than in the qprt(+/+) and qprt(+/-) mice (P < 0.01). These data suggest that we generated truly niacin-deficient mice.

  15. Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte-neuron interaction.

    PubMed

    Pierozan, Paula; Ferreira, Fernanda; de Lima, Bárbara Ortiz; Pessoa-Pureur, Regina

    2015-02-01

    Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN-mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 µM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 μM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N-methyl-D-aspartate (50 µM DL-AP5) and metabotropic glutamate receptor 1 (100 µM MPEP). Also, intra- and extracellular Ca(2+) chelators (10 µM BAPTA-AM and 1 mM EGTA, respectively) and Ca(2+) influx through L-type voltage-dependent Ca(2+) channel (10 µM verapamil) are implicated in QUIN-mediated effects. Cells immunostained for the neuronal markers βIII-tubulin and microtubule-associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN-treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron-astrocyte interaction playing a role in neuroprotection.

  16. Antiperoxidative and antiinflammatory effect of Sida cordifolia Linn. on quinolinic acid induced neurotoxicity.

    PubMed

    Swathy, S S; Panicker, Seema; Nithya, R S; Anuja, M M; Rejitha, S; Indira, M

    2010-09-01

    Sida cordifolia is a plant belonging to the Malvaceae family used in many ayurvedic preparations. This study aimed at assessing the effects of ethanolic extract of Sida cordifolia root on quinolinic acid (QUIN) induced neurotoxicity and to compare its effect with the standard drug deprenyl in rat brain. Rats were divided into six groups: (1) control group (2) QUIN (55 microg/100 g bwt/day) (3) 50% ethanolic plant extract treated group (50 mg/100 g bwt/day) (4) Deprenyl (100 microg/100 g bwt/day) (5) QUIN (55 microg/100 g bwt/day) + 50% ethanolic plant extract treated group (50 mg/100 g bwt/day) (6) QUIN (55 microg/100 g bwt/day) + Deprenyl (100 microg/100 g bwt/day). At the end of the experimental period a status of lipid peroxidation products, protein peroxidation product, activities of the scavenging enzymes and the activities of the inflammatory markers were analyzed. Results revealed that the lipid peroxidation products decreased and the activities of the scavenging enzymes increased significantly in the brain of the plant extract treated group, deprenyl treated group and also in the coadminstered groups. The activities of markers of inflammatory responses such as cyclooxygenase and lipoxygenase were found to be significantly increased in the QUIN treated rats and this was decreased upon the administration of plant extract and deprenyl. In short, the study revealed that 50% ethanolic extract of Sida cordifolia has got potent antioxidant and antiinflammatory activity and the activity is comparable with the standard drug deprenyl.

  17. Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder.

    PubMed

    Savitz, Jonathan; Drevets, Wayne C; Wurfel, Brent E; Ford, Bart N; Bellgowan, Patrick S F; Victor, Teresa A; Bodurka, Jerzy; Teague, T Kent; Dantzer, Robert

    2015-05-01

    Low-grade inflammation is characteristic of a subgroup of currently depressed patients with major depressive disorder (dMDD). It may lead to the activation of the kynurenine-metabolic pathway and the increased synthesis of potentially neurotoxic metabolites such as 3-hydroxykynurenine (3HK) and quinolinic acid (QA), relative to kynurenic acid (KynA). Nevertheless, few studies have examined whether abnormalities in this pathway are present in remitted patients with MDD (rMDD). Here we compared the serum concentrations of kynurenine metabolites, measured using high performance liquid chromatography with tandem mass spectrometry, across 49 unmedicated subjects meeting DSM-IV-TR criteria for MDD, 21 unmedicated subjects meeting DSM-IV-TR criteria for rMDD, and 58 healthy controls (HCs). There was no significant group difference in the concentrations of the individual kynurenine metabolites, however both the dMDD group and the rMDD group showed a reduction in KynA/QA, compared with the HCs. Further, there was an inverse correlation between KynA/QA and anhedonia in the dMDD group, while in the rMDD group, there was a negative correlation between lifetime number of depressive episodes and KynA/QA as well as a positive correlation between the number of months in remission and KynA/QA. Our results raise the possibility that a persistent abnormality exists within the kynurenine metabolic pathway in MDD that conceivably may worsen with additional depressive episodes. The question of whether persistent abnormalities in kynurenine metabolism predispose to depression and/or relapse in remitted individuals remains unresolved.

  18. C8-Selective Acylation of Quinoline N-Oxides with α-Oxocarboxylic Acids via Palladium-Catalyzed Regioselective C-H Bond Activation.

    PubMed

    Chen, Xiaopei; Cui, Xiuling; Wu, Yangjie

    2016-08-01

    A facile and efficient protocol for palladium-catalyzed C8-selective acylation of quinoline N-oxides with α-oxocarboxylic acids has been developed. In this approach, N-oxide was utilized as a stepping stone for the remote C-H functionalization. The reactions proceeded efficiently under mild reaction conditions with excellent regioselectivity and broad functional group tolerance. PMID:27441527

  19. Biochemical Characterization of Quinolinic Acid Phosphoribosyltransferase from Mycobacterium tuberculosis H37Rv and Inhibition of Its Activity by Pyrazinamide

    PubMed Central

    Kim, Hyun; Shibayama, Keigo; Rimbara, Emiko; Mori, Shigetarou

    2014-01-01

    Quinolinic acid phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) is a key enzyme in the de novo pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis and a target for the development of new anti-tuberculosis drugs. QAPRTase catalyzes the synthesis of nicotinic acid mononucleotide from quinolinic acid (QA) and 5-phosphoribosyl-1-pyrophosphate (PRPP) through a phosphoribosyl transfer reaction followed by decarboxylation. The crystal structure of QAPRTase from Mycobacterium tuberculosis H37Rv (MtQAPRTase) has been determined; however, a detailed functional analysis of MtQAPRTase has not been published. Here, we analyzed the enzymatic activities of MtQAPRTase and determined the effect on catalysis of the anti-tuberculosis drug pyrazinamide (PZA). The optimum temperature and pH for MtQAPRTase activity were 60°C and pH 9.2. MtQAPRTase required bivalent metal ions and its activity was highest in the presence of Mg2+. Kinetic analyses revealed that the Km values for QA and PRPP were 0.08 and 0.39 mM, respectively, and the kcat values for QA and PRPP were 0.12 and 0.14 [s-1], respectively. When the amino acid residues of MtQAPRTase, which may interact with QA, were substituted with alanine residues, catalytic activity was undetectable. Further, PZA, which is an anti-tuberculosis drug and a structural analog of QA, markedly inhibited the catalytic activity of MtQAPRTase. The structure of PZA may provide the basis for the design of new inhibitors of MtQAPRTase. These findings provide new insights into the catalytic properties of MtQAPRTase. PMID:24949952

  20. Synthesis of N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide derivatives as non-TZD peroxisome proliferator-activated receptor γ (PPARγ) agonist.

    PubMed

    Bajare, Swapnil; Anthony, Jessy; Nair, Amrutha; Marita, Rosalind; Damre, Anagha; Patel, Dharmeshkumar; Rao, Chandrika; Sivaramakrishnan, H; Deka, Nabajyoti

    2012-12-01

    The thiazolidinediones (TZDs) are a class of oral antidiabetic drugs that improve insulin sensitivity in patients with type 2 diabetes. Although the mechanism by which the TZDs lower insulin resistance is unclear, they are known to target the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor. Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. However, TZDs have several adverse effects, including weight gain and liver toxicity. Herein we report identification of non-TZD PPARγ agonists which exhibit beneficial effects similar to that of TZDs in animal models, but without the associated adverse effects.

  1. Cathepsin L Plays a Role in Quinolinic Acid-Induced NF-Κb Activation and Excitotoxicity in Rat Striatal Neurons

    PubMed Central

    Han, Rong; Wu, Jun-Chao; Liang, Zhong-Qin; Qin, Zheng-Hong; Wang, Yan

    2013-01-01

    The present study seeks to investigate the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-κB) activation and excitotoxicity in rats striatal neurons. Stereotaxic administration of the N-methyl-d-aspartate (NMDA) receptor agonist Quinolinic acid (QA) into the unilateral striatum was used to produce the in vivo excitotoxic model. Co-administration of QA and the cathepsin L inhibitor Z-FF-FMK or 1-Naphthalenesulfonyl-IW-CHO (NaphthaCHO) was used to assess the contribution of cathepsin L to QA-induced striatal neuron death. Western blot analysis and cathepsin L activity assay were used to assess the changes in the levels of cathepsin L after QA treatment. Western blot analysis was used to assess the changes in the protein levels of inhibitor of NF-κB alpha isoform (IκB-α) and phospho-IκB alpha (p-IκBα) after QA treatment. Immunohistochemical analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced NF-κB. Western blot analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced IκB-α phosphorylation and degradation, changes in the levels of IKKα, p-IKKα, TP53, caspase-3, beclin1, p62, and LC3II/LC3I. The results show that QA-induced loss of striatal neurons were strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced degradation of IκB-α, NF-κB nuclear translocation, up-regulation of NF-κB responsive gene TP53, and activation of caspase-3 was strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced increases in beclin 1, LC3II/LC3I, and down-regulation of p62 were reduced by Z-FF-FMK or NaphthaCHO. These results suggest that cathepsin L is involved in glutamate receptor-induced NF-κB activation. Cathepsin L inhibitors have neuroprotective effects by inhibiting glutamate receptor-induced IκB-α degradation and NF-κB activation. PMID:24073275

  2. Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects.

    PubMed

    Dvorak, Curt A; Liu, Changlu; Shelton, Jonathan; Kuei, Chester; Sutton, Steven W; Lovenberg, Timothy W; Carruthers, Nicholas I

    2012-08-01

    Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity.

  3. Identification of Hydroxybenzoic Acids as Selective Lactate Receptor (GPR81) Agonists with Antilipolytic Effects

    PubMed Central

    2012-01-01

    Following the characterization of the lactate receptor (GPR81), a focused screening effort afforded 3-hydroxybenzoic acid 1 as a weak agonist of both GPR81 and GPR109a (niacin receptor). An examination of structurally similar arylhydroxy acids led to the identification of 3-chloro-5-hydroxybenzoic acid 2, a selective GPR81 agonist that exhibited favorable in vivo effects on lipolysis in a mouse model of obesity. PMID:24900524

  4. Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.

    PubMed

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Jones, Stacey A; Kaldor, Istvan; Liu, Yaping; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Iii, Frank Navas; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Wisely, G Bruce

    2008-08-01

    Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.

  5. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    PubMed

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

  6. 3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes.

    PubMed

    Liu, Changlu; Kuei, Chester; Zhu, Jessica; Yu, Jingxue; Zhang, Li; Shih, Amy; Mirzadegan, Taraneh; Shelton, Jonathan; Sutton, Steven; Connelly, Margery A; Lee, Grace; Carruthers, Nicholas; Wu, Jiejun; Lovenberg, Timothy W

    2012-06-01

    Niacin raises high-density lipoprotein and lowers low-density lipoprotein through the activation of the β-hydroxybutyrate receptor hydroxycarboxylic acid 2 (HCA2) (aka GPR109a) but with an unwanted side effect of cutaneous flushing caused by vascular dilation because of the stimulation of HCA2 receptors in Langerhans cells in skin. HCA1 (aka GPR81), predominantly expressed in adipocytes, was recently identified as a receptor for lactate. Activation of HCA1 in adipocytes by lactate results in the inhibition of lipolysis, suggesting that agonists for HCA1 may be useful for the treatment of dyslipidemia. Lactate is a metabolite of glucose, suggesting that HCA1 may also be involved in the regulation of glucose metabolism. The low potency of lactate to activate HCA1, coupled with its fast turnover rate in vivo, render it an inadequate tool for studying the biological role of lactate/HCA1 in vivo. In this article, we demonstrate the identification of 3-hydroxybenzoic acid (3-HBA) as an agonist for both HCA2 and HCA1, whereas 3,5-dihydroxybenzoic acid (3,5-DHBA) is a specific agonist for only HCA1 (EC(50) ∼150 μM). 3,5-DHBA inhibits lipolysis in wild-type mouse adipocytes but not in HCA1-deficient adipocytes. Therefore, 3,5-DHBA is a useful tool for the in vivo study of HCA1 function and offers a base for further HCA1 agonist design. Because 3-HBA and 3,5-DHBA are polyphenolic acids found in many natural products, such as fruits, berries, and coffee, it is intriguing to speculate that other heretofore undiscovered natural substances may have therapeutic benefits.

  7. Inhibitors of cyclooxygenase-2, but not cyclooxygenase-1 provide structural and functional protection against quinolinic acid-induced neurodegeneration.

    PubMed

    Salzberg-Brenhouse, Heather C; Chen, Er-Yun; Emerich, Dwaine F; Baldwin, Sam; Hogeland, Ken; Ranelli, Sharon; Lafreniere, Denise; Perdomo, Brigido; Novak, Leah; Kladis, Theodora; Fu, Karen; Basile, Anthony S; Kordower, Jeffrey H; Bartus, Raymond T

    2003-07-01

    Cyclooxygenases (COXs) are implicated in neurodegenerative processes associated with acute and chronic neurological diseases. Given the potential utility of COX inhibitors in treating these disorders, we examined the nonselective COX inhibitor flurbiprofen, the specific COX-1 inhibitor valeryl salicylate (VS), and the COX-2 inhibitor N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide (NS-398) for their abilities to protect striatal neurons against a quinolinic acid (QA)-induced excitotoxic lesion. Rats were administered COX inhibitors 10 min before a unilateral QA lesion of the striatum, and then tested 2 to 3 weeks later in a battery of motor tasks (bracing, placing, akinesia, and apomorphine-induced rotations). Lesion volume was assessed using immunohistochemical methods 1 month after lesioning. Orally administered flurbiprofen (50 mg) was highly neuroprotective, preserving 84 to 99% of motor performance (ED50 = 8.6-9.7 mg) while reducing lesion volume 75% (ED50 = 3.2 mg). The identities of the COX isoforms associated with QA-induced neurodegeneration were determined using VS and NS-398. Oral VS was ineffective in virtually all indices of functional neuroprotection. In contrast, oral NS-398 was highly effective, preserving approximately 83% of motor performance at2mg(ED50 = 0.1-0.4 mg), and reducing lesion volume 100% (ED50 = 0.4 mg). Similar results were obtained using inhaled flurbiprofen (2 mg), which preserved 88 to 100% of motor performance while reducing striatal lesion size 92%. These results demonstrate that COX-2 inhibition protects neurons from acute, excitotoxic neurodegeneration. Moreover, formulating a nonselective COX inhibitor into an inhalable preparation dramatically improves its potency in treating acute neuronal damage, a situation where the rapidity of drug delivery and onset of action is critical to clinical efficacy.

  8. Protective Effect of Spermidine Against Excitotoxic Neuronal Death Induced by Quinolinic Acid in Rats: Possible Neurotransmitters and Neuroinflammatory Mechanism.

    PubMed

    Jamwal, Sumit; Singh, Shamsher; Kaur, Navneet; Kumar, Puneet

    2015-08-01

    Huntington disease is hyperkinetic movement disorder characterized by selective and immense degradation of GABAergic medium spiny neurons in striatum. Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as excitotoxicity, ATP depletion, oxidative stress, neuroinflammation, as well as selective GABAergic neuronal loss. Therefore, we investigated spermidine, an endogenous molecule with free radical scavenging, anti-inflammatory, and N-methyl-D-aspartate receptor antagonistic properties, for its beneficial potential if any, in QA-induced Huntington's like symptoms in rats. Rats were administered with QA (200 nmol/2 µl saline) bilaterally on 0 day. Spermidine (5 and 10 mg/kg, p.o.) was administered for 21 days once a day. Behavioral parameters (body weight, locomotor activity, grip strength, and narrow beam walk) observations were done on 1st, 7th, 14th, and 21st day after QA treatment. On 21st day, animals were sacrificed and rat striatum was isolated for biochemical (LPO, GSH, Nitrite), neuroinflammation (TNF-α, IL-1β, and IL-6), and neurochemical analysis (GABA, glutamate, dopamine, norepinephrine, serotonin, DOPAC, HVA, 5-HIAA, adenosine, adenine, hypoxanthine, and inosine). QA treatment significantly altered body weight, locomotor activity, motor coordination, oxidative defense (increased LPO, nitrite, and decreased GSH), pro-inflammatory levels (TNF-α, IL-6 and IL-1β), GABA, glutamate, catecholamines level (norepinephrine, dopamine, and serotonin and their metabolites), and purines level (adenosine, inosine, and hypoxanthine). Spermidine (5 and 10 mg/kg, p.o.) significantly attenuated these alterations in body weight, motor impairments, oxidative stress, neuroinflammatory markers, GABA, glutamate, catecholamines, adenosine, and their metabolites levels in striatum. The neuroprotective effect of spermidine against QA-induced excitotoxic cell death is attributed to its antioxidant, N-methyl-D-aspartate receptor antagonistic, anti

  9. Toxic synergism between quinolinic acid and organic acids accumulating in glutaric acidemia type I and in disorders of propionate metabolism in rat brain synaptosomes: Relevance for metabolic acidemias.

    PubMed

    Colín-González, A L; Paz-Loyola, A L; Serratos, I; Seminotti, B; Ribeiro, C A J; Leipnitz, G; Souza, D O; Wajner, M; Santamaría, A

    2015-11-12

    The brain of children affected by organic acidemias develop acute neurodegeneration linked to accumulation of endogenous toxic metabolites like glutaric (GA), 3-hydroxyglutaric (3-OHGA), methylmalonic (MMA) and propionic (PA) acids. Excitotoxic and oxidative events are involved in the toxic patterns elicited by these organic acids, although their single actions cannot explain the extent of brain damage observed in organic acidemias. The characterization of co-adjuvant factors involved in the magnification of early toxic processes evoked by these metabolites is essential to infer their actions in the human brain. Alterations in the kynurenine pathway (KP) - a metabolic route devoted to degrade tryptophan to form NAD(+) - produce increased levels of the excitotoxic metabolite quinolinic acid (QUIN), which has been involved in neurodegenerative disorders. Herein we investigated the effects of subtoxic concentrations of GA, 3-OHGA, MMA and PA, either alone or in combination with QUIN, on early toxic endpoints in rat brain synaptosomes. To establish specific mechanisms, we pre-incubated synaptosomes with different protective agents, including the endogenous N-methyl-d-aspartate (NMDA) receptor antagonist kynurenic acid (KA), the antioxidant S-allylcysteine (SAC) and the nitric oxide synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME). While the incubation of synaptosomes with toxic metabolites at subtoxic concentrations produced no effects, their co-incubation (QUIN+GA, +3-OHGA, +MMA or +PA) decreased the mitochondrial function and increased reactive oxygen species (ROS) formation and lipid peroxidation. For all cases, this effect was partially prevented by KA and l-NAME, and completely avoided by SAC. These findings suggest that early damaging events elicited by organic acids involved in metabolic acidemias can be magnified by toxic synergism with QUIN, and this process is mostly mediated by oxidative stress, and in a lesser extent by excitotoxicity and

  10. 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A

    PubMed Central

    2015-01-01

    The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure–activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PMID:25730262

  11. 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acids are selective inhibitors of DYRK1A.

    PubMed

    Falke, Hannes; Chaikuad, Apirat; Becker, Anja; Loaëc, Nadège; Lozach, Olivier; Abu Jhaisha, Samira; Becker, Walter; Jones, Peter G; Preu, Lutz; Baumann, Knut; Knapp, Stefan; Meijer, Laurent; Kunick, Conrad

    2015-04-01

    The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PMID:25730262

  12. Targeting neuro-inflammatory cytokines and oxidative stress by minocycline attenuates quinolinic-acid-induced Huntington's disease-like symptoms in rats.

    PubMed

    Kalonia, Harikesh; Mishra, Jitendriya; Kumar, Anil

    2012-11-01

    Recent experimental and clinical reports support the fact that the minocycline exhibits significant neuroprotective activity in neurodegenerative diseases. However, its mechanism of neuroprotection is still far from our understanding. Besides, minocycline does not always produce neuroprotective effect. Therefore, this study has been designed to explore the possible mechanism of minocycline in experimental model of HD in rats. Intrastriatal administration of quinolinic acid caused a significant reduction in body weight, motor dysfunction (impaired locomotor activity, rotarod performance, and beam walk test), oxidative damage (as evidenced by increase in lipid peroxidation, nitrite concentration, and depletion of super oxide dismutase and catalase), increased TNF-α and IL-6 levels as compared to the sham-treated animals. Minocycline (25, 50, and 100 mg/kg) treatment (for 21 days) significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, attenuated TNF-α and IL-6 levels as compared to quinolinic-acid (QA)-treated animals. This study provides evidence that minocycline might have neuroprotective effect against QA-induced Huntington-like behavioral, biochemical alterations, and neuroinflammation in rats. PMID:22392362

  13. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice.

    PubMed

    Wagner, Martin; Halilbasic, Emina; Marschall, Hanns-Ulrich; Zollner, Gernot; Fickert, Peter; Langner, Cord; Zatloukal, Kurt; Denk, Helmut; Trauner, Michael

    2005-08-01

    Induction of hepatic phase I/II detoxification enzymes and alternative excretory pumps may limit hepatocellular accumulation of toxic biliary compounds in cholestasis. Because the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate involved enzymes and transporters, we aimed to induce adaptive alternative pathways with different CAR and PXR agonists in vivo. Mice were treated with the CAR agonists phenobarbital and 1,4-bis-[2-(3,5-dichlorpyridyloxy)]benzene, as well as the PXR agonists atorvastatin and pregnenolone-16alpha-carbonitrile. Hepatic bile acid and bilirubin-metabolizing/detoxifying enzymes (Cyp2b10, Cyp3a11, Ugt1a1, Sult2a1), their regulatory nuclear receptors (CAR, PXR, farnesoid X receptor), and bile acid/organic anion and lipid transporters (Ntcp, Oatp1,2,4, Bsep, Mrp2-4, Mdr2, Abcg5/8, Asbt) in the liver and kidney were analyzed via reverse-transcriptase polymerase chain reaction and Western blotting. Potential functional relevance was tested in common bile duct ligation (CBDL). CAR agonists induced Mrp2-4 and Oatp2; PXR agonists induced only Mrp3 and Oatp2. Both PXR and CAR agonists profoundly stimulated bile acid-hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10. In addition, CAR agonists upregulated bile acid-sulfating Sult2a1 and bilirubin-glucuronidating Ugt1a1. These changes were accompanied by reduced serum levels of bilirubin and bile acids in healthy and CBDL mice and by increased levels of polyhydroxylated bile acids in serum and urine of cholestatic mice. Atorvastatin significantly increased Oatp2, Mdr2, and Asbt, while other transporters and enzymes were moderately affected. In conclusion, administration of specific CAR or PXR ligands results in coordinated stimulation of major hepatic bile acid/bilirubin metabolizing and detoxifying enzymes and hepatic key alternative efflux systems, effects that are predicted to counteract cholestasis. PMID:15986414

  14. Discovery of Azetidinone Acids as Conformationally-Constrained Dual PPARalpha/gamma Agonists

    SciTech Connect

    Wang, W.; Devasthale, P; Farrelly, D; Gu, L; Harrity, T; Cap, M; Chu, C; Kunselman, L; Morgan, N; et. al.

    2008-01-01

    A novel class of azetidinone acid-derived dual PPAR{alpha}/{gamma} agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARa and PPAR? receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

  15. Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes.

    PubMed

    Thacher, S M; Nagpal, S; Klein, E S; Arefieg, T; Krasinski, G; DiSepio, D; Agarwal, C; Johnson, A; Eckert, R L; Chandraratna, R A

    1999-04-01

    Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.

  16. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis

    PubMed Central

    Ho, Peggy P.; Steinman, Lawrence

    2016-01-01

    Bile acids are ligands for the nuclear hormone receptor, farnesoid X receptor (FXR). The bile acid–FXR interaction regulates bile acid synthesis, transport, and cholesterol metabolism. Recently, bile acid–FXR regulation has been reported to play an integral role in both hepatic and intestinal inflammation, and in atherosclerosis. In this study, we found that FXR knockout mice had more disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Obeticholic acid (6α-ethyl-chenodeoxycholic acid, 6-ECDCA), a synthetic FXR agonist, is an orally available drug that is currently in clinical trials for the treatment of inflammatory diseases such as alcoholic hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis. When we treated mice exhibiting established EAE with 6-ECDCA, or the natural FXR ligand chenodeoxycholic acid (CDCA), clinical disease was ameliorated by (i) suppressing lymphocyte activation and proinflammatory cytokine production; (ii) reducing CD4+ T cells and CD19+ B cell populations and their expression of negative checkpoint regulators programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and B and T lymphocyte attenuator (BTLA); (iii) increasing CD8+ T cells and PD1, PDl-1, and BTLA expression; and (iv) reducing VLA-4 expression in both the T- and B-cell populations. Moreover, adoptive transfer of 6-ECDCA– or CDCA-treated donor cells failed to transfer disease in naive recipients. Thus, we show that FXR functions as a negative regulator in neuroinflammation and we highlight that FXR agonists represent a potential previously unidentified therapy for MS. PMID:26811456

  17. The development of benzo- and naphtho-fused quinoline-2,4-dicarboxylic acids as vesicular glutamate transporter (VGLUT) inhibitors reveals a possible role for neuroactive steroids.

    PubMed

    Carrigan, Christina N; Patel, Sarjubhai A; Cox, Holly D; Bolstad, Erin S; Gerdes, John M; Smith, Wesley E; Bridges, Richard J; Thompson, Charles M

    2014-02-01

    Substituted quinoline-2,4-dicarboxylates (QDCs) are conformationally-restricted mimics of glutamate that were previously reported to selectively block the glutamate vesicular transporters (VGLUTs). We find that expanding the QDC scaffold to benzoquinoline dicarboxylic acids (BQDC) and naphthoquinoline dicarboxylic acids (NQDCs) improves inhibitory activity with the NQDCs showing IC50∼70 μM. Modeling overlay studies showed that the polycyclic QDCs resembled steroid structures and led to the identification and testing of estrone sulfate, pregnenolone sulfate and pregnanolone sulfate that blocked the uptake of l-Glu by 50%, 70% and 85% of control, respectively. Pregnanolone sulfate was further characterized by kinetic pharmacological determinations that demonstrated competitive inhibition and a Ki of ≈20 μM. PMID:24424130

  18. Selective Retinoic Acid Receptor γ Agonists Promote Repair of Injured Skeletal Muscle in Mouse

    PubMed Central

    Di Rocco, Agnese; Uchibe, Kenta; Larmour, Colleen; Berger, Rebecca; Liu, Min; Barton, Elisabeth R.; Iwamoto, Masahiro

    2016-01-01

    Retinoic acid signaling regulates several biological events, including myogenesis. We previously found that retinoic acid receptor γ (RARγ) agonist blocks heterotopic ossification, a pathological bone formation that mostly occurs in the skeletal muscle. Interestingly, RARγ agonist also weakened deterioration of muscle architecture adjacent to the heterotopic ossification lesion, suggesting that RARγ agonist may oppose skeletal muscle damage. To test this hypothesis, we generated a critical defect in the tibialis anterior muscle of 7-week-old mice with a cautery, treated them with RARγ agonist or vehicle corn oil, and examined the effects of RARγ agonist on muscle repair. The muscle defects were partially repaired with newly regenerating muscle cells, but also filled with adipose and fibrous scar tissue in both RARγ-treated and control groups. The fibrous or adipose area was smaller in RARγ agonist–treated mice than in the control. In addition, muscle repair was remarkably delayed in RARγ-null mice in both critical defect and cardiotoxin injury models. Furthermore, we found a rapid increase in retinoid signaling in lacerated muscle, as monitored by retinoid signaling reporter mice. Together, our results indicate that endogenous RARγ signaling is involved in muscle repair and that selective RARγ agonists may be beneficial to promote repair in various types of muscle injuries. PMID:26205250

  19. Synthesis, activity, and docking study of phenylthiazole acids as potential agonists of PPARγ

    PubMed Central

    Ma, Liang; Wang, Taijin; Shi, Min; Ye, Haoyu

    2016-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-mediated transcription factor playing key roles in glucose and lipid homeostasis, and PPARγ ligands possess therapeutic potential in these as well as other areas. In this study, a series of phenylthiazole acids have been synthesized and evaluated for agonistic activity by a convenient fluorescence polarization-based PPARγ ligand screening assay. Compound 4t, as a potential PPARγ agonist with half maximal effective concentration (EC50) 0.75±0.20 μM, exhibited in vitro potency comparable with a 0.83±0.14 μM of the positive control rosiglitazone. Molecular docking and molecular dynamics simulations indicated that phenylthiazole acid 4t interacted with the amino acid residues of the active site of the PPARγ complex in a stable manner, consistent with the result of the in vitro ligand assay. PMID:27313447

  20. Inhibitory effects of bile acids and synthetic farnesoid X receptor agonists on rotavirus replication.

    PubMed

    Kim, Yunjeong; Chang, Kyeong-Ok

    2011-12-01

    Rotaviruses (group A rotaviruses) are the most important cause of severe gastroenteritis in infants and children worldwide. Currently, an antiviral drug is not available and information on therapeutic targets for antiviral development is limited for rotavirus infection. Previously, it was shown that lipid homeostasis is important in rotavirus replication. Since farnesoid X receptor (FXR) and its natural ligands bile acids (such as chenodeoxycholic acid [CDCA]) play major roles in cholesterol and lipid homeostasis, we examined the effects of bile acids and synthetic FXR agonists on rotavirus replication in association with cellular lipid levels. In a mouse model of rotavirus infection, effects of oral administration of CDCA on fecal rotavirus shedding were investigated. The results demonstrate the following. First, the intracellular contents of triglycerides were significantly increased by rotavirus infection. Second, CDCA, deoxycholic acid (DCA), and other synthetic FXR agonists, such as GW4064, significantly reduced rotavirus replication in cell culture in a dose-dependent manner. The reduction of virus replication correlated positively with activation of the FXR pathway and reduction of cellular triglyceride contents (r(2) = 0.95). Third, oral administration of CDCA significantly reduced fecal virus shedding in mice (P < 0.05). We conclude that bile acids and FXR agonists play important roles in the suppression of rotavirus replication. The inhibition mechanism is proposed to be the downregulation of lipid synthesis induced by rotavirus infection.

  1. Effects of retinoic acid receptor-selective agonists on human nasal epithelial cell differentiation.

    PubMed

    Million, K; Tournier, F; Houcine, O; Ancian, P; Reichert, U; Marano, F

    2001-12-01

    Retinoids play a critical role in the maintenance of the mucociliary phenotype of epithelial cells in the upper respiratory tract. To determine the role of retinoic acid receptors (RARs) in the regulation of epithelial differentiation, we tested the effect of the synthetic retinoids CD336, CD2019, and CD666, selective agonists for RARalpha, RARbeta, and RARgamma, respectively, during differentiation of human nasal epithelial (HNE) cells in vitro. Using glutamylated tubulin and transglutaminase I (Tg I) as markers of ciliated cell and squamous cell differentiation, respectively, we showed that retinoic acid (RA) stimulated mucociliary differentiation and, in parallel, inhibited squamous cell differentiation. The agonists of the three RARs independently induced ciliogenesis and inhibited squamous cell differentiation by downregulating Tg I expression in a dose- and time-dependent manner. Antagonists specific for the three RARs abolished the effects of the corresponding agonists, demonstrating an RAR-specific mediated effect. Moreover, treatment of retinoid-deficient cultures with RAR agonists induced conversion of the squamous-like phenotype into a ciliated phenotype. In conclusion, all three RARs are potentially involved in the differentiating effects of RA in respiratory epithelial cells.

  2. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

    SciTech Connect

    Rogue, Alexandra; Anthérieu, Sébastien; Vluggens, Aurore; Umbdenstock, Thierry; Claude, Nancy; Moureyre-Spire, Catherine de la; Weaver, Richard J.; Guillouzo, André

    2014-04-01

    Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

  3. [Discovery of potential nicotinic acid receptor agonists from Chinese herbal medicines based on molecular simulation].

    PubMed

    Jiang, Lu-Di; He, Yu-Su; Zhang, Yan-Ling

    2014-12-01

    Nicotinic acid could increase high density lipoprotein and reduce serum total cholesterol, low density lipoprotein cholesterol and triglycerides in human bodies, thus is frequently applied in treating low high-density lipoprotein cholesterol and hypertriglyceridemia in clinic. However, according to the findings, nicotinic acid could also cause adverse effects, such as skin flush, beside its curative effects. In this study, bioisosterism, fragment-based search and Lipinski's Rule of Five were used to preliminarily screen out potential TCM ingredients that may have similar pharmacological effects with nicotinic acid from Traditional Chinese medicine database (TCMD). Afterwards, homology modeling and flexible docking were used to further screen out potential nicotinic acid receptor agonists. As a result, eleven candidate compounds were derived from eight commonly used traditional Chinese medicines. Specifically, all of the candidate compounds' interaction with nicotinic acid receptor was similar to nicotinic acid, and their docking scores were all higher than that of nicotinic acid, but their druggability remained to be further studied. Some of the eight source traditional Chinese medicines were used to lower lipid according to literature studies, implying that they may show effect through above means. In summary, this study provides basis and reference for extracting new nicotinic acid receptor agonists from traditional Chinese medicines and improving the medication status of hyperlipidemia.

  4. Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors.

    PubMed

    Toyama, Hirozumi; Nakamura, Masaharu; Nakamura, Masahiko; Matsumoto, Yotaro; Nakagomi, Madoka; Hashimoto, Yuichi

    2014-03-15

    Retinoic acid receptor (RAR)-related orphan receptors (RORs) regulate a variety of physiological processes, including hepatic gluconeogenesis, lipid metabolism, circadian rhythm and immune function. The RAR agonist: all-trans retinoic acid was reported to be an RORβ inverse agonist, but no information is available regarding ROR activity of its synthetic analogue Am580. Therefore, we screened Am580 and some related tetramethyltetrahydronaphthalene derivatives and carried out structural development studies, including substitution of carbon atoms with silicon, with the aim of creating a potent ROR transcriptional inhibitor. The phenyl amide disila compound 22 showed the most potent ROR-inhibitory activity among the compounds examined. Its activity towards RORα, RORβ and RORγ was increased compared to that of Am580. The IC₅₀ values for RORα, RORβ and RORγ are 1.3, >10 and 4.5 μM, respectively.

  5. Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors.

    PubMed

    Gududuru, Veeresa; Zeng, Kui; Tsukahara, Ryoko; Makarova, Natalia; Fujiwara, Yuko; Pigg, Kathryn R; Baker, Daniel L; Tigyi, Gabor; Miller, Duane D

    2006-01-15

    Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARgamma activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA(1-3) receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA(3) agonist with an EC(50) of 692 nM. Interestingly, regardless of their LPA(1/2/3) ligand properties all of the Darmstoff analogs tested activated PPARgamma. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics. PMID:16290140

  6. Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors.

    PubMed

    Gududuru, Veeresa; Zeng, Kui; Tsukahara, Ryoko; Makarova, Natalia; Fujiwara, Yuko; Pigg, Kathryn R; Baker, Daniel L; Tigyi, Gabor; Miller, Duane D

    2006-01-15

    Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARgamma activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA(1-3) receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA(3) agonist with an EC(50) of 692 nM. Interestingly, regardless of their LPA(1/2/3) ligand properties all of the Darmstoff analogs tested activated PPARgamma. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics.

  7. Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.

    PubMed

    Li, Zheng; Wang, Xuekun; Xu, Xue; Yang, Jianyong; Xia, Wenting; Zhou, Xianhao; Huang, Wenlong; Qian, Hai

    2015-11-15

    The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid derivatives. Herein, we describe the further chemical modification of this series directed by ligand efficiency and ligand lipophilicity efficiency. All of these efforts lead to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity (43.6 nM), desired LE and LLE values. Moreover, compound 16 revealed a great potential for improving the hyperglycemia levels in both normal and type 2 diabetic mice without the risk of hypoglycemia even at the high dose of 40 mg/kg. PMID:26482570

  8. A rat model of striatonigral degeneration generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum.

    PubMed

    Yoon, Hyung Ho; Kim, Yong Hwan; Shin, Eun Sil; Jeon, Sang Ryong

    2014-11-01

    A double toxin-double lesion strategy is well-known to generate a rat model of striatonigral degeneration (SND) such as multiple system atrophy-parkinsonian type. However, with this model it is difficult to distinguish SND from Parkinson's disease (PD). In this study, we propose a new rat model of SND, which is generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. Stepping tests performed 30 min after intraperitoneal L-dopa administration at 6 weeks post-surgery revealed an L-dopa response in the PD group but not the SND group. Apomorphine-induced rotation tests revealed no rotational bias in the SND group, which persisted for 2 months, but contralateral rotations in the PD group. MicroPET scans revealed glucose hypometabolism and dopamine transporter impairment on the lesioned striatum in the SND group. Tyrosine hydroxylase immunostaining in the SND group revealed that 74.7% of nigral cells on the lesioned side were lost after lesion surgery. These results suggest that the proposed simultaneous double toxin-double lesion method successfully created a rat model of SND that had behavioral outcomes, multitracer microPET evaluation, and histological aspects consistent with SND pathology. This model will be useful for future study of SND. PMID:25408589

  9. Pioglitazone ameliorates behavioral, biochemical and cellular alterations in quinolinic acid induced neurotoxicity: possible role of peroxisome proliferator activated receptor-Upsilon (PPARUpsilon) in Huntington's disease.

    PubMed

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2010-08-01

    Emerging evidence indicates that PPARUpsilon activators attenuate neurodegeneration and related complications. Therefore, the present study focused on the neuroprotective potential of pioglitazone against quinolinic acid (QUIN) induced neurotoxicity. Intrastriatal (unilaterally) administration of QUIN significantly altered body weight and motor function (locomotor activity, rotarod and beam walk performance). Further, QUIN treatment significantly caused oxidative damage (increased lipid peroxidation, nitrite concentration and depleted endogenous antioxidant defense enzymes), altered mitochondrial enzyme complex (I, II and IV) activities and TNF-alpha level as compared to sham treated animals. Pioglitazone (10, 20 and 40mg/kg, p.o.) treatment significantly improved body weight and motor functions, oxidative defense. Further, pioglitazone treatment restored mitochondrial enzyme complex activity as well as TNF-alpha level as compared to QUIN treated group. While Bisphenol A diglycidyl ether (BADGE) (15mg/kg), PPARUpsilon antagonist significantly reversed the protective effect of the pioglitazone (40mg/kg) in the QUIN treated animals. Further, pioglitazone treatment significantly attenuated the striatal lesion volume in QUIN treated animals, suggesting a role for the PPARUpsilon pathway in QUIN induced neurotoxicity. Altogether, this evidence indicates that PPARUpsilon activation by pioglitazone attenuated QUIN induced neurotoxicity in animals and which could be an important therapeutic avenue to ameliorate Huntington like symptoms. PMID:20450929

  10. Novel Retinoic Acid Receptor Alpha Agonists for Treatment of Kidney Disease

    PubMed Central

    Liu, Ruijie; Li, Zhengzhe; Chen, Yibang; Evans, Todd; Chuang, Peter; Das, Bhaskar; He, John Cijiang

    2011-01-01

    Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN. PMID:22125642

  11. Novel retinoic acid receptor alpha agonists for treatment of kidney disease.

    PubMed

    Zhong, Yifei; Wu, Yingwei; Liu, Ruijie; Li, Zhengzhe; Chen, Yibang; Evans, Todd; Chuang, Peter; Das, Bhaskar; He, John Cijiang

    2011-01-01

    Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.

  12. γ-Hydroxybutyric acid (GHB) is not an agonist of extrasynaptic GABAA receptors.

    PubMed

    Connelly, William M; Errington, Adam C; Crunelli, Vincenzo

    2013-01-01

    γ-Hydroxybutyric acid (GHB) is an endogenous compound and a drug used clinically to treat the symptoms of narcolepsy. GHB is known to be an agonist of GABAB receptors with millimolar affinity, but also binds with much higher affinity to another site, known as the GHB receptor. While a body of evidence has shown that GHB does not bind to GABAA receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4β1δ GABAA receptors, where GHB acts as an agonist with an EC50 of 140 nM. We investigated three neuronal cell types that express a tonic GABAA receptor current mediated by extrasynaptic receptors: ventrobasal (VB) thalamic neurons, dentate gyrus granule cells and striatal medium spiny neurons. Using whole-cell voltage clamp in brain slices, we found no evidence that GHB (10 µM) induced any GABAA receptor mediated current in these cell types, nor that it modulated inhibitory synaptic currents. Furthermore, a high concentration of GHB (3 mM) was able to produce a GABAB receptor mediated current, but did not induce any other currents. These results suggest either that GHB is not a high affinity agonist at native α4β1δ receptors, or that these receptors do not exist in classical areas associated with extrasynaptic currents.

  13. Effects of gamma-aminobutyric acid agonist and antagonist drugs on local cerebral glucose utilization

    SciTech Connect

    Palacios, J.M.; Kuhar, M.J.; Rapoport, S.I.; London, E.D.

    1982-07-01

    The (/sup 14/C)2-deoxy-D-glucose method of Sokoloff et al. was used to study local cerebral glucose utilization (LCGU) in rats treated with gamma-aminobutyric acid (GABA) agonist (muscimol and 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridin-3-ol, THIP) and antagonist (bicuculline) drugs. It was of interest to determine if the pattern of LCGU responses to GABA agonists and antagonists administered systemically in vivo would reflect the known distributions of markers for central GABAergic synapses. The patterns of LCGU responses to muscimol and THIP generally were similar. Most brain regions showed dose-dependent decreases in LCGU; others showed no effects; but the red nucleus showed an increase. The GABA antagonist bicuculline produced convulsions and variable LCGU responses, depending on the time of administration. Bicuculline also partially antagonized the depressant effects of muscimol of LCGU. The magnitudes and distribution of in vivo cerebral metabolic responses to specific GABA agonists were not correlated simply with markers for GABAergic synapses. This lack of correlation indicates that additional factors, such as neural circuitry, regulate the LCGU responses to GABAergic drugs.

  14. Therapeutic role of bile acids and nuclear receptor agonists in fibrosing cholangiopathies.

    PubMed

    Trauner, Michael; Halilbasic, Emina; Kazemi-Shirazi, Lili; Kienbacher, Christian; Staufer, Katharina; Traussnigg, Stefan; Hofer, Harald

    2014-01-01

    Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g., obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable interest. This review article is a summary of an overview talk given at Falk Symposium 191 on Advances in Pathogenesis and Treatment of Liver Diseases held in London, October 3-4, 2013, and summarizes the recent progress with novel therapeutic bile acids and bile acid derivatives as novel therapies for fibrosing cholangiopathies such as PBC and PSC.

  15. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat.

    PubMed

    Roda, Aldo; Pellicciari, Roberto; Gioiello, Antimo; Neri, Flavia; Camborata, Cecilia; Passeri, Daniela; De Franco, Francesca; Spinozzi, Silvia; Colliva, Carolina; Adorini, Luciano; Montagnani, Marco; Aldini, Rita

    2014-07-01

    We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6

  16. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat.

    PubMed

    Roda, Aldo; Pellicciari, Roberto; Gioiello, Antimo; Neri, Flavia; Camborata, Cecilia; Passeri, Daniela; De Franco, Francesca; Spinozzi, Silvia; Colliva, Carolina; Adorini, Luciano; Montagnani, Marco; Aldini, Rita

    2014-07-01

    We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6

  17. Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches

    PubMed Central

    Chen, Meimei; Yang, Xuemei; Lai, Xinmei; Kang, Jie; Gan, Huijuan; Gao, Yuxing

    2016-01-01

    In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field analysis. The obtained 2D-QSAR model gave a high predictive ability (R2train = 0.935, R2test = 0.902, Q2LOO = 0.899). It also uncovered that number of rotatable single bonds (b_rotN), relative negative partial charges (RPC−), oprea's lead-like (opr_leadlike), subdivided van der Waal’s surface area (SlogP_VSA2) and accessible surface area (ASA) were important features in defining activity. Additionally, the derived3D-QSAR model presented a higher predictive ability (R2train = 0.944, R2test = 0.892, Q2LOO = 0.802). Meanwhile, the derived contour maps from the 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving FXR agonist activity. Finally, nine newly designed AAD with higher predicted EC50 values than the known template compound were docked into the FXR active site. The excellent molecular binding patterns of these molecules also suggested that they can be robust and potent partial FXR agonists in agreement with the QSAR results. Overall, these derived models may help to identify and design novel AAD with better FXR agonist activity. PMID:27070594

  18. 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1H-pyrrol-1-yl)-quinoline-3-carb oxylic acid, a new fluorinated compounds of oxacin family with high broad-spectrum antibacterial activities.

    PubMed

    Stefancich, G; Artico, M; Corelli, F; Massa, S; Panico, S; Simonetti, N

    1985-04-01

    The synthesis of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1H-pyrrol-1-yl)quinoline-3-carboxy lic acid, a new fluorinated high broad-spectrum antibacterial agent related to nalidixic acid is described. The title compound has been prepared by the reaction of 4-fluoro-3-(1H-pyrrol-1-yl)aniline with diethyl ethoxymethylenemalonate, cyclization of the malonate obtained to the quinolinecarboxylate ester, ethylation of the ester, followed by hydrolysis with aqueous sodium hydroxide. The new derivative proved very active against both gram-positive and gram-negative bacteria. Its activities in comparison with those of nalidixic acid, pipemidic acid, piromidic acid and enoxacin were found to be greatly superior with regard to the unfluorinated compounds and somewhat superior also to enoxacin. The known 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(pyrrolidin-1-yl)quinoline-3- carboxylic acid, here prepared by catalytic hydrogenation of the pyrrole moiety of the title compound, has been found to be less active as an antibacterial agent. PMID:3926533

  19. Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: design, synthesis, structural biology, and molecular docking studies.

    PubMed

    Mahindroo, Neeraj; Wang, Chiung-Chiu; Liao, Chun-Chen; Huang, Chien-Fu; Lu, I-Lin; Lien, Tzu-Wen; Peng, Yi-Huei; Huang, Wei-Jan; Lin, Ying-Ting; Hsu, Ming-Chen; Lin, Chia-Hui; Tsai, Chia-Hua; Hsu, John T-A; Chen, Xin; Lyu, Ping-Chiang; Chao, Yu-Sheng; Wu, Su-Ying; Hsieh, Hsing-Pang

    2006-02-01

    A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPARgamma protein, were important for the potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARgamma protein resulting in potent activity. PMID:16451087

  20. The acid metabolite of ZD7114 is a partial agonist of lipolysis mediated by the rat beta 3-adrenoceptor.

    PubMed

    Mayers, R M; Quayle, S P; Thompson, A J; Grant, T L; Holloway, B R

    1996-01-11

    Experiments were performed to characterise the lipolytic effects of the acid metabolite, ZM215001, ((S)-4-[2-hydroxy-3-phenoxy-propylamino-ethoxy] phenoxyacetic acid) of the putative beta 3-adrenoceptor agonist, ZD7114 ((S)-4-[2-hydroxy-3-phenoxy-propylamino-ethoxy]-N-(2-methoxyethyl) phenoxyacetamide) on isolated rat white adipocytes. ZM215001 was used for these studies since it is the predominant moiety after in vivo administration of ZD7114. The agonist properties of ZM215001 were assessed in comparison to the standard nonselective beta-adrenoceptor agonist (+/-)-isoprenaline and the beta 3-adrenoceptor-selective agonist BRL 37344. Isoprenaline, BRL 37344 and ZM215001 all stimulated the rate of free fatty acid release from isolated adipocytes with the order of potency being BRL > isoprenaline > ZM215001. The maximum effect of BRL 37344 was equivalent to that of isoprenaline, but ZM215001 achieved only 30% of the maximum isoprenaline response. ZM215001 competitively antagonised the lipolytic response to BRL 37344 (pA2 = 7.26), whereas the agonist effects of BRL 37344 were not antagonised competitively by the selective antagonists ICI 118551 and CGP 20712A, at concentrations which would be expected to block beta 1- and beta 2-adrenoceptors respectively. These results indicate that ZM215001 has low intrinsic activity at the rat adipocyte beta 3-adrenoceptor, and is a partial agonist of lipolysis in rat white adipocytes. PMID:8720584

  1. Behavioural profile of Wistar rats with unilateral striatal lesion by quinolinic acid (animal model of Huntington disease) post-injection of apomorphine and exposure to static magnetic field.

    PubMed

    Giorgetto, Carolina; Silva, Elaine Cristina Mazzei; Kitabatake, Takae Tamy; Bertolino, Guilherme; de Araujo, João Eduardo

    2015-05-01

    We analysed the motor behaviour of Wistar rats after 7 days lesion in the left striatum, injected with apomorphine (APO) and stimulated by a continuous magnetic field of 3,200 Gauss. For the behaviour assessment, we utilised the activity cage test and the rotarod test. Sixty-eight male Wistar rats were divided into six groups: control, sham, sham magnetic, lesion, and stimulated South and North Poles. After the experiments, coronal sections of the striatum were taken and stained with Nissl for analysis of the lesion. In the activity cage test for distance (F = 3.19), time of activity (F = 5.46) and crossings (F = 3.31) in all groups, except for the North Pole-stimulated group, we observed a significant increase in these behaviours when compared to the control group. Considering the number of counterclockwise turns, we observed a significant increase in the lesion in the South and North Pole stimulation groups compared with the control group. Highlighting the minor number of counterclockwise turns observed in the North Pole-stimulated group in relation to the South Pole-stimulated and Lesion groups (F = 16.01). The rotarod test revealed a decrease in the time spent in this apparatus for the Lesion group when compared to all other groups (F = 5.46). The morphometric analysis showed a reduction in the number of neurons in the Lesion group in relation to all other groups (F = 5.13). Thus, the results suggest that the static magnetic field north and south promoted a distinct behavioural profile and morphological preservation after 7 days of lesion with quinolinic acid associated with APO. PMID:25665872

  2. Selective agonists of retinoic acid receptors: comparative toxicokinetics and embryonic exposure.

    PubMed

    Arafa, H M; Elmazar, M M; Hamada, F M; Reichert, U; Shroot, B; Nau, H

    2000-01-01

    Three biologically active synthetic retinoids were investigated that bind selectively to retinoic acid receptors RARs (alpha, beta and gamma). The retinoids were previously demonstrated to have different teratogenic effects in the mouse in terms of potency and regioselectivity. The teratogenic potency rank order (alpha >beta >gamma) was found to be more or less compatible with the receptor binding affinities and transactivation potencies of the retinoid ligands to their respective receptors. The RARalpha agonist (Am580; CD336) induced a wide spectrum of malformations; CD2019 (RARbeta agonist) and especially CD437 (RARgamma agonist) produced more restricted defects. In the current study we tried to address whether the differences in teratogenic effects are solely related to binding affinity and transactivation differences or also due to differences in embryonic exposure. Therefore, transplacental kinetics of the ligands were assessed following administration of a single oral dose of 15 mg/kg of either retinoid given to NMRI mice on day 11 of gestation. Am580 was rapidly transferred to the embryo resulting in the highest embryonic exposure [embryo to maternal plasma area under the time vs concentration curve (AUC)(0-24 h )ratio (E/M) was 1.7], in accordance with its highest teratogenic potency. The low placental transfer of CD2019 (E/M of 0.3) was compatible with its lower teratogenic potential. Of major interest was the finding that the CD437, though being least teratogenic, exhibited considerable embryonic exposure (E/M of 0.6). These findings suggest that both the embryonic exposure and receptor binding transactivation selectivity are crucial determinants of the teratogenicity of these retinoid ligands.

  3. Fish oil and the pan-PPAR agonist tetradecylthioacetic acid affect the amino acid and carnitine metabolism in rats.

    PubMed

    Bjørndal, Bodil; Brattelid, Trond; Strand, Elin; Vigerust, Natalya Filipchuk; Svingen, Gard Frodahl Tveitevåg; Svardal, Asbjørn; Nygård, Ottar; Berge, Rolf Kristian

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are important in the regulation of lipid and glucose metabolism. Recent studies have shown that PPARα-activation by WY 14,643 regulates the metabolism of amino acids. We investigated the effect of PPAR activation on plasma amino acid levels using two PPARα activators with different ligand binding properties, tetradecylthioacetic acid (TTA) and fish oil, where the pan-PPAR agonist TTA is a more potent ligand than omega-3 polyunsaturated fatty acids. In addition, plasma L-carnitine esters were investigated to reflect cellular fatty acid catabolism. Male Wistar rats (Rattus norvegicus) were fed a high-fat (25% w/w) diet including TTA (0.375%, w/w), fish oil (10%, w/w) or a combination of both. The rats were fed for 50 weeks, and although TTA and fish oil had hypotriglyceridemic effects in these animals, only TTA lowered the body weight gain compared to high fat control animals. Distinct dietary effects of fish oil and TTA were observed on plasma amino acid composition. Administration of TTA led to increased plasma levels of the majority of amino acids, except arginine and lysine, which were reduced. Fish oil however, increased plasma levels of only a few amino acids, and the combination showed an intermediate or TTA-dominated effect. On the other hand, TTA and fish oil additively reduced plasma levels of the L-carnitine precursor γ-butyrobetaine, as well as the carnitine esters acetylcarnitine, propionylcarnitine, valeryl/isovalerylcarnitine, and octanoylcarnitine. These data suggest that while both fish oil and TTA affect lipid metabolism, strong PPARα activation is required to obtain effects on amino acid plasma levels. TTA and fish oil may influence amino acid metabolism through different metabolic mechanisms. PMID:23826175

  4. Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure.

    PubMed

    Hiramatsu, Michiaki; Ichikawa, Yuki; Tomoshige, Shusuke; Makishima, Makoto; Muranaka, Atsuya; Uchiyama, Masanobu; Yamaguchi, Takao; Hashimoto, Yuichi; Ishikawa, Minoru

    2016-08-01

    Aqueous solubility is a key requirement for many functional molecules, e. g., drug candidates. Decrease of the partition coefficient (log P) by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical strategy for improving aqueous solubility. We have been investigating alternative strategies for improving the aqueous solubility of pharmaceutical compounds by disrupting intermolecular interactions. Here, we show that introducing a bend into the molecular structure of retinoic acid receptor (RAR) agonists by changing the substitution pattern from para to meta or ortho dramatically enhances aqueous solubility by up to 890-fold. We found that meta analogs exhibit similar hydrophobicity to the parent para compound, and have lower melting points, supporting the idea that the increase of aqueous solubility was due to decreased intermolecular interactions in the solid state as a result of the structural changes.

  5. Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure.

    PubMed

    Hiramatsu, Michiaki; Ichikawa, Yuki; Tomoshige, Shusuke; Makishima, Makoto; Muranaka, Atsuya; Uchiyama, Masanobu; Yamaguchi, Takao; Hashimoto, Yuichi; Ishikawa, Minoru

    2016-08-01

    Aqueous solubility is a key requirement for many functional molecules, e. g., drug candidates. Decrease of the partition coefficient (log P) by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical strategy for improving aqueous solubility. We have been investigating alternative strategies for improving the aqueous solubility of pharmaceutical compounds by disrupting intermolecular interactions. Here, we show that introducing a bend into the molecular structure of retinoic acid receptor (RAR) agonists by changing the substitution pattern from para to meta or ortho dramatically enhances aqueous solubility by up to 890-fold. We found that meta analogs exhibit similar hydrophobicity to the parent para compound, and have lower melting points, supporting the idea that the increase of aqueous solubility was due to decreased intermolecular interactions in the solid state as a result of the structural changes. PMID:27378357

  6. Electrochemical mineralization pathway of quinoline by boron-doped diamond anodes.

    PubMed

    Wang, Chunrong; Ma, Keke; Wu, Tingting; Ye, Min; Tan, Peng; Yan, Kecheng

    2016-04-01

    Boron-doped diamond anodes were selected for quinoline mineralization, and the resulting intermediates, phenylpropyl aldehyde, phenylpropionic acid, and nonanal were identified and followed during quinoline oxidation by gas chromatography-mass spectrometry and high-performance liquid chromatography. The evolutions of formic acid, acetic acid, oxalic acid, NO2(-), NO3(-), and NH4(+) were quantified. A new reaction pathway for quinoline mineralization by boron-doped diamond anodes has been proposed, where the pyridine ring in quinoline is cleaved by a hydroxyl radical giving phenylpropyl aldehyde and NH4(+). Phenylpropyl aldehyde is quickly oxidized into phenylpropionic acid, and the benzene ring is cleaved giving nonanal. This is further oxidized to formic acid, acetic acid, and oxalic acid. Finally, these organic intermediates are mineralized to CO2 and H2O. NH4(+) is also oxidized to NO2(-) and on to NO3(-). The results will help to gain basic reference for clearing intermediates and their toxicity.

  7. Early modulation of the transcription factor Nrf2 in rodent striatal slices by quinolinic acid, a toxic metabolite of the kynurenine pathway.

    PubMed

    Colín-González, A L; Luna-López, A; Königsberg, M; Ali, S F; Pedraza-Chaverrí, J; Santamaría, A

    2014-02-28

    Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor involved in the orchestration of antioxidant responses. Although its pharmacological activation has been largely hypothesized as a promising tool to ameliorate the progression of neurodegenerative events, the actual knowledge about its modulation in neurotoxic paradigms remains scarce. In this study, we investigated the early profile of Nrf2 modulation in striatal slices of rodents incubated in the presence of the toxic kynurenine pathway metabolite, quinolinic acid (QUIN). Tissue slices from rats and mice were obtained and used throughout the experiments in order to compare inter-species responses. Nuclear Nrf2 protein levels and oxidative damage to lipids were compared. Time- and concentration-response curves of all markers were explored. Nrf2 nuclear activation was corroborated through phase 2 antioxidant protein expression. The effects of QUIN on Nrf2 modulation and oxidative stress were also compared between slices of wild-type (Nrf2(+/+)) and Nrf2 knock-out (Nrf2(-/-)) mice. The possible involvement of the N-methyl-d-aspartate receptor (NMDAr) in the Nrf2 modulation and lipid peroxidation was further explored in mice striatal slices. In rat striatal slices, QUIN stimulated the Nrf2 nuclear translocation. This effect was accompanied by augmented lipid peroxidation. In the mouse striatum, QUIN per se exerted an induction of Nrf2 factor only at 1h of incubation, and a concentration-response effect on lipid peroxidation after 3h of incubation. QUIN stimulated the striatal content of phase 2 enzymes. Nrf2(-/-) mice were slightly more responsive than Nrf2(+/+) mice to the QUIN-induced oxidative damage, and completely unresponsive to the NMDAr antagonist MK-801 when tested against QUIN. Findings of this study indicate that: (1) Nrf2 is modulated in rodent striatal tissue in response to QUIN; (2) Nrf2(-/-) striatal tissue was moderately more vulnerable to oxidative damage than the Wt

  8. Development of betulinic acid as an agonist of TGR5 receptor using a new in vitro assay

    PubMed Central

    Lo, Shih-Hsiang; Cheng, Kai-Chung; Li, Ying-Xiao; Chang, Chin-Hong; Cheng, Juei-Tang; Lee, Kung-Shing

    2016-01-01

    Background G-protein-coupled bile acid receptor 1, also known as TGR5 is known to be involved in glucose homeostasis. In animal models, treatment with a TGR5 agonist induces incretin secretion to reduce hyperglycemia. Betulinic acid, a triterpenoid present in the leaves of white birch, has been introduced as a selective TGR5 agonist. However, direct activation of TGR5 by betulinic acid has not yet been reported. Methods Transfection of TGR5 into cultured Chinese hamster ovary (CHO-K1) cells was performed to establish the presence of TGR5. Additionally, TGR5-specific small interfering RNA was employed to silence TGR5 in cells (NCI-H716 cells) that secreted incretins. Uptake of glucose by CHO-K1 cells was evaluated using a fluorescent indicator. Amounts of cyclic adenosine monophosphate and glucagon-like peptide were quantified using enzyme-linked immunosorbent assay kits. Results Betulinic acid dose-dependently increases glucose uptake by CHO-K1 cells transfected with TGR5 only, which can be considered an alternative method instead of radioligand binding assay. Additionally, signals coupled to TGR5 activation are also increased by betulinic acid in cells transfected with TGR5. In NCI-H716 cells, which endogenously express TGR5, betulinic acid induces glucagon-like peptide secretion via increasing calcium levels. However, the actions of betulinic acid were markedly reduced in NCI-H716 cells that received TGR5-silencing treatment. Therefore, the present study demonstrates the activation of TGR5 by betulinic acid for the first time. Conclusion Similar to the positive control lithocholic acid, which is the established agonist of TGR5, betulinic acid has been characterized as a useful agonist of TGR5 and can be used to activate TGR5 in the future. PMID:27578964

  9. Nipecotic acid ethyl ester: a cholinergic agonist that may differentiate muscarinic receptor subtypes

    SciTech Connect

    Zorn, S.H.; Duman, R.S.; Enna, S.J.; Krogsgaard-Larsen, P.; Micheletti, R.; Giraldo, E.; Giachetti, A.

    1986-03-05

    Reports indicate that nipecotic acid ethyl ester (NAEE) displays cholinomimetic properties in vivo. In the present study a series of physiological and biochemical tests were conducted to characterize this action. NAEE had a negative inotropic effect on the guinea pig atrium, and stimulated contraction of the guinea pig ileum and isolated mouse stomach strip at concentrations similar to bethanechol (BCH). The atrial and ilial effects were reversed by atropine. Unlike BCH, NAEE had no effect on basal acid secretion in the isolated mouse stomach at concentrations < 100 ..mu..M. NAEE was more potent than carbachol (CCH) in displacing /sup 3/H-ONB binding from rat brain membranes. The potency of NAEE to inhibit antagonist binding in rat heart membranes was enhanced by Mg/sup + +/ (Hill coefficient < 1.0) and reduced by Gpp(NH)p. Like CCH, NAEE inhibited GTP-stimulated adenylate cyclase in rat brain striatal membranes. As compared to CCH, NAEE had little effect (< 5%) as a stimulator of inositol phosphate (IP) production in rat brain slices. The results indicate that NAEE is a direct-acting muscarinic receptor agonist. Moreover, its differential effects on acid secretion, IP accumulation, and adenylate cyclase suggest that it may be useful for defining cholinergic receptor subclasses.

  10. 2-Aryl(pyrrolidin-4-yl)acetic acids are potent agonists of sphingosine-1-phosphate (S1P) receptors.

    PubMed

    Yan, Lin; Budhu, Richard; Huo, Pei; Lynch, Christopher L; Hale, Jeffrey J; Mills, Sander G; Hajdu, Richard; Keohane, Carol A; Rosenbach, Mark J; Milligan, James A; Shei, Gan-Ju; Chrebet, Gary; Bergstrom, James; Card, Deborah; Mandala, Suzanne M

    2006-07-01

    A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.

  11. Enhancement of the inducible NO synthase activation by retinoic acid is mimicked by RARalpha agonist in vivo.

    PubMed

    Seguin-Devaux, Carole; Devaux, Yvan; Latger-Cannard, Véronique; Grosjean, Sandrine; Rochette-Egly, Cécile; Zannad, Faiez; Meistelman, Claude; Mertes, Paul-Michel; Longrois, Dan

    2002-09-01

    We have previously shown that all-trans retinoic acid (atRA), the active metabolite of vitamin A, enhances the activation of the inducible nitric oxide synthase (NOS II) pathway, a component of innate immunity, in rats in vivo. We investigated the relative contribution of retinoic acid receptor-alpha (RARalpha) and retinoid X receptors (RXRs) to NOS II activation triggered by LPS. Five-day supplementation with 10 mg/kg of either atRA or the RARalpha selective agonist Ro-40-6055, but not with 10 mg/kg of the pan-RXR agonist Ro-25-7386, enhanced the LPS-induced NOS II mRNA, protein expression in liver, and plasma nitrite/nitrate concentration. Both atRA and the RARalpha agonist (but not the RXR agonist) increased the number of peripheral T helper lymphocytes and plasma interferon-gamma concentration. Synergism between retinoids and LPS on NOS II activation within an organ coincided with synergism on interferon regulatory factor-1 mRNA expression but not with the level of expression of the RARalpha protein. These results suggest that, in vivo, atRA activates NOS II through RARalpha and contributes to characterizing the complex effect of retinoids on the host inflammatory/immune response.

  12. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis

    PubMed Central

    Verbeke, Len; Mannaerts, Inge; Schierwagen, Robert; Govaere, Olivier; Klein, Sabine; Vander Elst, Ingrid; Windmolders, Petra; Farre, Ricard; Wenes, Mathias; Mazzone, Massimiliano; Nevens, Frederik; van Grunsven, Leo A.; Trebicka, Jonel; Laleman, Wim

    2016-01-01

    Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis. PMID:27634375

  13. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis.

    PubMed

    Verbeke, Len; Mannaerts, Inge; Schierwagen, Robert; Govaere, Olivier; Klein, Sabine; Vander Elst, Ingrid; Windmolders, Petra; Farre, Ricard; Wenes, Mathias; Mazzone, Massimiliano; Nevens, Frederik; van Grunsven, Leo A; Trebicka, Jonel; Laleman, Wim

    2016-01-01

    Hepatic inflammation drives hepatic stellate cells (HSC), resulting in liver fibrosis. The Farnesoid-X receptor (FXR) antagonizes inflammation through NF-κB inhibition. We investigated preventive and therapeutic effects of FXR agonist obeticholic acid (OCA) on hepatic inflammation and fibrosis in toxic cirrhotic rats. Cirrhosis was induced by thioacetamide (TAA) intoxication. OCA was given during or after intoxication with vehicle-treated rats as controls. At sacrifice, fibrosis, hemodynamic and biochemical parameters were assessed. HSC activation, cell turn-over, hepatic NF-κB activation, pro-inflammatory and pro-fibrotic cytokines were determined. The effect of OCA was further evaluated in isolated HSC, Kupffer cells, hepatocytes and liver sinusoidal endothelial cells (LSEC). OCA decreased hepatic inflammation and fibrogenesis during TAA-administration and reversed fibrosis in established cirrhosis. Portal pressure decreased through reduced intrahepatic vascular resistance. This was paralleled by decreased expression of pro-fibrotic cytokines (transforming growth-factor β, connective tissue growth factor, platelet-derived growth factor β-receptor) as well as markers of hepatic cell turn-over, by blunting effects of pro-inflammatory cytokines (e.g. monocyte chemo-attractant protein-1). In vitro, OCA inhibited both LSEC and Kupffer cell activation; while HSC remained unaffected. This related to NF-κB inhibition via up-regulated IκBα. In conclusion, OCA inhibits hepatic inflammation in toxic cirrhotic rats resulting in decreased HSC activation and fibrosis. PMID:27634375

  14. Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists.

    PubMed

    Hale, Jeffrey J; Doherty, George; Toth, Leslie; Mills, Sander G; Hajdu, Richard; Keohane, Carol Ann; Rosenbach, Mark; Milligan, James; Shei, Gan-Ju; Chrebet, Gary; Bergstrom, James; Card, Deborah; Forrest, Michael; Sun, Shu-Yu; West, Sarah; Xie, Huijuan; Nomura, Naomi; Rosen, Hugh; Mandala, Suzanne

    2004-07-01

    Structurally modified 3-(N-benzylamino)propylphosphonic acid S1P receptor agonists that maintain affinity for S1P1, and have decreased affinity for S1P3 are efficacious, but exhibit decreased acute cardiovascular toxicity in rodents than do nonselective agonists.

  15. Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages.

    PubMed

    Ayaori, Makoto; Yakushiji, Emi; Ogura, Masatsune; Nakaya, Kazuhiro; Hisada, Tetsuya; Uto-Kondo, Harumi; Takiguchi, Shunichi; Terao, Yoshio; Sasaki, Makoto; Komatsu, Tomohiro; Iizuka, Maki; Yogo, Makiko; Uehara, Yoshinari; Kagechika, Hiroyuki; Nakanishi, Tsuyoshi; Ikewaki, Katsunori

    2012-04-01

    ABC transporter G1 (ABCG1) plays a pivotal role in HDL-mediated cholesterol efflux and atherogenesis. We investigated whether, and how, retinoic acid receptors (RARs) regulate ABCG1 expression in macrophages. All-trans retinoic acid (ATRA), an RAR ligand, increased ABCG1 protein levels and apoA-I/HDL-mediated cholesterol efflux from the macrophages. Both ATRA and other RAR agonists, TTNPB and Am580, increased major transcripts driven by promoter B upstream of exon 5, though minor transcripts driven by promoter A upstream of exon 1 were only increased by ATRA. The stimulatory effects of ATRA on ABCG1 expression were completely abolished in the presence of RAR/RXR antagonists but were only partially canceled in the presence of an LXR antagonist. Adenovirus with overexpressed oxysterol sulfotransferase abolished the LXR pathway, as previously reported, and ATRA-responsiveness in ABCA1/ABCG1 expressions were respectively attenuated by 38 and 22% compared to the control virus. Promoter assays revealed that ABCG1 levels were regulated more by promoter B than promoter A, and ATRA activated promoter B in a liver X receptor-responsive element (LXRE)-dependent manner. Further, LXRE-B in intron 7, but not LXRE-A in intron 5, enhanced ATRA responsiveness under overexpression of all RAR isoforms-RARα/β/γ. In contrast, the activation of promoter B by TTNPB depended on LXRE-B and RARα, but not on RARβ/γ. Finally, chromatin immunoprecipitation and gel-shift assays revealed a specific and direct repeat 4-dependent binding of RARα to LXRE-B. In conclusion, RAR ligands increase ABCA1/G1 expression and apoA-I/HDL-mediated cholesterol efflux from macrophages, and modulate ABCG1 promoter activity via LXRE-dependent mechanisms.

  16. Nazarov cyclization of 1,4-pentadien-3-ols: preparation of cyclopenta[b]indoles and spiro[indene-1,4'-quinoline]s.

    PubMed

    Wang, Zhiming; Xu, Xingzhu; Gu, Zhanshou; Feng, Wei; Qian, Houjun; Li, Zhengyi; Sun, Xiaoqiang; Kwon, Ohyun

    2016-02-14

    The first Lewis acid-catalyzed intramolecular interrupted Nazarov cyclization of 1,4-pentadien-3-ols is described. Using FeBr3 as the catalyst, a series of new substituted cyclopenta[b]indoles was prepared-through a sequence of Nazarov cyclization, nucleophilic amination, and isomerization-with good yields and high diastereo- and regioselectivities. A similar catalytic process was also developed for the synthesis of structurally interesting spiro[indene-1,4'-quinoline]s. PMID:26771024

  17. 40 CFR 721.9100 - Substituted quinoline.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Substituted quinoline. 721.9100... Substances § 721.9100 Substituted quinoline. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as substituted quinoline (PMN P-93-1183)...

  18. 40 CFR 721.9100 - Substituted quinoline.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Substituted quinoline. 721.9100... Substances § 721.9100 Substituted quinoline. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as substituted quinoline (PMN P-93-1183)...

  19. Α-amino-β-fluorocyclopropanecarboxylic acids as a new tool for drug development: synthesis of glutamic acid analogs and agonist activity towards metabotropic glutamate receptor 4.

    PubMed

    Lemonnier, Gérald; Lion, Cédric; Quirion, Jean-Charles; Pin, Jean-Philippe; Goudet, Cyril; Jubault, Philippe

    2012-08-01

    Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM.

  20. Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells.

    PubMed

    Liu, Ze; Hopkins, Mandi M; Zhang, Zhihong; Quisenberry, Chrystal B; Fix, Louise C; Galvan, Brianna M; Meier, Kathryn E

    2015-02-01

    Omega-3 fatty acids (n-3 FAs) are proposed to have many beneficial effects on human health. However, the mechanisms underlying their potential cancer preventative effects are unclear. G protein-coupled receptors (GPCRs) of the free fatty acid receptor (FFAR) family, FFA1/GPR40 and FFA4/GPR120, specifically bind n-3 FAs as agonist ligands. In this study, we examined the effects of n-3 FAs in human prostate cancer cell lines. Initial studies established that the long-chain n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid, inhibit proliferation of DU145 cells in response to lysophosphatidic acid (LPA), a mitogenic lipid mediator. When added alone to serum-starved DU145 cells, EPA transiently activates signaling events, including p70S6K phosphorylation. However, when added 15 minutes prior to LPA, EPA suppresses LPA-induced activating phosphorylations of ERK, FAK, and p70S6K, and expression of the matricellular protein CCN1. The rapid onset of the inhibitory action of EPA suggested involvement of a GPCR. Further studies showed that DU145 and PC-3 cells express mRNA and protein for both FFA4 and FFA1. TUG-891 (4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]-benzenepropanoic acid), a selective agonist for FFA4, exerts inhibitory effects on LPA- and epidermal growth factor-induced proliferation and migration, similar to EPA, in DU145 and PC-3 cells. The effects of TUG-891 and EPA are readily reversible. The FFA1/FFA4 agonist GW9508 (4-[[(3-phenoxyphenyl)methyl]amino]-benzenepropranoic acid) likewise inhibits proliferation at doses that block FFA4. Knockdown of FFA4 expression prevents EPA- and TUG-891-induced inhibition of growth and migration. Together, these results indicate that activation of FFA4 initiates signaling events that can inhibit growth factor-induced signaling, providing a novel mechanism for suppression of cancer cell proliferation.

  1. Eicosopentaneoic Acid and Other Free Fatty Acid Receptor Agonists Inhibit Lysophosphatidic Acid- and Epidermal Growth Factor-Induced Proliferation of Human Breast Cancer Cells

    PubMed Central

    Hopkins, Mandi M.; Zhang, Zhihong; Liu, Ze; Meier, Kathryn E.

    2016-01-01

    Many key actions of ω-3 (n-3) fatty acids have recently been shown to be mediated by two G protein-coupled receptors (GPCRs) in the free fatty acid receptor (FFAR) family, FFA1 (GPR40) and FFA4 (GPR120). n-3 Fatty acids inhibit proliferation of human breast cancer cells in culture and in animals. In the current study, the roles of FFA1 and FFA4 were investigated. In addition, the role of cross-talk between GPCRs activated by lysophosphatidic acid (LPA), and the tyrosine kinase receptor activated by epidermal growth factor (EGF), was examined. In MCF-7 and MDA-MB-231 human breast cancer cell lines, both LPA and EGF stimulated proliferation, Erk activation, Akt activation, and CCN1 induction. LPA antagonists blocked effects of LPA and EGF on proliferation in MCF-7 and MDA-MB-231, and on cell migration in MCF-7. The n-3 fatty acid eicosopentaneoic acid inhibited LPA- and EGF-induced proliferation in both cell lines. Two synthetic FFAR agonists, GW9508 and TUG-891, likewise inhibited LPA- and EGF-induced proliferation. The data suggest a major role for FFA1, which was expressed by both cell lines. The results indicate that n-3 fatty acids inhibit breast cancer cell proliferation via FFARs, and suggest a mechanism involving negative cross-talk between FFARS, LPA receptors, and EGF receptor. PMID:26821052

  2. Multicomponent Dipolar Cycloaddition Strategy: Combinatorial Synthesis of Novel Spiro-Tethered Pyrazolo[3,4-b]quinoline Hybrid Heterocycles.

    PubMed

    Sumesh, Remani Vasudevan; Muthu, Muthumani; Almansour, Abdulrahman I; Suresh Kumar, Raju; Arumugam, Natarajan; Athimoolam, S; Jeya Yasmi Prabha, E Arockia; Kumar, Raju Ranjith

    2016-05-01

    The stereoselective syntheses of a library of novel spiro-tethered pyrazolo[3,4-b]quinoline-pyrrolidine/pyrrolothiazole/indolizine-oxindole/acenaphthene hybrid heterocycles have been achieved through the 1,3-dipolar cycloaddition of azomethine ylides generated in situ from α-amino acids and 1,2-diketones to dipolarophiles derived from pyrazolo[3,4-b]quinoline derivatives.

  3. Inhibition by a retinoic acid receptor γ agonist of extracellular matrix remodeling mediated by human Tenon fibroblasts

    PubMed Central

    Liu, Yang; Orita, Tomoko; Suzuki, Katsuyoshi; Teranishi, Shinichiro; Mori, Takuya; Sonoda, Koh-Hei

    2015-01-01

    Purpose Scar formation is most frequently responsible for the failure of glaucoma filtration surgery. Retinoic acids are vitamin A derivatives that play diverse roles in development, immunity, and tissue repair. The effects of the retinoic acid receptor (RAR) γ agonist R667 on the contractility of human Tenon fibroblasts (HTFs) cultured in a three-dimensional collagen gel as well as on intraocular pressure (IOP) in a rat model of glaucoma filtration surgery were investigated. Methods HTFs were cultured in a type I collagen gel, the contraction of which was evaluated by measurement of the gel diameter. The release of matrix metalloproteinases (MMPs) into culture supernatants was assessed with immunoblot analysis and gelatin zymography. Phosphorylation of focal adhesion kinase (FAK) was examined with immunoblot analysis, and production of fibronectin and type I collagen was measured with immunoassays. Results R667 inhibited transforming growth factor-β1 (TGF-β1)-induced collagen gel contraction mediated by HTFs in a concentration- and time-dependent manner, whereas an RARα agonist inhibited this process to a lesser extent and an RARβ agonist had no effect. TGF-β1-induced MMP-1 and MMP-3 release, FAK phosphorylation, and fibronectin and type I collagen production in HTFs were also attenuated by R667. Furthermore, R667 lowered IOP in rats after glaucoma filtration surgery. Conclusions R667 inhibited TGF-β1-induced contraction and extracellular matrix synthesis in HTFs. Such effects might have contributed to the lowering of IOP by R667 in a rat model of glaucoma filtration surgery. RARγ agonists might thus prove effective for inhibition of scar formation after such surgery. PMID:26788029

  4. Potent complement C3a receptor agonists derived from oxazole amino acids: Structure-activity relationships.

    PubMed

    Singh, Ranee; Reed, Anthony N; Chu, Peifei; Scully, Conor C G; Yau, Mei-Kwan; Suen, Jacky Y; Durek, Thomas; Reid, Robert C; Fairlie, David P

    2015-12-01

    Potent ligands for the human complement C3a receptor (C3aR) were developed from the almost inactive tripeptide Leu-Ala-Arg corresponding to the three C-terminal residues of the endogenous peptide agonist C3a. The analogous Leu-Ser-Arg was modified by condensing the serine side chain with the leucine carbonyl with elimination of water to form leucine-oxazole-arginine. Subsequent elaboration with a variety of N-terminal amide capping groups produced agonists as potent as human C3a itself in stimulating Ca(2+) release from human macrophages. Structure-activity relationships are discussed.

  5. Involvement of Nitric Oxide on Calcium Mobilization and Arachidonic Acid Pathway Activation during Platelet Aggregation with different aggregating agonists

    PubMed Central

    Banerjee, Debipriya; Mazumder, Sahana; Kumar Sinha, Asru

    2016-01-01

    Platelet aggregation by different aggregating agonists is essential in the normal blood coagulation process, the excess of which caused acute coronary syndrome (ACS). In all cases, the activation of arachidonic acid by cycloxygenase was needed for the synthesis of thromboxane A2 (TXA2) but the mechanism of arachidonic acid release in platelets remains obscure. Studies were conducted to determine the role of nitric oxide (NO), if any, on the release of arachidonic acid in platelets. The cytosolic Ca2+ was visualized and quantitated by fluorescent spectroscopy by using QUIN-2. NO was measured by methemoglobin method. Arachidonic acid was determined by HPLC. TXA2 was measured as ThromboxaneB2 (TXB2) by ELISA. Treatment of platelets in platelet-rich plasma (PRP) with different aggregating agents resulted in the inhibition of nitric oxide synthase (NOS) which inhibited the production of NO synthesis and increased TXA2 synthesis. Furthermore, the treatment of washed PRP with different platelet aggregating agents resulted in the increase of [Ca2+] in nM ranges. In contrast, the pre-treatment of washed PRP with aspirin increased platelet NO level and inhibited the Ca2+ mobilization and TXA2 synthesis. These results indicated that the aggregation of platelets by different aggregating agonists was caused by the cytosolic Ca2+ mobilization due to the inhibition of NOS. PMID:27127451

  6. Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist.

    PubMed

    Goncalves, Maria B; Clarke, Earl; Hobbs, Carl; Malmqvist, Tony; Deacon, Robert; Jack, Julian; Corcoran, Jonathan P T

    2013-04-01

    The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.

  7. Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist

    PubMed Central

    Goncalves, Maria B; Clarke, Earl; Hobbs, Carl; Malmqvist, Tony; Deacon, Robert; Jack, Julian; Corcoran, Jonathan P T

    2013-01-01

    The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD. PMID:23379615

  8. CoMSIA study on substituted aryl alkanoic acid analogs as GPR40 agonists.

    PubMed

    Bhatt, Aaditya; Patel, Pallav D; Patel, Maulik R; Singh, Satyakam; Lau-Cam, Cesar A; Talele, Tanaji T

    2011-05-01

    GPR40, a G-protein-coupled receptor has been well established to play a crucial role in regulating blood glucose levels. Hence, GPR40 is a potential target for future antidiabetic agents. The present 3D QSAR study is aimed at delineating structural parameters governing GPR40 agonistic activity. To meet this objective, a comparative molecular similarity indices analysis for 63 different GPR40 agonists was performed using two methods; a ligand-based 3D QSAR model employing the atom fit alignment method and a receptor-based 3D QSAR model that was derived from the predicted binding conformations obtained by docking all the GPR40 agonists at the active site of GPR40. The results of these studies showed the ligand-based model to be superior (r(cv)(2) value of 0.610) to the receptor-based model (r(cv)(2) value of 0.519) in terms of statistical data. The predictive ability of these models was evaluated using a test set of 15 compounds not included in the preliminary training set of 48 compounds. The predictive r(2) values for the ligand- and the receptor-based models were found to be 0.863 and 0.599, respectively. Further, interpretation of the comparative molecular similarity indices analysis contour maps with reference to the active site of GPR40 provided an insight into GPR40-agonist interactions. PMID:21352503

  9. CoMSIA study on substituted aryl alkanoic acid analogs as GPR40 agonists.

    PubMed

    Bhatt, Aaditya; Patel, Pallav D; Patel, Maulik R; Singh, Satyakam; Lau-Cam, Cesar A; Talele, Tanaji T

    2011-05-01

    GPR40, a G-protein-coupled receptor has been well established to play a crucial role in regulating blood glucose levels. Hence, GPR40 is a potential target for future antidiabetic agents. The present 3D QSAR study is aimed at delineating structural parameters governing GPR40 agonistic activity. To meet this objective, a comparative molecular similarity indices analysis for 63 different GPR40 agonists was performed using two methods; a ligand-based 3D QSAR model employing the atom fit alignment method and a receptor-based 3D QSAR model that was derived from the predicted binding conformations obtained by docking all the GPR40 agonists at the active site of GPR40. The results of these studies showed the ligand-based model to be superior (r(cv)(2) value of 0.610) to the receptor-based model (r(cv)(2) value of 0.519) in terms of statistical data. The predictive ability of these models was evaluated using a test set of 15 compounds not included in the preliminary training set of 48 compounds. The predictive r(2) values for the ligand- and the receptor-based models were found to be 0.863 and 0.599, respectively. Further, interpretation of the comparative molecular similarity indices analysis contour maps with reference to the active site of GPR40 provided an insight into GPR40-agonist interactions.

  10. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists.

    PubMed

    Liberato, Marcelo Vizoná; Nascimento, Alessandro S; Ayers, Steven D; Lin, Jean Z; Cvoro, Aleksandra; Silveira, Rodrigo L; Martínez, Leandro; Souza, Paulo C T; Saidemberg, Daniel; Deng, Tuo; Amato, Angela Angelica; Togashi, Marie; Hsueh, Willa A; Phillips, Kevin; Palma, Mário Sérgio; Neves, Francisco A R; Skaf, Munir S; Webb, Paul; Polikarpov, Igor

    2012-01-01

    Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.

  11. Structural identification of Diindole agonists of the aryl hydrocarbon receptor derived from degradation of indole-3-pyruvic acid.

    PubMed

    Chowdhury, Goutam; Dostalek, Miroslav; Hsu, Erin L; Nguyen, Linh P; Stec, Donald F; Bradfield, Christopher A; Guengerich, F Peter

    2009-12-01

    Aerobic incubation of the tryptophan transamination/oxidation product indole-3-pyruvic acid (I3P) at pH 7.4 and 37 degrees C yielded products with activity as Ah receptor (AHR) agonists. The extracts were fractionated using HPLC and screened for AHR agonist activity. Two compounds were identified as agonists: 1,3-di(1H-indol-3-yl)propan-2-one (1) and 1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene) propan-2-one (2), with the potency of 2 being 100-fold > 1 [ Nguyen et al. ( 2009 ) Chem. Res. Toxicol. , DOI: 10.1021/tx900043s . ]. Both 1 and 2 showed UV spectra indicative of indole. The molecular formulas were established by high-resolution mass spectrometry (HRMS), and the structures were determined by a combination of NMR methods, including (1)H, natural abundance (13)C, and two-dimensional methods. An intermediate in the oxidation of I3P to 1 is 3-hydroxy-2,4-di(1H-indol-3-yl)butanal (HRMS established the presence of a compound with the formula C(20)H(19)N(2)O(2)). Compound 1 was converted to 2 in air or (faster) with mild oxidants, and 2 could be further oxidized to 1,3-di(3H-indol-3-ylidene)propan-2-one. Determination of the structures allowed estimation of the molar Ah receptor agonist activity of these natural products, similar in potency to known classical AHR inducers. PMID:19860413

  12. Agonist-directed signaling of serotonin 5-HT2C receptors: differences between serotonin and lysergic acid diethylamide (LSD).

    PubMed

    Backstrom, J R; Chang, M S; Chu, H; Niswender, C M; Sanders-Bush, E

    1999-08-01

    For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular techniques, we are beginning to understand the complexity of LSD's actions at the serotonin 5-HT2 family of receptors. Here, we discuss evidence that signaling of LSD at 5-HT2C receptors differs from the endogenous agonist serotonin. In addition, RNA editing of the 5-HT2C receptor dramatically alters the ability of LSD to stimulate phosphatidylinositol signaling. These findings provide a unique opportunity to understand the mechanism(s) of partial agonism.

  13. Omega-3 Fatty Acids and Other FFA4 Agonists Inhibit Growth Factor Signaling in Human Prostate Cancer Cells

    PubMed Central

    Liu, Ze; Hopkins, Mandi M.; Zhang, Zhihong; Quisenberry, Chrystal B.; Fix, Louise C.; Galvan, Brianna M.

    2015-01-01

    Omega-3 fatty acids (n-3 FAs) are proposed to have many beneficial effects on human health. However, the mechanisms underlying their potential cancer preventative effects are unclear. G protein–coupled receptors (GPCRs) of the free fatty acid receptor (FFAR) family, FFA1/GPR40 and FFA4/GPR120, specifically bind n-3 FAs as agonist ligands. In this study, we examined the effects of n-3 FAs in human prostate cancer cell lines. Initial studies established that the long-chain n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid, inhibit proliferation of DU145 cells in response to lysophosphatidic acid (LPA), a mitogenic lipid mediator. When added alone to serum-starved DU145 cells, EPA transiently activates signaling events, including p70S6K phosphorylation. However, when added 15 minutes prior to LPA, EPA suppresses LPA-induced activating phosphorylations of ERK, FAK, and p70S6K, and expression of the matricellular protein CCN1. The rapid onset of the inhibitory action of EPA suggested involvement of a GPCR. Further studies showed that DU145 and PC-3 cells express mRNA and protein for both FFA4 and FFA1. TUG-891 (4-[(4-fluoro-4′-methyl[1,1′-biphenyl]-2-yl)methoxy]-benzenepropanoic acid), a selective agonist for FFA4, exerts inhibitory effects on LPA- and epidermal growth factor–induced proliferation and migration, similar to EPA, in DU145 and PC-3 cells. The effects of TUG-891 and EPA are readily reversible. The FFA1/FFA4 agonist GW9508 (4-[[(3-phenoxyphenyl)methyl]amino]-benzenepropranoic acid) likewise inhibits proliferation at doses that block FFA4. Knockdown of FFA4 expression prevents EPA- and TUG-891–induced inhibition of growth and migration. Together, these results indicate that activation of FFA4 initiates signaling events that can inhibit growth factor–induced signaling, providing a novel mechanism for suppression of cancer cell proliferation. PMID:25491146

  14. A study of the analytical behaviour of selected synthetic and naturally occurring quinolines using electrospray ionisation ion trap mass spectrometry, liquid chromatography and gas chromatography and the construction of an appropriate database for quinoline characterisation.

    PubMed

    O'Donnell, F; Ramachandran, V N; Smyth, W F; Hack, C J; Patton, E

    2006-07-14

    Mass spectral fragmentation of quinoline alkaloids of significance in plants has been investigated using electrospray ionisation ion trap mass spectrometry (ESI-MS(n)) with a view to characterisation of molecules of unknown structure isolated from these natural sources. This investigation has led to the generation of an appropriate database incorporating data from ESI-MS(n) and also from gas liquid chromatography (GLC) and liquid chromatography (HPLC) for these low molecular mass quinolines. This has been put to practical application in the identification of quinoline alkaloids in a plant extract. Thus, an acid extraction of the leaves of Choisya ternata containing such tertiary alkaloids was analysed by liquid chromatography-electrospray ionisation mass spectrometry (HPLC-ESI-MS) and the resulting behaviour of the quinolines was compared with that of the quinoline alkaloids in the database.

  15. Potent and selective activation of abscisic acid receptors in vivo by mutational stabilization of their agonist-bound conformation

    PubMed Central

    Mosquna, Assaf; Peterson, Francis C.; Park, Sang-Youl; Lozano-Juste, Jorge; Volkman, Brian F.; Cutler, Sean R.

    2011-01-01

    Pyrabactin resistance (PYR) 1 and its relatives belong to a family of soluble abscisic acid (ABA) receptors that inhibit type 2C protein phosphatases (PP2C) when in their agonist-stabilized conformation. Given their switch-like properties, we envisioned that mutations that stabilize their agonist-bound conformation could be used to activate signaling in vivo. To identify such mutations, we subjected PYR1 to site-saturation mutagenesis at 39 highly conserved residues that participate in ABA or PP2C contacts. All 741 possible single amino acid substitutions at these sites were tested to identify variants that increase basal PYR1-PP2C interactions, which uncovered activating mutations in 10 residues that preferentially cluster in PYR1's gate loop and C-terminal helix. The mutations cause measurable but incomplete receptor activation in vitro; however, specific triple and quadruple mutant combinations were constructed that promote an agonist-bound conformation, as measured by heteronuclear single quantum coherence NMR, and lead to full receptor activation. Moreover, these mutations retain functionality when introduced into divergent family members, and can therefore be used to dissect individual receptor function in vivo, which has been problematic because of redundancy and family size. Expression of activated PYL2 in Arabidopsis seeds activates ABA signaling by a number of measures: modulation of ABA-regulated gene expression, induction of hyperdormancy, and suppression of ABA deficiency phenotypes in the aba2-1 mutant. Our results set the stage for systematic gain-of-function studies of PYR1 and related ABA receptors and reveal that, despite the large number of receptors, activation of a single receptor is sufficient to activate signaling in planta. PMID:22139369

  16. Omega-3 Fatty Acids Augment the Actions of Nuclear Receptor Agonists in a Mouse Model of Alzheimer's Disease.

    PubMed

    Casali, Brad T; Corona, Angela W; Mariani, Monica M; Karlo, J Colleen; Ghosal, Kaushik; Landreth, Gary E

    2015-06-17

    Alzheimer's disease (AD) is a highly prevalent disorder for which there are no effective therapies. Accumulation of amyloid β (Aβ) peptides in the brain is associated with impaired cognition and memory, pronounced inflammatory dysregulation, and subsequent amyloid plaque deposition. Thus, drugs that promote the clearance of Aβ peptides and resolution of inflammation may represent viable therapeutic approaches. Agonists of nuclear receptors LXR:RXR and PPAR:RXR act to ameliorate AD-related cognitive impairment and amyloid accumulation in murine models of AD. The use of an agonist to the nuclear receptor RXR, bexarotene, as monotherapy against AD, presents potential challenges due to the metabolic perturbations it induces in the periphery, most prominently hypertriglyceridemia. We report that the ω-3 fatty acid docosahexaenoic acid (DHA), in combination with bexarotene, enhances LXR:RXR target gene expression of Abca1 and ApoE, reduces soluble forms of Aβ, and abrogates release of pro-inflammatory cytokines and mediators both in vitro and in a mouse model of AD. Moreover, DHA abrogates bexarotene-induced hypertriglyceridemia in vivo. Importantly, dual therapy promotes reductions in AD pathology and resultant amelioration of cognitive deficits. While monotherapy with either bexarotene or DHA resulted in modest effects in vitro and in vivo, combined treatment with both agents produced a significant additive benefit on associated AD-related phenotypes, suggesting that targeted combinatorial agents may be beneficial over single agents alone in treating AD. PMID:26085639

  17. Activities of new quinoline derivatives against genital pathogens.

    PubMed Central

    Aznar, J; Caballero, M C; Lozano, M C; de Miguel, C; Palomares, J C; Perea, E J

    1985-01-01

    The in vitro activities of four quinoline carboxylic acids against 48 strains of Neisseria gonorrhoeae, 10 of Chlamydia trachomatis, and 32 of Ureaplasma urealyticum were compared. Ciprofloxacin was the most active against N. gonorrhoeae and C. trachomatis but had poor bactericidal activity against U. urealyticum, whereas ofloxacin showed the most bactericidal activity against U. urealyticum but was less active than ciprofloxacin against the two former pathogens. Norfloxacin and enoxacin were less active against all the studied pathogens. PMID:3920959

  18. Design, synthesis and structure-activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes.

    PubMed

    Li, Zheng; Wang, Xuekun; Xu, Xue; Yang, Jianyong; Qiu, Qianqian; Qiang, Hao; Huang, Wenlong; Qian, Hai

    2015-10-15

    The free fatty acid receptor 1 (FFA1) has attracted extensive attention as a novel antidiabetic target in the last decade. Several FFA1 agonists reported in the literature have been suffered from relatively high molecular weight and lipophilicity. We have previously reported the FFA1 agonist 1. Based on the common amide structural characteristic of SAR1 and NIH screened compound, we here describe the continued structure-activity exploration to decrease the molecular weight and lipophilicity of the compound 1 series by converting various amide linkers. All of these efforts lead to the discovery of the preferable lead compound 18, a compound with considerable agonistic activity, high LE and LLE values, lower lipophilicity than previously reported agonists, and appreciable efficacy on glucose tolerance in both normal and type 2 diabetic mice. PMID:26420383

  19. SAR studies of 3-arylpropionic acids as potent and selective agonists of sphingosine-1-phosphate receptor-1 (S1P1) with enhanced pharmacokinetic properties.

    PubMed

    Yan, Lin; Huo, Pei; Hale, Jeffrey J; Mills, Sander G; Hajdu, Richard; Keohane, Carol A; Rosenbach, Mark J; Milligan, James A; Shei, Gan-Ju; Chrebet, Gary; Bergstrom, James; Card, Deborah; Mandala, Suzanne M

    2007-02-01

    Structure-activity relationship (SAR) studies of 3-arylpropionic acids-a class of novel S1P(1) selective agonists-by introducing substitution to the propionic acid chain and replacing the adjacent phenyl ring with pyridine led to a series of modified 3-arylpropionic acids with enhanced half-life in rat. These analogs (e.g., cyclopropanecarboxylic acids) exhibited longer half-life in rat than did unmodified 3-arylpropionic acids. This result suggests that metabolic oxidation at the propionic acid chain, particularly at the C3 benzylic position of 3-arylpropionic acids, is probably responsible for their short half-life in rodent.

  20. (+)Lysergic acid diethylamide, but not its nonhallucinogenic congeners, is a potent serotonin 5HT1C receptor agonist

    SciTech Connect

    Burris, K.D.; Breeding, M.; Sanders-Bush, E. )

    1991-09-01

    Activation of central serotonin 5HT2 receptors is believed to be the primary mechanism whereby lysergic acid diethylamide (LSD) and other hallucinogens induce psychoactive effects. This hypothesis is based on extensive radioligand binding and electrophysiological and behavioral studies in laboratory animals. However, the pharmacological profiles of 5HT2 and 5HT1C receptors are similar, making it difficult to distinguish between effects due to activation of one or the other receptor. For this reason, it was of interest to investigate the interaction of LSD with 5HT1C receptors. Agonist-stimulated phosphoinositide hydrolysis in rat choroid plexus was used as a direct measure of 5HT1C receptor activation. (+)LSD potently stimulated phosphoinositide hydrolysis in intact choroid plexus and in cultures of choroid plexus epithelial cells, with EC50 values of 9 and 26 nM, respectively. The effect of (+)LSD in both systems was blocked by 5HT receptor antagonists with an order of activity consistent with interaction at 5HT1C receptors. Neither (+)-2-bromo-LSD nor lisuride, two nonhallucinogenic congeners of LSD, were able to stimulate 5HT1C receptors in cultured cells or intact choroid plexus. In contrast, lisuride, like (+)LSD, is a partial agonist at 5HT2 receptors in cerebral cortex slices and in NIH 3T3 cells transfected with 5HT2 receptor cDNA. The present finding that (+)LSD, but not its nonhallucinogenic congeners, is a 5HT1C receptor agonist suggests a possible role for these receptors in mediating the psychoactive effects of LSD.

  1. Actions of Xanthurenic acid, a putative endogenous Group II metabotropic glutamate receptor agonist, on sensory transmission in the thalamus.

    PubMed

    Copeland, C S; Neale, S A; Salt, T E

    2013-03-01

    Xanthurenic acid (XA), a molecule arising from tryptophan metabolism by transamination of 3-hydroxykynurenine, has recently been identified as an endogenous Group II (mGlu2 and mGlu3) metabotropic glutamate (mGlu) receptor ligand in vitro. Impairments in Group II mGlu receptor expression and function have been implicated in the pathophysiology of schizophrenia, as have multiple steps in the kynurenine metabolism pathway. Therefore, we examined XA in vivo to further investigate its potential as a Group II mGlu receptor ligand using a preparation that has been previously demonstrated to efficiently reveal the action of other Group II mGlu receptor ligands in vivo. Extracellular single-neurone recordings were made in the rat ventrobasal thalamus (VB) in conjunction with iontophoresis of agonists, an antagonist and a positive allosteric modulator and/or intravenous (i.v.) injection of XA. We found the XA effect on sensory inhibition, when applied iontophoretically and i.v., was similar to that of other Group II mGlu receptor agonists in reducing inhibition evoked in the VB from the thalamic reticular nucleus upon physiological sensory stimulation. Furthermore, we postulate that XA may be the first potential endogenous allosteric agonist (termed 'endocoid') for the mGlu receptors. As the Group II receptors and kynurenine metabolism pathway have both been heavily implicated in the pathophysiology of schizophrenia, XA could play a pivotal role in antipsychotic research as this potential endocoid represents both a convergence within these two biological parameters and a novel class of Group II mGlu receptor ligand. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID:22491023

  2. Identification of 6-octadecynoic acid from a methanol extract of Marrubium vulgare L. as a peroxisome proliferator-activated receptor γ agonist

    SciTech Connect

    Ohtera, Anna; Miyamae, Yusaku; Nakai, Naomi; Kawachi, Atsushi; Kawada, Kiyokazu; Han, Junkyu; Isoda, Hiroko; Neffati, Mohamed; Akita, Toru; Maejima, Kazuhiro; Masuda, Seiji; Kambe, Taiho; Mori, Naoki; Irie, Kazuhiro; Nagao, Masaya

    2013-10-18

    Highlights: •6-ODA, a rare fatty acid with a triple bond, was identified from Marrubium vulgare. •6-ODA was synthesized from petroselinic acid as a starting material. •6-ODA stimulated lipid accumulation in HSC-T6 and 3T3-L1 cells. •The first report of a fatty acid with a triple bond functioning as a PPARγ agonist. •This study sheds light on novel functions of a fatty acid with a triple bond. -- Abstract: 6-Octadecynoic acid (6-ODA), a fatty acid with a triple bond, was identified in the methanol extract of Marrubium vulgare L. as an agonist of peroxisome proliferator-activated receptor γ (PPARγ). Fibrogenesis caused by hepatic stellate cells is inhibited by PPARγ whose ligands are clinically used for the treatment of diabetes. Plant extracts of Marrubium vulgare L., were screened for activity to inhibit fibrosis in the hepatic stellate cell line HSC-T6 using Oil Red-O staining, which detects lipids that typically accumulate in quiescent hepatic stellate cells. A methanol extract with activity to stimulate accumulation of lipids was obtained. This extract was found to have PPARγ agonist activity using a luciferase reporter assay. After purification using several chromatographic methods, 6-ODA, a fatty acid with a triple bond, was identified as a candidate of PPARγ agonist. Synthesized 6-ODA and its derivative 9-octadecynoic acid (9-ODA), which both have a triple bond but in different positions, activated PPARγ in a luciferase reporter assay and increased lipid accumulation in 3T3-L1 adipocytes in a PPARγ-dependent manner. There is little information about the biological activity of fatty acids with a triple bond, and to our knowledge, this is the first report that 6-ODA and 9-ODA function as PPARγ agonists.

  3. Benzodiazepine receptor agonists affect both binding and gating of recombinant alpha1beta2gamma2 gamma-aminobutyric acid-A receptors.

    PubMed

    Mercik, Katarzyna; Piast, Michał; Mozrzymas, Jerzy W

    2007-05-28

    Benzodiazepines are known to act by enhancing the effect of gamma-aminobutyric acid-A receptor agonists. Positive modulation by benzodiazepines is typically ascribed to upregulation of agonist binding affinity but their effect on gamma-aminobutyric acid-A receptor gating remain unclear. In this work, we have used the ultrafast application system to examine the impact of flurazepam and zolpidem on recombinant alpha1beta2gamma2 gamma-aminobutyric acid-A receptors. As expected, both drugs strongly enhanced currents evoked by low [gamma-aminobutyric acid]. These compounds, however, also affected currents elicited by saturating agonist concentration. In particular, flurazepam and zolpidem reduced current amplitudes and slowed down the recovery process in paired-pulse experiments. Moreover, flurazepam accelerated the current rise time and zolpidem enhanced the rate and extent of desensitization. We propose that flurazepam and zolpidem modulate gamma-aminobutyric acid-A receptors by strong enhancement of agonist binding with a superimposed limited effect on the receptor gating.

  4. Identification of 6-octadecynoic acid from a methanol extract of Marrubium vulgare L. as a peroxisome proliferator-activated receptor γ agonist.

    PubMed

    Ohtera, Anna; Miyamae, Yusaku; Nakai, Naomi; Kawachi, Atsushi; Kawada, Kiyokazu; Han, Junkyu; Isoda, Hiroko; Neffati, Mohamed; Akita, Toru; Maejima, Kazuhiro; Masuda, Seiji; Kambe, Taiho; Mori, Naoki; Irie, Kazuhiro; Nagao, Masaya

    2013-10-18

    6-Octadecynoic acid (6-ODA), a fatty acid with a triple bond, was identified in the methanol extract of Marrubium vulgare L. as an agonist of peroxisome proliferator-activated receptor γ (PPARγ). Fibrogenesis caused by hepatic stellate cells is inhibited by PPARγ whose ligands are clinically used for the treatment of diabetes. Plant extracts of Marrubium vulgare L., were screened for activity to inhibit fibrosis in the hepatic stellate cell line HSC-T6 using Oil Red-O staining, which detects lipids that typically accumulate in quiescent hepatic stellate cells. A methanol extract with activity to stimulate accumulation of lipids was obtained. This extract was found to have PPARγ agonist activity using a luciferase reporter assay. After purification using several chromatographic methods, 6-ODA, a fatty acid with a triple bond, was identified as a candidate of PPARγ agonist. Synthesized 6-ODA and its derivative 9-octadecynoic acid (9-ODA), which both have a triple bond but in different positions, activated PPARγ in a luciferase reporter assay and increased lipid accumulation in 3T3-L1 adipocytes in a PPARγ-dependent manner. There is little information about the biological activity of fatty acids with a triple bond, and to our knowledge, this is the first report that 6-ODA and 9-ODA function as PPARγ agonists.

  5. Cannabinoid receptor agonist WIN 55,212-2 inhibits rat cortical dialysate gamma-aminobutyric acid levels.

    PubMed

    Ferraro, L; Tomasini, M C; Cassano, T; Bebe, B W; Siniscalchi, A; O'Connor, W T; Magee, P; Tanganelli, S; Cuomo, V; Antonelli, T

    2001-10-15

    The effects of the cannabinoid receptor agonist WIN 55,212-2 (0.1-5 mg/kg i.p.) on endogenous extracellular gamma-aminobutyric acid (GABA) levels in the cerebral cortex of the awake rat was investigated by using microdialysis. WIN 55,212-2 (1 and 5 mg/kg i.p.) was associated with a concentration-dependent decrease in dialysate GABA levels (-16% +/- 4% and -26% +/- 4% of basal values, respectively). The WIN 55,212-2 (5 mg/kg i.p.) induced-inhibition was counteracted by a dose (0.1 mg/kg i.p.) of the CB(1) receptor antagonist SR141716A, which by itself was without effect on cortical GABA levels. These findings suggest that cannabinoids decrease cortical GABA levels in vivo, an action that might underlie some of the cognitive and behavioral effects of acute exposure to marijuana.

  6. The conjugated linoleic acid isomer trans-9,trans-11 is a dietary occurring agonist of liver X receptor {alpha}

    SciTech Connect

    Ecker, Josef; Liebisch, Gerhard; Patsch, Wolfgang; Schmitz, Gerd

    2009-10-30

    Conjugated linoleic acid (CLA) isomers are dietary fatty acids that modulate gene expression in many cell types. We have previously reported that specifically trans-9,trans-11 (t9,t11)-CLA induces expression of genes involved in lipid metabolism of human macrophages. To elucidate the molecular mechanism underlying this transcriptional activation, we asked whether t9,t11-CLA affects activity of liver X receptor (LXR) {alpha}, a major regulator of macrophage lipid metabolism. Here we show that t9,t11-CLA is a regulator of LXR{alpha}. We further demonstrate that the CLA isomer induces expression of direct LXR{alpha} target genes in human primary macrophages. Knockdown of LXR{alpha} with RNA interference in THP-1 cells inhibited t9,t11-CLA mediated activation of LXR{alpha} including its target genes. To evaluate the effective concentration range of t9,t11-CLA, human primary macrophages were treated with various doses of CLA and well known natural and synthetic LXR agonists and mRNA expression of ABCA1 and ABCG1 was analyzed. Incubation of human macrophages with 10 {mu}M t9,t11-CLA led to a significant modulation of ABCA1 and ABCG1 transcription and caused enhanced cholesterol efflux to high density lipoproteins and apolipoprotein AI. In summary, these data show that t9,t11-CLA is an agonist of LXR{alpha} in human macrophages and that its effects on macrophage lipid metabolism can be attributed to transcriptional regulations associated with this nuclear receptor.

  7. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis.

    PubMed

    Wu, Lizhi; Chaudhary, Sandeep C; Atigadda, Venkatram R; Belyaeva, Olga V; Harville, Steven R; Elmets, Craig A; Muccio, Donald D; Athar, Mohammad; Kedishvili, Natalia Y

    2016-01-01

    UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood. In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA), the natural agonist of RAR nuclear receptors. Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB) irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas. However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes. Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations. PMID:27078158

  8. Metabolic Profiling of Chicken Embryos Exposed to Perfluorooctanoic Acid (PFOA) and Agonists to Peroxisome Proliferator-Activated Receptors

    PubMed Central

    Mattsson, Anna; Kärrman, Anna; Pinto, Rui; Brunström, Björn

    2015-01-01

    Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA), and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor α (PPARα) and PPARγ, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARα. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic profile resulting

  9. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis

    PubMed Central

    Wu, Lizhi; Chaudhary, Sandeep C.; Atigadda, Venkatram R.; Belyaeva, Olga V.; Harville, Steven R.; Elmets, Craig A.; Muccio, Donald D.; Athar, Mohammad; Kedishvili, Natalia Y.

    2016-01-01

    UAB30 is an RXR selective agonist that has been shown to have potential cancer chemopreventive properties. Due to high efficacy and low toxicity, it is currently being evaluated in human Phase I clinical trials by the National Cancer Institute. While UAB30 shows promise as a low toxicity chemopreventive drug, the mechanism of its action is not well understood. In this study, we investigated the effects of UAB30 on gene expression in human organotypic skin raft cultures and mouse epidermis. The results of this study indicate that treatment with UAB30 results in upregulation of genes responsible for the uptake and metabolism of all-trans-retinol to all-trans-retinoic acid (ATRA), the natural agonist of RAR nuclear receptors. Consistent with the increased expression of these genes, the steady-state levels of ATRA are elevated in human skin rafts. In ultraviolet B (UVB) irradiated mouse skin, the expression of ATRA target genes is found to be reduced. A reduced expression of ATRA sensitive genes is also observed in epidermis of mouse models of UVB-induced squamous cell carcinoma and basal cell carcinomas. However, treatment of mouse skin with UAB30 prior to UVB irradiation prevents the UVB-induced decrease in expression of some of the ATRA-responsive genes. Considering its positive effects on ATRA signaling in the epidermis and its low toxicity, UAB30 could be used as a chemoprophylactic agent in the treatment of non-melanoma skin cancer, particularly in organ transplant recipients and other high risk populations. PMID:27078158

  10. A novel PPARα agonist propane-2-sulfonic acid octadec-9-enyl-amide inhibits inflammation in THP-1 cells.

    PubMed

    Zhao, Yun; Yan, Lu; Luo, Xiu-Mei; Peng, Lu; Guo, Han; Jing, Zuo; Yang, Li-Chao; Hu, Rong; Wang, Xuan; Huang, Xue-Feng; Wang, Yi-Qing; Jin, Xin

    2016-10-01

    Our group synthesized propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator activated receptor alpha (PPARα) agonist. Because PPARα activation is associated with inflammation control, we hypothesize that N15 may have anti-inflammatory effects. We investigated the effect of N15 on the regulation of inflammation in THP-1 cells stimulated with lipopolysaccharide (LPS). In particular, we assessed the production of chemokines, adhesion molecules and proinflammatory cytokines, three important types of cytokines that are released from monocytes and are involved in the development of atherosclerosis. The results showed that N15 remarkably reduced the mRNA expression of chemokines, such as monocyte chemotactic protein 1 (MCP-1 or CCL2), interleukin-8 (IL-8) and interferon-inducible protein-10 (IP-10 or CXCL10), and proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). N15 also decreased the protein expression of vascular cell adhesion molecule (VCAM) and matrix metalloproteinase (MMP) 2 and 9. The reduction in the expression of cytokine mRNAs observed following N15 treatment was abrogated in THP-1 cells treated with PPARα siRNA, indicating that the anti-inflammatory effects of N15 are dependent on PPARα activation. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) inhibition, which are dependent on PPARα activation, were also involved in the mechanism underlying the anti-inflammatory effects of N15. In conclusion, the novel PPARα agonist, N15, exerts notable anti-inflammatory effects, which are mediated via PPARα activation and TLR4/NF-κB and STAT3 inhibition, in LPS-stimulated THP-1 cells. In our study, N15 exhibits promise for the treatment of atherosclerosis.

  11. Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α.

    PubMed

    Dwivedi, Shailendra Kumar Dhar; Singh, Nidhi; Kumari, Rashmi; Mishra, Jay Sharan; Tripathi, Sarita; Banerjee, Priyam; Shah, Priyanka; Kukshal, Vandana; Tyagi, Abdul Malik; Gaikwad, Anil Nilkanth; Chaturvedi, Rajnish Kumar; Mishra, Durga Prasad; Trivedi, Arun Kumar; Sanyal, Somali; Chattopadhyay, Naibedya; Ramachandran, Ravishankar; Siddiqi, Mohammad Imran; Bandyopadhyay, Arun; Arora, Ashish; Lundåsen, Thomas; Anakk, Sayee Priyadarshini; Moore, David D; Sanyal, Sabyasachi

    2011-06-01

    Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α target genes involved in mitochondrial function. Using FXR-rich or FXR-nonexpressing cell lines and tissues, we found that this effect of GW4064 is not mediated directly by FXR but occurs via activation of estrogen receptor-related receptor α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differences revealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXR-PGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.

  12. Metabolic Profiling of Chicken Embryos Exposed to Perfluorooctanoic Acid (PFOA) and Agonists to Peroxisome Proliferator-Activated Receptors.

    PubMed

    Mattsson, Anna; Kärrman, Anna; Pinto, Rui; Brunström, Björn

    2015-01-01

    Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA), and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor α (PPARα) and PPARγ, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARα. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic profile resulting

  13. A novel PPARα agonist propane-2-sulfonic acid octadec-9-enyl-amide inhibits inflammation in THP-1 cells.

    PubMed

    Zhao, Yun; Yan, Lu; Luo, Xiu-Mei; Peng, Lu; Guo, Han; Jing, Zuo; Yang, Li-Chao; Hu, Rong; Wang, Xuan; Huang, Xue-Feng; Wang, Yi-Qing; Jin, Xin

    2016-10-01

    Our group synthesized propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator activated receptor alpha (PPARα) agonist. Because PPARα activation is associated with inflammation control, we hypothesize that N15 may have anti-inflammatory effects. We investigated the effect of N15 on the regulation of inflammation in THP-1 cells stimulated with lipopolysaccharide (LPS). In particular, we assessed the production of chemokines, adhesion molecules and proinflammatory cytokines, three important types of cytokines that are released from monocytes and are involved in the development of atherosclerosis. The results showed that N15 remarkably reduced the mRNA expression of chemokines, such as monocyte chemotactic protein 1 (MCP-1 or CCL2), interleukin-8 (IL-8) and interferon-inducible protein-10 (IP-10 or CXCL10), and proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). N15 also decreased the protein expression of vascular cell adhesion molecule (VCAM) and matrix metalloproteinase (MMP) 2 and 9. The reduction in the expression of cytokine mRNAs observed following N15 treatment was abrogated in THP-1 cells treated with PPARα siRNA, indicating that the anti-inflammatory effects of N15 are dependent on PPARα activation. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) inhibition, which are dependent on PPARα activation, were also involved in the mechanism underlying the anti-inflammatory effects of N15. In conclusion, the novel PPARα agonist, N15, exerts notable anti-inflammatory effects, which are mediated via PPARα activation and TLR4/NF-κB and STAT3 inhibition, in LPS-stimulated THP-1 cells. In our study, N15 exhibits promise for the treatment of atherosclerosis. PMID:27318324

  14. Effect of stilbene and chalcone scaffolds incorporation in clofibric acid on PPARα agonistic activity.

    PubMed

    Giampietro, Letizia; D'Angelo, Alessandra; Giancristofaro, Antonella; Ammazzalorso, Alessandra; De Filippis, Barbara; Di Matteo, Mauro; Fantacuzzi, Marialuigia; Linciano, Pasquale; Maccallini, Cristina; Amoroso, Rosa

    2014-01-01

    In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and trans-stilbene, chalcone, and other lipophilic groups were synthesized. They were evaluated for PPARα transactivation activity; all branched derivatives showed an increase of the transcriptional activity of receptor compared to the linear ones. Noteworthy, stilbene and benzophenone branched derivatives activated the PPARα better than clofibric acid. PMID:23432317

  15. Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors.

    PubMed

    Yan, Lin; Hale, Jeffrey J; Lynch, Christopher L; Budhu, Richard; Gentry, Amy; Mills, Sander G; Hajdu, Richard; Keohane, Carol Ann; Rosenbach, Mark J; Milligan, James A; Shei, Gan-Ju; Chrebet, Gary; Bergstrom, James; Card, Deborah; Rosen, Hugh; Mandala, Suzanne M

    2004-10-01

    A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.

  16. Synthesis of 2-Alkenylquinoline by Reductive Olefination of Quinoline N-Oxide under Metal-Free Conditions.

    PubMed

    Xia, Hong; Liu, Yuanhong; Zhao, Peng; Gou, Shaohua; Wang, Jun

    2016-04-15

    Synthesis of 2-alkenylquinoline by reductive olefination of quinoline N-oxide under metal-free conditions is disclosed. Practically, the reaction could be performed with quinoline as starting material via a one-pot, two-step process. A possible mechanism is proposed that involves a sequential 1,3-dipolar cycloaddition and acid-assisted ring opening followed by a dehydration process. PMID:26987040

  17. Duodenal mucosal bicarbonate secretion in man. Stimulation by acid and inhibition by the alpha 2-adrenoceptor agonist clonidine.

    PubMed Central

    Knutson, L; Flemström, G

    1989-01-01

    A multi-channel small diameter tube was used to study the secretion of bicarbonate by 3 cm long segments of the proximal duodenum isolated between balloons. The tube had an outer diameter of 5.3 mm and two central and four smaller, peripheral channels. Measurements of infused phenol red, 14C-PEG and vitamin B12 and of trypsin activity were performed to rule out contamination of the perfusate by gastric and pancreatic secretions. Basal secretion of bicarbonate by the duodenal mucosa in healthy subjects varied between 135 and 220 mumol/cm of intestine per hour. Perfusion of the lumen with acid (100 mM HCl for five minutes) increased the secretion to greater than 400 mumol/cm/h and the alpha 2-adrenoreceptor agonist clonidine (150 micrograms iv) decreased the HCO3- secretion by 70 mumol/cm/h. Clonidine simultaneously reduced the mean arterial blood pressure and plasma noradrenaline concentration, but did not affect the plasma glucose or adrenaline concentration. Duodenal bicarbonate secretion is important in the protection of this mucosa against acid discharged from the stomach. Increased sympathetic activity may, by inhibiting the bicarbonate secretion, decrease the protection in proximal duodenum in man and facilitate ulceration. Images Fig. 2 PMID:2558985

  18. Synthesis and evaluation of novel [alpha]-heteroaryl-phenylpropanoic acid derivatives as PPAR[alpha/gamma] dual agonists

    SciTech Connect

    Casimiro-Garcia, Agustin; Bigge, Christopher F.; Davis, Jo Ann; Padalino, Teresa; Pulaski, James; Ohren, Jeffrey F.; McConnell, Patrick; Kane, Christopher D.; Royer, Lori J.; Stevens, Kimberly A.; Auerbach, Bruce; Collard, Wendy; McGregor, Christine; Song, Kun; Pfizer

    2010-09-27

    The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the {alpha}-position and their evaluation for binding and activation of PPAR{alpha} and PPAR{gamma} are presented in this report. Among the new compounds, (S)-3-{l_brace}4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl{r_brace}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPAR{alpha}/{gamma} dual agonist (EC{sub 50} = 0.013 and 0.061 {micro}M, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.

  19. Evaluation of effectiveness of chemical and physical sewage treatment technologies for removal of retinoic acid receptor agonistic activity detected in sewage effluent.

    PubMed

    Inoue, D; Matsui, H; Sei, K; Hu, J; Yang, M; Aragane, J; Hirotsuji, J; Ike, M

    2009-01-01

    Retinoic acid receptor (RAR) is a nuclear receptor involved in vertebrate morphogenesis, growth, cellular differentiation, and tissue homeostasis. Excess expression of the retinoid signaling can cause various developmental toxicities in animals and humans. We previously found that influents from sewage treatment plants (STPs) in Japan had a RAR agonistic activity and the activity cannot be removed completely by conventional biological treatments. In this study, we assessed the performance of chemical and physical sewage treatment technologies-ozonation, ultraviolet treatment, chlorination, coagulation using polyaluminium chloride (PAC) and ferric sulfate, and filtration with ultrafiltration (UF), nanofiltration (NF), and reverse osmosis (RO) membranes-in removal of RAR agonistic activity of STP effluent. All water treatment experiments were conducted in laboratory-scale reactors. The RAR agonistic activity of samples was measured using a yeast two-hybrid assay. Results showed that the effectiveness of tested technologies on the removal of RAR agonistic activity can be ranked as RO or NF > chlorination > ozonation > MF > UV > coagulation with ferric sulfate>coagulation with PAC. Furthermore, the effectiveness of chlorination might rank lower because excess reaction might bring a side effect by producing some RAR agonistic by-product(s).

  20. Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes.

    PubMed

    Li, Zheng; Qiu, Qianqian; Xu, Xue; Wang, Xuekun; Jiao, Lei; Su, Xin; Pan, Miaobo; Huang, Wenlong; Qian, Hai

    2016-05-01

    The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists. PMID:26945112

  1. Quinoline-based antimalarial hybrid compounds.

    PubMed

    Vandekerckhove, Stéphanie; D'hooghe, Matthias

    2015-08-15

    Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014. PMID:25593097

  2. In vitro metabolism and metabolic effects of ajulemic acid, a synthetic cannabinoid agonist.

    PubMed

    Burstein, Sumner H; Tepper, Mark A

    2013-12-01

    Ajulemic acid is a synthetic analog of Δ(8)-THC-11-oic acid, the terminal metabolite of Δ(8)-THC. Unlike Δ(9)-THC, the psychoactive principle of Cannabis, it shows potent anti-inflammatory action and has minimal CNS cannabimimetic activity. Its in vitro metabolism by hepatocytes from rats, dogs, cynomolgus monkeys and humans was studied and the results are reported here. Five metabolites, M1 to M5, were observed in human hepatocyte incubations. One metabolite, M5, a glucuronide, was observed in the chromatogram of canine hepatocyte incubations. In monkey hepatocyte incubations, M5 was observed in the chromatograms of both the 120 and 240 min samples, trace metabolite M1 (side-chain hydroxyl) was observed in the 120 min samples, and trace metabolite M4 (side-chain dehydrogenation) was observed in the 240 min samples. No metabolites were found in the rat hepatocyte incubations. Unchanged amounts of ajulemic acid detected after the 2-h incubation were 103%, 90%, 86%, and 83% for rat, dog, monkey, and human hepatocytes, respectively. Additional studies were done to ascertain if ajulemic acid can inhibit the activities of five principal human cytochrome P450 isozymes; CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. In contrast to the phytocannabinoids Δ(9)-THC and CBD, no significant inhibition of cytochrome activity was observed. These data further support the conclusions reached in earlier reports on ajulemic acid's high margin of safety and suggest that it undergoes minimal metabolism and is not likely to interfere with the normal metabolism of drugs or endogenous substances. PMID:25505570

  3. In vitro metabolism and metabolic effects of ajulemic acid, a synthetic cannabinoid agonist

    PubMed Central

    Burstein, Sumner H; Tepper, Mark A

    2013-01-01

    Ajulemic acid is a synthetic analog of Δ8-THC-11-oic acid, the terminal metabolite of Δ8-THC. Unlike Δ9-THC, the psychoactive principle of Cannabis, it shows potent anti-inflammatory action and has minimal CNS cannabimimetic activity. Its in vitro metabolism by hepatocytes from rats, dogs, cynomolgus monkeys and humans was studied and the results are reported here. Five metabolites, M1 to M5, were observed in human hepatocyte incubations. One metabolite, M5, a glucuronide, was observed in the chromatogram of canine hepatocyte incubations. In monkey hepatocyte incubations, M5 was observed in the chromatograms of both the 120 and 240 min samples, trace metabolite M1 (side-chain hydroxyl) was observed in the 120 min samples, and trace metabolite M4 (side-chain dehydrogenation) was observed in the 240 min samples. No metabolites were found in the rat hepatocyte incubations. Unchanged amounts of ajulemic acid detected after the 2-h incubation were 103%, 90%, 86%, and 83% for rat, dog, monkey, and human hepatocytes, respectively. Additional studies were done to ascertain if ajulemic acid can inhibit the activities of five principal human cytochrome P450 isozymes; CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. In contrast to the phytocannabinoids Δ9-THC and CBD, no significant inhibition of cytochrome activity was observed. These data further support the conclusions reached in earlier reports on ajulemic acid's high margin of safety and suggest that it undergoes minimal metabolism and is not likely to interfere with the normal metabolism of drugs or endogenous substances. PMID:25505570

  4. Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro.

    PubMed

    Dietz, Birgit M; Mahady, Gail B; Pauli, Guido F; Farnsworth, Norman R

    2005-08-18

    Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA(A) receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT(5a) receptor, but only weak binding affinity to the 5-HT(2b) and the serotonin transporter. Subsequent binding studies focused on the 5-HT(5a) receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep-wake cycle. The PE extract inhibited [(3)H]lysergic acid diethylamide (LSD) binding to the human 5-HT(5a) receptor (86% at 50 microg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC(50) curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC(50) of 15.7 ng/ml for the high-affinity state and 27.7 microg/ml for the low-affinity state. The addition of GTP (100 microM) resulted in a right-hand shift of the binding curve with an IC(50) of 11.4 microg/ml. Valerenic acid, the active constituent of both extracts, had an IC(50) of 17.2 microM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT(5a) receptor. PMID:15921820

  5. Non-equivalence of Key Positively Charged Residues of the Free Fatty Acid 2 Receptor in the Recognition and Function of Agonist Versus Antagonist Ligands*

    PubMed Central

    Sergeev, Eugenia; Hansen, Anders Højgaard; Pandey, Sunil K.; MacKenzie, Amanda E.; Hudson, Brian D.; Ulven, Trond; Milligan, Graeme

    2016-01-01

    Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor. PMID:26518871

  6. Comprehensive X-Ray Structural Studies of the Quinolinate Phosphoribosyl Transferase (BNA6) From Saccharomyces Cerevisiae

    SciTech Connect

    di Luccio, E.; Wilson, D.K.

    2009-05-14

    Quinolinic acid phosphoribosyl transferase (QAPRTase, EC 2.4.2.19) is a 32 kDa enzyme encoded by the BNA6 gene in yeast and catalyzes the formation of nicotinate mononucleotide from quinolinate and 5-phosphoribosyl-1-pyrophosphate (PRPP). QAPRTase plays a key role in the tryptophan degradation pathway via kynurenine, leading to the de novo biosynthesis of NAD{sup +} and clearing the neurotoxin quinolinate. To improve our understanding of the specificity of the eukaryotic enzyme and the course of events associated with catalysis, we have determined the crystal structures of the apo and singly bound forms with the substrates quinolinate and PRPP. This reveals that the enzyme folds in a manner similar to that of various prokaryotic forms which are {approx}30% identical in sequence. In addition, the structure of the Michaelis complex is approximated by PRPP and the quinolinate analogue phthalate bound to the active site. These results allow insight into the kinetic mechanism of QAPRTase and provide an understanding of structural diversity in the active site of the Saccharomyces cerevisiae enzyme when compared to prokaryotic homologues.

  7. Agonist-induced production of 1,2-diacylglycerol and phosphatidic acid in intact resistance arteries. Evidence that accumulation of diacylglycerol is not a prerequisite for contraction.

    PubMed

    Ohanian, J; Ollerenshaw, J; Collins, P; Heagerty, A

    1990-05-25

    The production of total amounts of 1,2-diacylglycerol as well as those specifically derived from inositol lipid hydrolysis was studied in intact rat resistance arteries stimulated with either noradrenaline, vasopressin, or angiotensin II at 20 s when the onset of contraction would be nearing its maximum, and at 5 min during the sustained phase of contraction. Total amounts of 1,2-diacylglycerol were not altered by any agonist at 20 s, or at 5 min. However, arachidonate-containing species of 1,2-diacylglycerol were differentially influenced being increased at 5 min by noradrenaline, and decreased at 20 s and 5 min by vasopressin. Only angiotensin II produced substantial increases in this class of 1,2-diacylglycerol at both time points. In order to investigate the fate of this second messenger total and inositol lipid derived phosphatidic acids were then measured at both 20 s and 5 min. Noradrenaline induced a rise in both total and arachidonate-containing phosphatidic acid at both times as did vasopressin. Only small increases were induced by angiotensin II at 20 s. These data demonstrate that the accumulation of 1,2-diacylglycerol generated from inositol lipid breakdown is only observed with activation by angiotensin II. Other agonists produced phosphatidic acids with time and the rate of generation of these lipids is agonist-specific. Thus phosphatidic acid may play a more prominent role during the sustained phase of contraction than previously anticipated.

  8. Substituted quinoline quinones as surrogates for the PQQ cofactor: an electrochemical and computational study.

    PubMed

    Dorfner, Walter L; Carroll, Patrick J; Schelter, Eric J

    2015-04-17

    Pyrroloquinoline quinones (PQQ) are important cofactors that shuttle redox equivalents in diverse metalloproteins. Quinoline 7,8-quinones have been synthesized and characterized as surrogates for PQQ to elucidate redox energetics within metalloenzyme active sites. The quinoline 7,8-quinones were accessed using polymer-supported iodoxybenzoic acid and the compounds evaluated using solution electrochemistry. Together with a family of quinones, the products were evaluated computationally and used to generate a predictive correlation between a computed ΔG and the experimental reduction potentials.

  9. Structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: potential impact in diabetes.

    PubMed

    Genet, Cédric; Strehle, Axelle; Schmidt, Céline; Boudjelal, Geoffrey; Lobstein, Annelise; Schoonjans, Kristina; Souchet, Michel; Auwerx, Johan; Saladin, Régis; Wagner, Alain

    2010-01-14

    We describe here the biological screening of a collection of natural occurring triterpenoids against the G protein-coupled receptor TGR5, known to be activated by bile acids and which mediates some important cell functions. This work revealed that betulinic (1), oleanolic (2), and ursolic acid (3) exhibited TGR5 agonist activity in a selective manner compared to bile acids, which also activated FXR, the nuclear bile acid receptor. The most potent natural triterpenoid betulinic acid was chosen as a reference compound for an SAR study. Hemisyntheses were performed on the betulinic acid scaffold, and we focused on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. In particular, structural variations around the C-3 position gave rise to major improvements of potency exemplified with derivatives 18 dia 2 (RG-239) and 19 dia 2. The best derivative was tested in vitro and in vivo, and its biological profile is discussed.

  10. Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease.

    PubMed

    Halilbasic, Emina; Fuchs, Claudia; Traussnigg, Stefan; Trauner, Michael

    2016-01-01

    The intracellular nuclear receptor farnesoid X receptor (FXR) and the transmembrane G protein-coupled receptor 5 (TGR5) respond to bile acids (BAs) by activating transcriptional networks and/or signaling cascades. These cascades affect the expression of a great number of target genes relevant for BA, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. FXR activation in the liver tissue and beyond, such as the gut-liver axis, kidney and adipose tissue, plays a role in metabolic diseases. These BA receptors activators hold promise to become a new class of drugs to be used in the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This review discusses the relevant BA receptors, the new drugs that target BA transport and signaling and their possible applications. PMID:27332721

  11. Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain.

    PubMed

    Rangel-López, E; Colín-González, A L; Paz-Loyola, A L; Pinzón, E; Torres, I; Serratos, I N; Castellanos, P; Wajner, M; Souza, D O; Santamaría, A

    2015-01-29

    The endocannabinoid system (ECS) is involved in a considerable number of physiological processes in the Central Nervous System. Recently, a modulatory role of cannabinoid receptors (CBr) and CBr agonists on the reduction of the N-methyl-d-aspartate receptor (NMDAr) activation has been demonstrated. Quinolinic acid (QUIN), an endogenous analog of glutamate and excitotoxic metabolite produced in the kynurenine pathway (KP), selectively activates NMDAr and has been shown to participate in different neurodegenerative disorders. Since the early pattern of toxicity exerted by this metabolite is relevant to explain the extent of damage that it can produce in the brain, in this work we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) and other agonists (anandamide or AEA, and CP 55,940 or CP) on early markers of QUIN-induced toxicity in rat striatal cultured cells and rat brain synaptosomes. WIN, AEA and CP exerted protective effects on the QUIN-induced loss of cell viability. WIN also preserved the immunofluorescent signals for neurons and CBr labeling that were decreased by QUIN. The QUIN-induced early mitochondrial dysfunction, lipid peroxidation and reactive oxygen species (ROS) formation were also partially or completely prevented by WIN pretreatment, but not when this CBr agonist was added simultaneously with QUIN to brain synaptosomes. These findings support a neuroprotective and modulatory role of cannabinoids in the early toxic events elicited by agents inducing excitotoxic processes.

  12. 40 CFR 721.9080 - Nitro methyl quinoline.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Nitro methyl quinoline. 721.9080... Substances § 721.9080 Nitro methyl quinoline. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as nitro methyl quinoline (PMN P-96-1319)...

  13. 40 CFR 721.9080 - Nitro methyl quinoline.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Nitro methyl quinoline. 721.9080... Substances § 721.9080 Nitro methyl quinoline. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as nitro methyl quinoline (PMN P-96-1319)...

  14. Poly (γ-glutamic acid) based combination of water-insoluble paclitaxel and TLR7 agonist for chemo-immunotherapy.

    PubMed

    Seth, Anushree; Heo, Min Beom; Lim, Yong Taik

    2014-09-01

    Advanced anti-cancer regimens are being introduced for more effective cancer treatment with improved life expectancy. In this research, immuno-stimulating agent toll-like receptor-7 (TLR-7) agonist-imiquimod and low dose chemotherapeutic agent-paclitaxel were synergized to demonstrate tumor therapy along with anti-tumor memory effect. Both therapeutic agents being water insoluble were dispersed in water with the help of water soluble polymer: poly (γ-glutamic acid) (γ-PGA) using a co-solvent systems leading to formation of micro-dispersions of drugs. Paclitaxel and imiquimod formed crystalline microstructures in the size range of 2-3 μm and were stably dispersed in γ-PGA matrix for more than 6 months. Paclitaxel and combination of paclitaxel and imiquimod had significant tumor killing effect in-vitro on various tumor cell lines, while antigen presenting cells (dendritic cells-DCs) treated with the same concentration of imiquimod along with the combination led to enhanced proliferation (250%). In DCs, enhanced secretion of pro-inflammatory and Th1 cytokines was observed in cells co-treated with paclitaxel and imiquimod dispersed in γ-PGA. When administered by intra-tumoral injection in mouse melanoma tumor model, the treatment with combination exemplified drastic inhibition of tumor growth leading to 70% survival as compared to individual components with 0% survival at day 41. The anti-tumor response generated was also found to have systemic memory response since the vaccinated mice significantly deferred secondary tumor development at distant site 6 weeks after treatment. The relative number and activation status of DCs in-vivo was found to be dramatically increased in case of mice treated with combination. The dramatic inhibition of tumor treated with combination is expected to be mediated by both chemotherapeutic killing of tumor cells followed by uptake of released antigen by the DCs and due to enhanced proliferation and activation of the DCs.

  15. Effects of abomasal infusion of nicotinic acid on responses to glucose and β-agonist challenges in underfed lactating cows.

    PubMed

    Pires, J A A; Stumpf, L F; Soutullo, I D; Pescara, J B; Stocks, S E; Grummer, R R

    2016-03-01

    The objectives were to assess the use of nicotinic acid (NA) to chronically (i.e., 74 h) manipulate plasma nonesterified fatty acid (NEFA) concentrations in partially feed-restricted lactating cows, determine whether the reduction of plasma NEFA altered responses to i.v. glucose tolerance test (ivGTT) and whether NA would attenuate an acute lipolytic stimuli of a β-agonist challenge (ivBAC). Eight lactating dairy cows [244 ± 31 d in milk; 696 ± 63 kg of body weight (BW)] were blocked by breed and body condition score (3.2 ± 0.4) and randomly assigned to a sequence of 2 treatments in a crossover design. Treatments were 74-h continuous abomasal infusion of NA solution (3mg/h per kg of BW) as an antilipolytic agent to decrease plasma NEFA concentrations or the same volume of water (200 mL/h), concomitant with partial feed restriction. From 0 to 74 h of each experimental period, cows were feed-restricted to 33% of the ad libitum intake recorded during the prior 5 d. An ivGTT (0.25 g/kg of BW of glucose i.v.) and an ivBAC (4 nmol/kg of BW of isoproterenol hydrochloride, i.v.) were performed at 48 and 72 h, respectively. Intake was 24.1, 8.2, 8.0, and 8.0 kg of dry matter/d before restriction, on d 1, 2 and 3, respectively. Nicotinic acid decreased plasma NEFA and increased insulin and glucose concentrations during feed restriction. Nicotinic acid also led to greater glucose and insulin response areas under the curve during ivGTT [glucose: 6,562 vs. 5,056 (mg/dL) × 180 min; insulin: 6,042 vs. 2,502 (µIU/mL) × 180 min] and ivBAC [glucose: 535 vs. 240 (mg/dL) × 120 min; insulin: 1,283 vs. 222 (µIU/mL) × 120 min], and enhanced NEFA area under the curve during ivBAC [45,521 vs. 22,862 (µEq/L) × 120 min]. Milk, fat, and protein yields (29.1, 1.2, and 0.93 kg on d -2, respectively) decreased to 17.9, 0.81, and 0.56 kg for control, and 11.5, 0.54, and 0.39 kg for NA on d 3, respectively. Nicotinic acid may have decreased production by inhibiting the supply of NEFA

  16. Identification of potent 11mer glucagon-like peptide-1 receptor agonist peptides with novel C-terminal amino acids: Homohomophenylalanine analogs.

    PubMed

    Haque, Tasir S; Lee, Ving G; Riexinger, Douglas; Lei, Ming; Malmstrom, Sarah; Xin, Li; Han, Songping; Mapelli, Claudio; Cooper, Christopher B; Zhang, Ge; Ewing, William R; Krupinski, John

    2010-05-01

    We report the identification of potent agonists of the Glucagon-Like Peptide-1 Receptor (GLP-1R). These compounds are short, 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of homohomophenylalanine (hhPhe) at the C-terminal position. Typically the functional activity of the more potent peptides in this class is in the low picomolar range in an in vitro cAMP assay, with one example demonstrating excellent in vivo activity in an ob/ob mouse model of diabetes.

  17. An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor β (RARβ, NR1B2) Selective Agonist

    PubMed Central

    Delfosse, Vanessa; Vivat, Valérie; Krishnasamy, Gunasekaran; Gronemeyer, Hinrich; Bourguet, William; Germain, Pierre

    2015-01-01

    Retinoic acid is an important regulator of cell differentiation which plays major roles in embryonic development and tissue remodeling. The biological action of retinoic acid is mediated by three nuclear receptors denoted RARα, β and γ. Multiple studies support that RARβ possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RARβ could also play a role in mammary gland tumorigenesis, thus demonstrating the important but yet incompletely understood function of this receptor in cancer development. As a consequence, there is a great need for RARβ-selective agonists and antagonists as tools to facilitate the pharmacological analysis of this protein in vitro and in vivo as well as for potential therapeutic interventions. Here we provide experimental evidences that the novel synthetic retinoid BMS948 is an RARβ-selective ligand exhibiting a full transcriptional agonistic activity and activating RARβ as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RARβ ligand-binding domain in complex with BMS948 and two related compounds, BMS641 and BMS411. These structures provided a rationale to explain how a single retinoid can be at the same time an RARα antagonist and an RARβ full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180° of the amide linker, that usually confers RARα selectivity, accounts for the RARβ selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RARβ-selective antagonists. PMID:25933005

  18. Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

    SciTech Connect

    Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Mills, Wendy Y.; Navas, III, Frank; Parks, Derek J.; Smalley, Jr., Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2014-08-13

    To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.

  19. Exploring amino acids derivatives as potent, selective, and direct agonists of sphingosine-1-phosphate receptor subtype-1.

    PubMed

    Evindar, Ghotas; Deng, Hongfeng; Bernier, Sylvie G; Doyle, Elisabeth; Lorusso, Jeanine; Morgan, Barry A; Westlin, William F

    2013-01-15

    In the quest to discover a potent and selective class of direct agonists to the sphingosine-1-phosphate receptor, we explored the carboxylate functional group as a replacement to previously reported lead phosphates. This has led to the discovery of potent and selective direct agonists with moderate to substantial in vivo lymphopenia. The previously reported selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) in the phenylamide and phenylimidazole scaffolds were crucial to obtaining selectivity for S1P receptor subtype 1 over 3. PMID:23245510

  20. Novel potent and selective bile acid derivatives as TGR5 agonists: biological screening, structure-activity relationships, and molecular modeling studies.

    PubMed

    Sato, Hiroyuki; Macchiarulo, Antonio; Thomas, Charles; Gioiello, Antimo; Une, Mizuho; Hofmann, Alan F; Saladin, Régis; Schoonjans, Kristina; Pellicciari, Roberto; Auwerx, Johan

    2008-03-27

    TGR5, a metabotropic receptor that is G-protein-coupled to the induction of adenylate cyclase, has been recognized as the molecular link connecting bile acids to the control of energy and glucose homeostasis. With the aim of disclosing novel selective modulators of this receptor and at the same time clarifying the molecular basis of TGR5 activation, we report herein the biological screening of a collection of natural occurring bile acids, bile acid derivatives, and some steroid hormones, which has resulted in the discovery of new potent and selective TGR5 ligands. Biological results of the tested collection of compounds were used to extend the structure-activity relationships of TGR5 agonists and to develop a binary classification model of TGR5 activity. This model in particular could unveil some hidden properties shared by the molecular shape of bile acids and steroid hormones that are relevant to TGR5 activation and may hence be used to address the design of novel selective and potent TGR5 agonists.

  1. Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists

    PubMed Central

    Ang, Zhiwei; Er, Jun Zhi; Tan, Nguan Soon; Lu, Jinhua; Liou, Yih-Cherng; Grosse, Johannes; Ding, Jeak Ling

    2016-01-01

    Knockout mice studies implicate the mammalian short-chain fatty acid (SCFA) receptors, FFAR2 and FFAR3– in colitis, arthritis and asthma. However, the correlation with human biology is uncertain. Here, we detected FFAR2 and FFAR3 expression in human monocytes via immunohistochemistry. Upon treatment with acetate SCFA or FFAR2- and FFAR3-specific synthetic agonists, human monocytes displayed elevated p38 phosphorylation and attenuated C5, CCL1, CCL2, GM-CSF, IL-1α, IL-1β and ICAM-1 inflammatory cytokine expression. Acetate and FFAR2 agonist treatment also repressed Akt and ERK2 signalling. Surprisingly, mouse monocytes displayed a distinct response to acetate treatment, elevating GM-CSF, IL-1α, and IL-1β cytokine expression. This effect persisted in FFAR2/3-knockout mouse monocytes and was not reproduced by synthetic agonists, suggesting a FFAR2/3 independent mechanism in mice. Collectively, we show that SCFAs act via FFAR2/3 to modulate human monocyte inflammatory responses– a pathway that is absent in mouse monocytes. PMID:27667443

  2. Effects of the peroxisome proliferator-activated receptor-alpha agonists clofibrate and fish oil on hepatic fatty acid metabolism in weaned dairy calves.

    PubMed

    Litherland, N B; Bionaz, M; Wallace, R L; Loor, J J; Drackley, J K

    2010-06-01

    Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists increase fatty acid oxidation in liver of nonruminants. If similar effects occur in dairy cattle, enhanced hepatic oxidative capacity could decrease circulating nonesterified fatty acids and hepatic triacylglycerol accumulation in periparturient cows. The objectives of this study were 1) to determine whether partitioning of fatty acid metabolism by liver slices from weaned Holstein calves treated with PPARalpha agonists in vivo is altered compared with partitioning by liver slices from control (untreated) calves, and 2) to measure in vitro metabolism of palmitate and oleate by bovine liver slices and relate these to mRNA abundance for key enzymes. Weaned male Holstein calves (7 wk old; n=15) were assigned to 1 of 3 groups for a 5-d treatment period: control (untreated), clofibrate (62.5 mg/kg of BW), or fish oil (250 mg/kg of BW). Calves treated with clofibrate consumed less dry matter. Body weight, liver weight, liver weight:body weight ratio, blood nonesterified fatty acids, beta-hydroxybutyrate, and liver composition were not significantly different among treatments. Liver slices were incubated for 2, 4, and 8 h to determine in vitro conversion of [1-(14)C] palmitate and [1-(14)C] oleate to CO(2), acid-soluble products, esterified products, and total metabolism. In liver slices incubated for 8 h, conversion of palmitate to CO(2) was greater for calves treated with clofibrate compared with control calves or calves treated with fish oil. Conversion of palmitate to esterified products, total palmitate metabolism, and metabolism of oleate were not different among treatments. Conversion of palmitate to CO(2) was greater than that from oleate for all treatments, but rates of total metabolism did not differ. Clofibrate increased or tended to increase liver expression of several PPARalpha target genes involved in fatty acid oxidation (e.g., ACADVL, ACOX1, CPT1A), whereas fish oil did not significantly

  3. Synthesis and evaluation of (E)-2-(acrylamido)cyclohex-1-enecarboxylic acid derivatives as HCA1, HCA2, and HCA3 receptor agonists.

    PubMed

    Bobileva, Olga; Bokaldere, Rasma; Gailite, Vija; Kaula, Ilze; Ikaunieks, Martins; Duburs, Gunars; Petrovska, Ramona; Mandrika, Ilona; Klovins, Janis; Loza, Einars

    2014-07-15

    2-(3-(Naphthalen-2-yl)propanamido)cyclohex-1-enecarboxylic acid and its 6-hydroxynaphthalen-2-yl analogue are well-known hydroxyl-carboxylic acid (HCA) receptor HCA2 agonists. A series of novel aryl derivatives of 2-amidocyclohex-1-ene carboxylic acid that contained rigidity elements, such as an E-double bond, triple bond, and trans or cis-substituted cyclopropane rings, instead of the saturated ethane linker in the amide part of the molecules were designed and synthesized, and the derivatives' potency for the activation of HCA1, HCA2, and HCA3 receptors by 3'-5'-cyclic adenosine monophosphate (cAMP) assay were evaluated. The SAR studies revealed that the rigidifying of appropriate molecules enabled modulation of the potency and selectivity of the HCA2 receptor activation.

  4. Microbial degradation of quinoline and methylquinolines. [Pseudomonas aeruginosa

    SciTech Connect

    Aislabie, J.; Bej, A.K.; Hurst, H.; Rothenburger, S.; Atlas, R.M. )

    1990-02-01

    Several bacterial cultures were isolated that are able to degrade quinoline and to transform or to degrade methylquinolines. The degradation of quinoline by strains of Pseudomonas aeruginosa QP and Pseudomonas. putida QP produced hydroxyquinolines, a transient pink compound, and other undetermined products. The quinoline-degrading strains of P. aeruginosa QP and P. putida QP hydroxylated a limited number of methylquinolines but could not degrade them, nor could they transform 2-methylquinoline, isoquinoline, or pyridine. Another pseudomonad, Pseudomonas sp. strain MQP, was isolated that could degrade 2-methylquinoline. P. aeruginosa QP was able to degrade or to transform quinoline and a few methylquinolines in a complex heterocyclic nitrogen-containing fraction of a shale oil. All of the quinoline- and methylquinoline-degrading strains have multiple plasmids including a common 250-kilobase plasmid. The 225-, 250-, and 320-kilobase plasmids of the P. aeruginosa QP strain all contained genes involved in quinoline metabolism.

  5. Rh(I)-Catalyzed Direct Arylation of Pyridines and Quinolines

    SciTech Connect

    Berman, Ashley; Lewis, Jared; Bergman, Robert; Ellman, Jonathan

    2008-07-29

    additive proved even more effective, with the yield of 1a improving to 61% (entry 2). Further enhancement in yield was not observed upon the inclusion of other additives such as MgO (entry 3), various organic bases (entries 4, 5), or a protic acid source (entry 6). Absolute concentration proved very important, with the best results being obtained at relatively high concentrations of the aryl bromide (compare entries 7 and 8). A marginal improvement was observed upon running the reaction with 6 equivalents of 2-methyl pyridine (entry 9). The reaction temperature could also be increased to 175 or 190 C while maintaining reaction yield, to enable the reaction time to be reduced to 24 h (entries 10 and 11). In summary, we have developed a Rh(I)-catalyzed strategy for the direct arylation of pyridines and quinolines. The heterocycle is used without the need for prefunctionalization, and all reaction components are inexpensive and readily available. The strategy represents an expeditious route to an important class of bis(hetero)aryls and should be of broad utility.

  6. A novel electrochemical sensor for the analysis of β-agonists: the poly(acid chrome blue K)/graphene oxide-nafion/glassy carbon electrode.

    PubMed

    Lin, Xiaoyun; Ni, Yongnian; Kokot, Serge

    2013-09-15

    A novel modified electrode was constructed by the electro-polymerization of 4,5-dihydroxy-3-[(2-hydroxy-5-sulfophenyl)azo]-2,7-naphthalenedisulfonic acid trisodium salt (acid chrome blue K (ACBK)) at a graphene oxide (GO)-nafion modified glassy carbon electrode (GCE). The characterization of an electrochemically synthesized poly-ACBK/GO-nafion film was investigated by electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), atomic force microscopy (AFM) and scanning electron microscopy (SEM) techniques, and the results were interpreted and compared at each stage of the electrode construction. Electrochemical oxidation of eight β-agonists - clenbuterol, salbutamol, terbutaline, ractopamine, dopamine, dobutamine, adrenaline, and isoprenaline, was investigated by CV at the different electrodes. At the poly-ACBK/GO-nafion/GCE, the linear sweep voltammetry peak currents of the eight β-agonists increased linearly with their concentrations in the range of 1.0-36.0 ng mL(-1), respectively, and their corresponding limits of detection (LODs) were within the 0.58-1.46 ng mL(-1) range. This electrode showed satisfactory reproducibility and stability, and was used successfully for the quantitative analysis of clenbuterol in pork samples.

  7. Synthesis of 5-iodopyrrolo[1,2-a]quinolines and indolo[1,2-a]quinolines via iodine-mediated electrophilic and regioselective 6-endo-dig ring closure.

    PubMed

    Verma, Akhilesh Kumar; Shukla, Satya Prakash; Singh, Jaspal; Rustagi, Vineeta

    2011-07-15

    The endo-cyclic ring closure of 1-(2-(substituted ethynyl)phenyl)-1H-pyrroles 3a-t and 1-(2-(substituted ethynyl)phenyl)-H-indole 4a-o mediated by Lewis acid (I(2)) under mild conditions afforded substituted 5-iodopyrrolo[1,2-a]quinolines 5a-t and 5-iodoindolo[1,2-a]quinolines 6a-o in good to excellent yields. The reaction shows selective C-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-cyclized product. Iodo derivatives of pyrrolo- and indoloquinolines allow functional group diversification on the quinoline nucleus, which proves to be highly advantageous for structural and biological activity assessments.

  8. Retinoic acid receptor agonist Am80 inhibits CXCL2 production from microglial BV-2 cells via attenuation of NF-κB signaling.

    PubMed

    Takaoka, Yuichiro; Takahashi, Moeka; Kurauchi, Yuki; Hisatsune, Akinori; Seki, Takahiro; Shudo, Koichi; Katsuki, Hiroshi

    2016-09-01

    Accumulating lines of evidence suggest that retinoic acid receptor agonists such as Am80 exerts anti-inflammatory actions in the central nervous system, although detailed mechanisms of the action remain largely unknown. Our previous findings suggest that Am80 provides therapeutic effect on intracerebral hemorrhage in mice via suppression of expression of chemokine (C-X-C motif) ligand 2 (CXCL2). Here we investigated the mechanisms of inhibitory action of Am80 on expression of CXCL2 and other pro-inflammatory factors in microglial BV-2 cells. Pretreatment with Am80 markedly suppressed lipopolysaccharide (LPS)-induced expression of CXCL2 mRNA and release of CXCL2 protein. Am80 had no effect on LPS-induced activation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. On the other hand, Am80 prevented LPS-induced nuclear translocation of p65 subunit of NF-κB complex. In addition, total expression levels of p65 and IκBα proteins, as well as of mRNAs encoding p65 and IκBα, were lowered by Am80. Dependence of CXCL2 expression on NF-κB was confirmed by the effect of an NF-κB inhibitor caffeic acid phenethyl ester that abolished LPS-induced CXCL2 expression. Caffeic acid phenethyl ester also abolished LPS-induced expression of inducible nitric oxide synthase, interleukin-1β and tumor necrosis factor α, which may be relevant to the inhibitory effect of Am80 on expression of these pro-inflammatory factors. We additionally found that Am80 attenuated LPS-induced up-regulation of CD14, a co-receptor for Toll-like receptor 4 (TLR4). These results suggest that inhibitory effect on TLR4 signaling mediated by NF-κB pathway underlies the anti-inflammatory action of retinoic acid receptor agonists in microglia. PMID:27351827

  9. Quinolines derivatives as novel sunscreening agents.

    PubMed

    Polonini, Hudson C; Dias, Rafael M P; Souza, Isabela O; Gonçalves, Karla Mara; Gomes, Tiago B B; Raposo, Nádia R B; da Silva, Adilson David

    2013-08-15

    Currently, the research and development of sunscreens play an important role on the synthesis of actives that are stable in various kinds of formulations-in addition to their efficiency and broad spectrum of protection against ultraviolet radiation. Our objective here was to synthesize new sunscreening chemical agents using quinoline as a base molecule. Twelve quinoline derivatives were synthesized, four of them novel molecules, and their photoprotective activity was determined in vitro using diffuse transmittance spectrophotometry. We determined their SPF, UVAPF, UVA/UVB ratio, critical wavelength and Boots Star Rating. The quinolines derivatives presented a varied profile of photoprotection, their SPF ranging from 2 to 11 and their UVAPF from 2 to 7. In terms of the critical wavelength, all molecules were considered of broad-spectrum by different classifications. Regarding the Boots Star Rating, one compound received no rating, seven of them received a three stars rating, three received a four stars rating and three were given a five stars rating. The molecules showed in the present work have a wide range of possibilities for creating new sunscreen products, once they have good SPF or UVAPF for single molecules, and they also possess other different qualities that can act synergistically.

  10. Metal free carboamination of internal alkynes--an easy access to polysubstituted quinolines.

    PubMed

    Stopka, T; Niggemann, M

    2016-04-28

    A metal free carboamination of unactivated alkynes towards highly substituted quinolines was realized in the presence of a synergistic Brønsted acid catalyst system. Supported by mechanistic probes, the reaction proceeds via a highly reactive vinyl cation in a C-C bond formation--Schmidt reaction sequence. The irreversible extrusion of N2, as a powerful driving force, allows for a general conversion of poorly nucleophilic aliphatic alkynes. PMID:27049140

  11. TLR Agonist Augments Prophylactic Potential of Acid Inducible Antigen Rv3203 against Mycobacterium tuberculosis H37Rv in Experimental Animals

    PubMed Central

    Faisal, Syed Mohd; Azhar, Asim; Rauf, Mohd Ahmar; Gupta, Umesh Dutt; Gupta, Pushpa; Pal, Rahul; Zubair, Swaleha

    2016-01-01

    In general, the members of Lip gene family of Mycobacterium tuberculosis evoke strong immune response in the host. Keeping this fact into consideration, we investigated role of Rv3203, a cell wall associated protein with lipolytic activity, in imparting protection against experimental murine tuberculosis. The data of the present study suggested that archaeosome encapsulated Rv3203 induce strong lymphocyte proliferation, up-regulated Th-1 biased cytokines profile, increased expression of co-stimulatory markers on both antigen presenting cells and T lymphocytes. The immuno-prophylactic response was further modulated by exposure of the animals to zymosan, a TLR2/6 agonist, prior to immunization with archaeosome encapsulated Rv3203. Interestingly, pre-treatment of experimental animals with zymosan boosted strong immunological memory as compared to archaeosome encapsulated Rv3203 as well as BCG vaccine. We conclude that priming of immunized animal with TLR agonist followed by immunization with archaeosomes encapsulated Rv3203 offer substantial protection against tuberculosis infection and could be a potential subunit vaccine based prophylactic strategy. PMID:27023750

  12. TLR Agonist Augments Prophylactic Potential of Acid Inducible Antigen Rv3203 against Mycobacterium tuberculosis H37Rv in Experimental Animals.

    PubMed

    Mohammad, Owais; Kaur, Jagdeep; Singh, Gurpreet; Faisal, Syed Mohd; Azhar, Asim; Rauf, Mohd Ahmar; Gupta, Umesh Dutt; Gupta, Pushpa; Pal, Rahul; Zubair, Swaleha

    2016-01-01

    In general, the members of Lip gene family of Mycobacterium tuberculosis evoke strong immune response in the host. Keeping this fact into consideration, we investigated role of Rv3203, a cell wall associated protein with lipolytic activity, in imparting protection against experimental murine tuberculosis. The data of the present study suggested that archaeosome encapsulated Rv3203 induce strong lymphocyte proliferation, up-regulated Th-1 biased cytokines profile, increased expression of co-stimulatory markers on both antigen presenting cells and T lymphocytes. The immuno-prophylactic response was further modulated by exposure of the animals to zymosan, a TLR2/6 agonist, prior to immunization with archaeosome encapsulated Rv3203. Interestingly, pre-treatment of experimental animals with zymosan boosted strong immunological memory as compared to archaeosome encapsulated Rv3203 as well as BCG vaccine. We conclude that priming of immunized animal with TLR agonist followed by immunization with archaeosomes encapsulated Rv3203 offer substantial protection against tuberculosis infection and could be a potential subunit vaccine based prophylactic strategy. PMID:27023750

  13. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure.

    PubMed

    Watanabe, Mitsuhiro; Horai, Yasushi; Houten, Sander M; Morimoto, Kohkichi; Sugizaki, Taichi; Arita, Eri; Mataki, Chikage; Sato, Hiroyuki; Tanigawara, Yusuke; Schoonjans, Kristina; Itoh, Hiroshi; Auwerx, Johan

    2011-07-29

    We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.

  14. Hydrodenitrogenation of quinoline over carbon-supported transition metal sulfides

    SciTech Connect

    Eijsbouts, S.; De Beer, V.H.J.; Prins, R. )

    1991-02-01

    Transition metal sulfide (TMS) catalysts were prepared by impregnation of an activated carbon support with aqueous solutions of first-, second-, and third-row (group V-VIII) transition metal salts, drying and in situ sulfidation. The catalysts were tested in the hydrodenitrogenation of quinoline (653 K, 5.5 MPa) in microautoclaves and microflow reactors. The first-row transition metal sulfides had low quinoline conversions to hydrocarbons, and their periodic trend formed a U-shaped curve with a minimum at Mn/C and Fe/C and maxima at V/C and Ni/C. The quinoline conversions to hydrocarbons of the second- and third-row TMS formed volcano curves with maxima at Rh/C and Ir/C and with Mo/C and W/C having the lowest conversions. The transition metal sulfide catalysts with a low quinoline hydrogenation (first-row transition metal sulfides, Mo/C and W/C) also had a low quinoline conversion to hydrocarbons. The transition metal sulfides with the highest quinoline conversions to hydrocarbons (Rh/C, Pd/C, Os/C, Ir/C and Pt/C) had a very highquinoline hydrogenation and a high selectivity for propylcyclohexane. Ru/C and especially Re/C had a good quinoline conversion to hydrocarbons, but also an exceptionally high selectivity for propylbenzene.

  15. Discovery of 3-arylpropionic acids as potent agonists of sphingosine-1-phosphate receptor-1 (S1P1) with high selectivity against all other known S1P receptor subtypes.

    PubMed

    Yan, Lin; Huo, Pei; Doherty, George; Toth, Lesile; Hale, Jeffrey J; Mills, Sander G; Hajdu, Richard; Keohane, Carol A; Rosenbach, Mark J; Milligan, James A; Shei, Gan-Ju; Chrebet, Gary; Bergstrom, James; Card, Deborah; Quackenbush, Elizabeth; Wickham, Alexandra; Mandala, Suzanne M

    2006-07-15

    A series of 3-arylpropionic acids were synthesized as S1P1 receptor agonists. Structure-activity relationship studies on the pendant phenyl ring revealed several structural features offering selectivity of S1P1 binding against S1P2-5. These highly selective S1P1 agonists induced peripheral blood lymphocyte lowering in mice and one of them was found to be efficacious in a rat skin transplantation model, supporting that S1P1 agonism is primarily responsible for the immunosuppressive efficacy observed in preclinical animal models.

  16. The β2-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity.

    PubMed

    Gleeson, Lorna C; Ryan, Katie J; Griffin, Eadaoin W; Connor, Thomas J; Harkin, Andrew

    2010-11-01

    Excitotoxicity is a mechanism of neuronal cell death implicated in a range of neurodegenerative conditions. Systemic administration of the excitotoxin kainic acid (KA) induces inflammation and apoptosis in the hippocampus, resulting in neuronal loss. Evidence indicates that stimulation of glial β(2)-adrenoceptors has anti-inflammatory and neurotrophic properties that could result in neuroprotection. Consequently, in this study we examined the effect of the β(2)-adrenoceptor agonist clenbuterol on KA-induced inflammation, neurotrophic factor expression and apoptosis in the hippocampus. Clenbuterol (0.5mg/kg) was administered to rats one hour prior to KA (10mg/kg). Epileptic behaviour induced by KA was assessed for three hours following administration using the Racine scale. Twenty-four hours later TUNEL staining in the CA3 hippocampal subfield and hippocampal caspase-3 activity was assessed to measure KA-induced apoptosis. In addition, expression of inflammatory cytokines (IL-1β and IFN-γ), inducible nitric oxide synthase (iNOS), kynurenine pathway enzymes indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO), the microglial activation marker CD11b, and the neurotrophins BDNF and NGF were quantified in the hippocampus using real-time PCR. Whilst clenbuterol treatment did not significantly alter KA-induced epileptic behavior it ameliorated KA-induced apoptosis, and this neuroprotective effect was accompanied by reduced inflammatory cytokine expression, reduced expression of iNOS, IDO, KMO and CD11b, coupled with increased BDNF and NGF expression in KA-treated rats. In conclusion, the β(2)-adrenoceptor agonist clenbuterol has anti-inflammatory and neurotrophic actions and elicits a neuroprotective effect in the KA model of neurodegeneration. PMID:20599496

  17. The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells

    PubMed Central

    Ching, Jared; Amiridis, Stephanie; Stylli, Stanley S.; Bjorksten, Andrew R.; Kountouri, Nicole; Zheng, Thomas; Paradiso, Lucy; Luwor, Rodney B.; Morokoff, Andrew P.; O'Brien, Terence J.; Kaye, Andrew H.

    2015-01-01

    Glioma cells release glutamate through expression of system xc−, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate. PMID:26046374

  18. Iron porphyrinate Fe(TPPS) reduces brain cell damage in rats intrastriatally lesioned by quinolinate.

    PubMed

    González-Cortés, Carolina; Salinas-Lara, Citlaltepetl; Gómez-López, Marcos Artemio; Tena-Suck, Martha Lilia; Pérez-De La Cruz, Verónica; Rembao-Bojórquez, Daniel; Pedraza-Chaverrí, José; Gómez-Ruiz, Celedonio; Galván-Arzate, Sonia; Ali, Syed F; Santamaría, Abel

    2008-01-01

    It has been recently demonstrated that the reactive nitrogen species (RNS) peroxynitrite (ONOO(-)) is involved in the neurotoxic pattern produced by quinolinic acid in the rat brain [V. Pérez-De La Cruz, C. González-Cortés, S. Galván-Arzate, O.N. Medina-Campos, F. Pérez-Severiano, S.F. Ali, J. Pedraza-Chaverrí, A. Santamaría, Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III), Neuroscience 135 (2005) 463-474.]. The aim of this work was to investigate whether ONOO(-) can also be responsible for morphological alterations and inflammatory events in the same paradigm. For this purpose, we evaluated the effect of a pre-treatment with the iron porphyrinate Fe(TPPS), a well-known ONOO(-) decomposition catalyst (10 mg/kg, i.p., 120 min before lesion), on the quinolinate-induced striatal cell damage and immunoreactivities to glial-fibrilar acidic protein (GFAP), interleukin 6 (IL-6) and inducible nitric oxide synthase (iNOS), one and seven days after the intrastriatal infusion of quinolinate (240 nmol/microl) to rats. The striatal tissue from animals lesioned by quinolinate showed a significant degree of damage and enhanced immunoreactivities to GFAP, IL-6 and iNOS, both at 1 and 7 days post-lesion. Pre-treatment of rats with Fe(TPPS) significantly attenuated or prevented all these markers at both post-lesion times tested, except for GFAP immunoreactivity at 7 days post-lesion and iNOS immunoreactivity at 1 day post-lesion. Altogether, our results suggest that ONOO(-) is actively participating in triggering inflammatory events and morphological alterations in the toxic model produced by quinolinate, since the use of agents affecting its formation, such as Fe(TPPS), are effective experimental tools to reduce the brain lesions associated to excitotoxic and oxidative damage.

  19. Metabolomics analysis reveals elevation of 3-indoxyl sulfate in plasma and brain during chemically-induced acute kidney injury in mice: Investigation of nicotinic acid receptor agonists

    SciTech Connect

    Zgoda-Pols, Joanna R.; Chowdhury, Swapan; Wirth, Mark; Milburn, Michael V.; Alexander, Danny C.; Alton, Kevin B.

    2011-08-15

    An investigative renal toxicity study using metabolomics was conducted with a potent nicotinic acid receptor (NAR) agonist, SCH 900424. Liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were used to identify small molecule biomarkers of acute kidney injury (AKI) that could aid in a better mechanistic understanding of SCH 900424-induced AKI in mice. The metabolomics study revealed 3-indoxyl sulfate (3IS) as a more sensitive marker of SCH 900424-induced renal toxicity than creatinine or urea. An LC-MS assay for quantitative determination of 3IS in mouse matrices was also developed. Following treatment with SCH 900424, 3IS levels were markedly increased in murine plasma and brain, thereby potentially contributing to renal- and central nervous system (CNS)-related rapid onset of toxicities. Furthermore, significant decrease in urinary excretion of 3IS in those animals due to compromised renal function may be associated with the elevation of 3IS in plasma and brain. These data suggest that 3IS has a potential to be a marker of renal and CNS toxicities during chemically-induced AKI in mice. In addition, based on the metabolomic analysis other statistically significant plasma markers including p-cresol-sulfate and tryptophan catabolites (kynurenate, kynurenine, 3-indole-lactate) might be of toxicological importance but have not been studied in detail. This comprehensive approach that includes untargeted metabolomic and targeted bioanalytical sample analyses could be used to investigate toxicity of other compounds that pose preclinical or clinical development challenges in a pharmaceutical discovery and development. - Research Highlights: > Nicotinic acid receptor agonist, SCH 900424, caused acute kidney injury in mice. > MS-based metabolomics was conducted to identify potential small molecule markers of renal toxicity. > 3-indoxyl-sulfate was found to be as a more sensitive marker of renal toxicity than creatinine

  20. Synthesis and in vitro antiproliferative activities of quinoline derivatives.

    PubMed

    Broch, Sidonie; Aboab, Bettina; Anizon, Fabrice; Moreau, Pascale

    2010-04-01

    The synthesis of new di- and trimeric quinoline derivatives is described as well as their in vitro antiproliferative activities toward a human fibroblast primary culture and two human solid cancer cell lines (MCF-7 and PA 1).

  1. Acid-induced sweetness of neoculin is ascribed to its pH-dependent agonistic-antagonistic interaction with human sweet taste receptor.

    PubMed

    Nakajima, Ken-ichiro; Morita, Yuji; Koizumi, Ayako; Asakura, Tomiko; Terada, Tohru; Ito, Keisuke; Shimizu-Ibuka, Akiko; Maruyama, Jun-ichi; Kitamoto, Katsuhiko; Misaka, Takumi; Abe, Keiko

    2008-07-01

    Neoculin (NCL) is a sweet protein that also has taste-modifying activity to convert sourness to sweetness. However, it has been unclear how NCL induces this unique sensation. Here we quantitatively evaluated the pH-dependent acid-induced sweetness of NCL using a cell-based assay system. The human sweet taste receptor, hT1R2-hT1R3, was functionally expressed in HEK293T cells together with G alpha protein. When NCL was applied to the cells under different pH conditions, it activated hT1R2-hT1R3 in a pH-dependent manner as the condition changed from pH 8 to 5. The pH-response sigmoidal curve resembled the imidazole titration curve, suggesting that His residues were involved in the taste-modifying activity. We then constructed an NCL variant in which all His residues were replaced with Ala and found that the variant elicited strong sweetness at neutral pH as well as at acidic pH. Since NCL and the variant elicited weak and strong sweetness at the same neutral pH, respectively, we applied different proportions of NCL-variant mixtures to the cells at this pH. As a result, NCL competitively inhibits the variant-induced receptor activation. All these data suggest that NCL acts as an hT1R2-hT1R3 agonist at acidic pH but functionally changes into its antagonist at neutral pH.

  2. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  3. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  4. Effects of bile acids and the bile acid receptor FXR agonist on the respiratory rhythm in the in vitro brainstem medulla slice of neonatal Sprague-Dawley rats.

    PubMed

    Zhao, Cong; Wang, Xianbao; Cong, Yuling; Deng, Yi; Xu, Yijun; Chen, Aihua; Yin, Yanru

    2014-01-01

    Intrahepatic cholestasis of pregnancy is always accompanied by adverse fetal outcomes such as malfunctions of respiration. Farnesoid X receptor (FXR) plays a critical role in the homeostasis of bile acids. Thus, we are determined to explore the effects of farnesoid X receptor (FXR) and five bile acids on respiratory rhythm generation and modulation of neonatal rats. Spontaneous periodic respiratory-related rhythmical discharge activity (RRDA) was recorded from hypoglossal nerves during the perfusion of modified Krebs solution. Group 1-6 was each given GW4064 and five bile acids of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), cholic acid (CA) as well as ursodeoxycholic acid (UDCA) at different concentrations to identify their specific functions on respiratory rhythm modulations. Group 7 was applied to receive FXR blocker Z-guggulsterone and Z-guggulsterone with the above bile acids separately to explore the role of FXR in the respiratory rhythm modulation. Group 8 was given dimethyl sulfoxide (DMSO) as controls. Apart from UDCA, CDCA, DCA LCA and CA all exerted effects on RRDA recorded from hypoglossal nerves in a concentration-dependent manner. Respiratory cycle (RC), Inspiratory time (TI), Expiratory Time (TE) and Integral Amplitude (IA) were influenced and such effects could be reversed by Z-guggulsterone. FXR may contribute to the effects on the modulation of respiratory rhythm exerted by bile acids.

  5. Differential neuroprotective effects of the NMDA receptor-associated glycine site partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and D-cycloserine in lithium-pilocarpine status epilepticus.

    PubMed

    Peterson, Steven L; Purvis, Rebecca S; Griffith, James W

    2004-09-01

    The status epilepticus (SE) induced in rats by lithium-pilocarpine (Li-pilo) shares many common features with soman-induced SE including a glutamatergic phase that is inhibited by NMDA antagonists. The present study determined whether 1-aminocyclopropanecarboxylic acid (ACPC) or D-cycloserine (DCS), both partial agonists of the strychnine-insensitive glycine site on the NMDA receptor ionophore complex, exerted anticonvulsant or neuroprotectant activity in Li-pilo SE. ACPC or DCS were administered either immediately following pilocarpine (exposure treatment) or 5 min after the onset of SE as determined by ECoG activity. SE was allowed to proceed for 3 h before termination with propofol. The rats were sacrificed 24 h following pilocarpine administration. Neither drug had an effect on the latency to seizure onset or the duration of seizure activity. ACPC administered 5 min after SE onset produced significant neuroprotection in cortical regions, amygdala and CA1 of the hippocampus. In contrast, when administered as exposure treatment ACPC enhanced the neural damage in the thalamus and CA3 of the hippocampus suggesting the neuropathology in those regions is mediated by a different subset of NMDA receptors. DCS had no neuroprotectant activity in Li-pilo SE but exacerbated neuronal damage in the thalamus. Neither drug affected the cholinergic convulsions but both had differential effects on neural damage. This suggests that the SE-induced seizure activity and subsequent neuronal damage involve independent mechanisms.

  6. Mechanism of the Skraup and Doebner-von Miller quinoline syntheses: Cyclization of. alpha. ,. beta. -unsaturated N-aryliminium salts via 1,3-dizaetidinium ion intermediates

    SciTech Connect

    Eisch, J.J.; Dluzniewski, T. )

    1989-03-17

    The hydrochlorides of cinnamaldehyde anils of the type ArCH=CHCH=NAr{prime}, where Ar and Ar{prime} are phenyl or p-tolyl groups, have been shown to react between 25{degree}C and 100{degree}C, in a toluene suspension or in a solution of DMSO or acetonitrile, to yield 2-substituted quinolines and N-cinnamylanilines ArCH=CHCH{sub 2}NHAr{prime}. The reaction proceeds under anhydrous conditions by cyclization of the anil hydrochlorides themselves to produce ultimately 2-substituted quinolines. The kinetics of the reaction follow a first-order dependence on the anil hydrochloride. Rapid exchange occurring between dissimilar anil hydrochlorides suggests that such anil metatheses take place by way of 1,3-diazetidinium ion intermediates, which previous studies have shown would possess the requisite metastability. The foregoing experimental observations are reconciled in terms of a novel mechanism for the formation of quinolines directly from anils under acidic conditions, namely, the reversible formation of diazetidinium ions and their irreversible cyclization to quinolines. It is proposed that this pathway is the operative mechanism in the classic Skraup and Doehner-von Miller quinoline syntheses. 28 refs., 2 tabs.

  7. Possible Role of Intestinal Fatty Acid Oxidation in the Eating-Inhibitory Effect of the PPAR-α Agonist Wy-14643 in High-Fat Diet Fed Rats

    PubMed Central

    Karimian Azari, Elnaz; Leitner, Claudia; Jaggi, Thomas; Langhans, Wolfgang; Mansouri, Abdelhak

    2013-01-01

    PPAR-α plays a key role in lipid metabolism; it enhances fatty acid oxidation (FAO) and ketogenesis. Pharmacological PPAR-α activation improves insulin sensitivity and reduces food intake, but its mechanisms of action remain unknown. We here report that intraperitoneal (IP) administration of the PPAR-α agonist Wy-14643 (40 mg/kg BW) reduced food intake in adult male rats fed a high-fat diet (HFD, 49% of the energy) mainly through an increase in the latency to eat after injection, and without inducing a conditioned taste avoidance. Also, IP administered Wy-14643 caused an acute (the first 60 min) decrease in the respiratory quotient (RQ) and an increase in hepatic portal vein β-hydroxybutyrate level (at 35 min) without affecting plasma non-esterified fatty acids. Given the known stimulatory effect of PPAR-α on FAO and ketogenesis, we measured the protein expression level of carnitine palmitoyltransferase-1 (CPT 1A) and mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMG-CoAS2), two key enzymes for FAO and ketogenesis, respectively, in liver, duodenum and jejunum. Wy-14643 induced a significant increase in the expression of CPT 1A in the jejunum and duodenum and of HMG-CoAS2 in the jejunum, but neither CPT 1A nor HMG-CoAS2 expression was increased in the liver. The induction of CPT 1A and HMG-CoAS2 expression was associated with a decrease in the lipid droplet content selectively in the jejunum. Our findings indicate that Wy-14643 stimulates FAO and ketogenesis in the intestine, in particular in the jejunum, rather than in the liver, thus supporting the hypothesis that PPAR-α activation inhibits eating by stimulating intestinal FAO. PMID:24069361

  8. Topographic probes of angiotensin and receptor: potent angiotensin II agonist containing diphenylalanine and long-acting antagonists containing biphenylalanine and 2-indan amino acid in position 8.

    PubMed

    Hsieh, K H; LaHann, T R; Speth, R C

    1989-04-01

    A series of phenylalanine-mimicking amino acids with increasing conformational restraint were prepared and incorporated into angiotensin II, in order to develop topographic probes of angiotensin useful for probing receptor boundaries by molecular graphics analysis and for conformational analysis of the ligand by NMR. In binding studies, all analogues displayed high affinity for rat uterus (Ki of 0.74-6.08 nM) and brain (0.46-1.82 nM) receptors. In smooth muscle (rat uterus) contraction assay, the diphenylalanine-containing [Sar1,Dip8]AII and [Sar1,D-Dip8]AII were potent agonists with respectively 284% and 48% activity of [Asn1]AII. In contrast, the biphenylalanine-containing [Sar1,Bip8]AII, [Sar1,D-Bip8]AII, and the 2-indan amino acid containing [Sar1,2-Ind8]AII were potent inhibitors, approximately 9, 2, and 1.4 times more effective than a standard antagonist, [Sar1,Leu8]AII. Their respective pA10 values in rat uterus assay were 8.87, 8.70, and 8.82. By comparison, the pA10 value for [Sar1,Leu8]AII was 8.35. In rats, a single dose of 10 micrograms of [Sar1,2-Ind8]AII or [Sar1,Bip8]AII produced prolonged blockade of the pressor response toward angiotensin II for over 90 min. The very different pharmacological profiles of these rigid aromatic analogues suggest that the angiotensin receptor activation site consists of a relatively wide and elongated pocket with a narrow opening.

  9. Synthesis of (iso)quinoline, (iso)coumarin and (iso)chromene derivatives from acetylene compounds

    NASA Astrophysics Data System (ADS)

    Ryabukhin, D. S.; Vasilyev, A. V.

    2016-06-01

    Published data on the methods of synthesis of quinoline, isoquinoline, coumarin, isocoumarin, chromene and isochromene derivatives from acetylene compounds are summarized. The reactions catalyzed by metal complexes (Pd, Pt, Ru, Rh, Au, Ag, Ni, Cu, etc.) and transformations induced by various electrophilic reagents (Brynsted and Lewis acids) are considered. Moieties of the mentioned heterocyclic systems are present in many biologically active natural products and pharmaceutical agents. Besides, derivatives of these heterocycles are used in the manufacture of catalysts, dyes, perfumery and cosmetic products, corrosion inhibitors and so on. The bibliography includes 211 references.

  10. Three-component Povarov reaction-heteroannulation with arynes: synthesis of 5,6-dihydroindolo[1,2-a]quinolines.

    PubMed

    Bunescu, Ala; Wang, Qian; Zhu, Jieping

    2014-03-21

    A reaction of 2-acyl substituted tetrahydroquinolines, prepared by Lewis acid-catalyzed three-component reaction of α-oxo aldehydes, anilines, and dienophiles, with in situ generated arynes afforded 5,6-dihydroindolo[1,2-a]quinolines in good to excellent yields.

  11. (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11) is a partial agonist of the androgen receptor.

    PubMed

    Kanno, Yuichiro; Hikosaka, Ritsuko; Zhang, Shu-Yun; Inoue, Yoshimi; Nakahama, Takayuki; Kato, Keisuke; Yamaguchi, Akemi; Tominaga, Nobuaki; Kohra, Shinya; Arizono, Koji; Inouye, Yoshio

    2011-01-01

    A novel steroid compound, (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), was found to be a partial agonist of the androgen receptor (AR) in an androgen responsive element (ARE)-luciferase reporter assay. YK11 accelerates nuclear translocation of AR. Furthermore, YK11 does not induce amino/carboxyl-terminal (N/C) interaction and prevents 5-α-dihydrotestosterone (DHT)-mediated N/C interaction. Thus, YK11 activates AR without causing N/C interaction, which may in turn be responsible for the partially agonistic nature of YK11 observed in the ARE-luciferase reporter system. YK11 acts as a gene-selective agonist of AR in MDA-MB 453 cells. The effect of YK11 on gene expression relative to that of androgen agonist varies depending on the gene context. YK11 activated the reporter gene by inducing the translocation of the AR into the nuclear compartment, where its amino-terminal domain (NTD) functions as a constitutive activator of AR target genes. Our results suggest that YK11 might act as selective androgen receptor modulator (SARM). PMID:21372378

  12. Indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups, a new class of potent PPAR alpha/gamma/delta pan agonists: synthesis, structure-activity relationship, and in vivo efficacy.

    PubMed

    Rudolph, Joachim; Chen, Libing; Majumdar, Dyuti; Bullock, William H; Burns, Michael; Claus, Thomas; Dela Cruz, Fernando E; Daly, Michelle; Ehrgott, Frederick J; Johnson, Jeffrey S; Livingston, James N; Schoenleber, Robert W; Shapiro, Jeffrey; Yang, Ling; Tsutsumi, Manami; Ma, Xin

    2007-03-01

    Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models. PMID:17274610

  13. Treatment with PPARδ agonist alleviates non-alcoholic fatty liver disease by modulating glucose and fatty acid metabolic enzymes in a rat model.

    PubMed

    Li, Xiuli; Li, Jin; Lu, Xiaolan; Ma, Huihui; Shi, Haitao; Li, Hong; Xie, Danhong; Dong, Lei; Liang, Chunlian

    2015-09-01

    Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition which is associated with certain features of metabolic syndrome and insulin resistance. Peroxisome proliferator‑activated receptor (PPAR)δ is an important regulator of energy metabolism and insulin resistance in diabetes. However, the function of PPARδ in NAFLD has not yet been fully elucidated. In the present study, in order to explore the function of PPARδ in NAFLD, we created a rat model of NALFD induced by a high-fat diet (HFD) and treated the rats with GW501516, a PPARδ agonist. We found that the lipid levels decreased, and hepatocellular ballooning and inflammatory cell infiltration were also significantly decreased following treatment of the rats with GW501516 compared to the untreated rats. Treatment with GW501516 also significantly decreased the homeostasis model assessment of insulin resistance (HOMA-IR) index, as well as the low‑density lipoprotein (LDL) levels. In addition, treatment with GW501516 increased the levels of insulin‑like growth factor‑1 (IGF-1) and high‑density lipoprotein (HDL) compared to the HFD group. Furthermore, the elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma‑glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) in the HFD group were all restored to the normal control levels following treatment with GW501516. RT‑qPCR and immunohistochemical staining revealed that the expression levels of sterol regulatory element binding protein‑1c (SREBP‑1c) and glucose transporter 2 (GLUT‑2) were both restored to normal control levels following treatment with GW501516. Also, the levels of enzymes related to lipid metabolism were increased following treatment with GW501516. In conclusion, our findings demonstrate that treatment with GW501516 alleviates NAFLD by modulating glucose and fatty acid metabolism. PMID:26133486

  14. Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro.

    PubMed

    Giacomelli, S; Palmery, M; Romanelli, L; Cheng, C Y; Silvestrini, B

    1998-01-01

    The hallucinogenic effects of lysergic acid diethylamide (LSD) have mainly been attributed to the interaction of this drug with the serotoninergic system, but it seems more likely that they are the result of the complex interactions of the drug with both the serotoninergic and dopaminergic systems. The aim of the present study was to investigate the functional actions of LSD at dopaminergic receptors using prolactin secretion by primary cultures of rat pituitary cells as a model. LSD produced a dose-dependent inhibition of prolactin secretion in vitro with an IC50 at 1.7x10(-9) M. This action was antagonized by spiperone but not by SKF83566 or cyproheptadine, which indicates that LSD has a specific effect on D2 dopaminergic receptors. The maximum inhibition of prolactin secretion achieved by LSD was lower than that by dopamine (60% versus 80%). Moreover, the fact that LSD at 10(-8)-10(-6) M antagonized the inhibitory effect of dopamine (10(-7) M) and bromocriptine (10(-11) M) suggests that LSD acts as a partial agonist at D2 receptors on lactotrophs in vitro. Interestingly, LSD at 10(-13)-10(-10) M, the concentrations which are 10-1000-fold lower than those required to induce direct inhibition on pituitary prolactin secretion, potentiated the dopamine (10(-10)-2.5x10(-9) M)-mediated prolactin secretion by pituitary cells in vitro. These results suggest that LSD not only interacts with dopaminergic receptors but also has a unique capacity for modulating dopaminergic transmission. These findings may offer new insights into the hallucinogenic effect of LSD.

  15. Recent Advances in Metal-Free Quinoline Synthesis.

    PubMed

    Ramann, Ginelle A; Cowen, Bryan J

    2016-01-01

    The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes. Quinolines were first synthesized in 1879, and since then a multitude of synthetic routes have been developed. Many of these methods, such as the Skraup, Doebner-Von Miller, and Friedlander quinoline syntheses, are well-known but suffer from inefficiency, harsh reaction conditions, and toxic reagents. This review focuses on recent transition metal-free processes toward these important heterocycles, including both novel routes and modifications to established methods. For example, variations on the Skraup method include microwave irradiation, ionic liquid media, and novel annulation partners, all of which have shown increased reaction efficiency and improved yield of the heteroring-unsubstituted quinoline products. Similarly, modifications to other synthetic routes have been implemented, with the quinoline products displaying a wide variety of substitution patterns. PMID:27483222

  16. Antifungal Quinoline Alkaloids from Waltheria indica.

    PubMed

    Cretton, Sylvian; Dorsaz, Stéphane; Azzollini, Antonio; Favre-Godal, Quentin; Marcourt, Laurence; Ebrahimi, Samad Nejad; Voinesco, Francine; Michellod, Emilie; Sanglard, Dominique; Gindro, Katia; Wolfender, Jean-Luc; Cuendet, Muriel; Christen, Philippe

    2016-02-26

    Chemical investigation of a dichloromethane extract of the aerial parts of Waltheria indica led to the isolation and characterization of five polyhydroxymethoxyflavonoids, namely, oxyanin A (1), vitexicarpin (3), chrysosplenol E (4), flindulatin (5), 5-hydroxy-3,7,4'-trimethoxyflavone (6), and six quinolone alkaloids, waltheriones M-Q (2, 7, 8, 10, 11) and 5(R)-vanessine (9). Among these, compounds 2, 7, 8, 10, and 11 have not yet been described in the literature. Their chemical structures were established by means of spectroscopic data interpretation including (1)H and (13)C, HSQC, HMBC, COSY, and NOESY NMR experiments and UV, IR, and HRESIMS. The absolute configurations of the compounds were established by ECD. The isolated constituents and 10 additional quinoline alkaloids previously isolated from the roots of the plant were evaluated for their in vitro antifungal activity against the human fungal pathogen Candida albicans, and 10 compounds (7, 9, 11-16, 18, 21) showed growth inhibitory activity on both planktonic cells and biofilms (MIC ≤ 32 μg/mL). Their spectrum of activity against other pathogenic Candida species and their cytotoxicity against human HeLa cells were also determined. In addition, the cytological effect of the antifungal isolated compounds on the ultrastructure of C. albicans was evaluated by transmission electron microscopy.

  17. The Neutrophil Response Induced by an Agonist for Free Fatty Acid Receptor 2 (GPR43) Is Primed by Tumor Necrosis Factor Alpha and by Receptor Uncoupling from the Cytoskeleton but Attenuated by Tissue Recruitment.

    PubMed

    Björkman, Lena; Mårtensson, Jonas; Winther, Malene; Gabl, Michael; Holdfeldt, André; Uhrbom, Martin; Bylund, Johan; Højgaard Hansen, Anders; Pandey, Sunil K; Ulven, Trond; Forsman, Huamei; Dahlgren, Claes

    2016-10-15

    Ligands with improved potency and selectivity for free fatty acid receptor 2 (FFA2R) have become available, and we here characterize the neutrophil responses induced by one such agonist (Cmp1) and one antagonist (CATPB). Cmp1 triggered an increase in the cytosolic concentration of Ca(2+), and the neutrophils were then desensitized to Cmp1 and to acetate, a naturally occurring FFA2R agonist. The antagonist CATPB selectively inhibited responses induced by Cmp1 or acetate. The activated FFA2R induced superoxide anion secretion at a low level in naive blood neutrophils. This response was largely increased by tumor necrosis factor alpha (TNF-α) in a process associated with a recruitment of easily mobilizable granules, but neutrophils recruited to an aseptic inflammation in vivo were nonresponding. Superoxide production induced by Cmp1 was increased in latrunculin A-treated neutrophils, but no reactivation of desensitized FFA2R was induced by this drug, suggesting that the cytoskeleton is not directly involved in terminating the response. The functional and regulatory differences between the receptors that recognize short-chain fatty acids and formylated peptides, respectively, imply different roles of these receptors in the orchestration of inflammation and confirm the usefulness of a selective FFA2R agonist and antagonist as tools for the exploration of the precise role of the FFA2R. PMID:27503855

  18. Synthesis and characterization of diphenyl quinoline and bromine-activated diphenyl quinoline organic phosphors.

    PubMed

    Pimpalshende, D M; Dhoble, S J

    2014-08-01

    A diphenyl quinoline (DPQ)-conjugated derivative and bromine-activated DPQ (Br-DPQ) were synthesized in an inert gas atmosphere at 140 °C using Friedlander condensation. The compounds showed blue emission under a UV source. The structures were characterized by X-ray diffraction and Fourier transform infrared spectroscopy. The photoluminescence properties of the compounds were analysed using excitation and emission spectra. The synthesized organic phosphors shows bright emission in the blue region, with peaks at 445 and 453 nm, respectively, for DPQ and Br-DPQ in the powder form. The physical and photoluminescence properties of these organic compounds reveal promising blue emitters for high-efficiency organic light-emitting diodes.

  19. [Combination of TLR7 agonist T7-ethacrynic acid conjugate with ROR1 has a stronger anti-breast cancer effect].

    PubMed

    Zhang, Na; Jin, Guangyi; Jin, Zhenchao; Liu, Bing; Peng, Boya; Gao, Ningning; Hu, Yunlong; Tang, Li

    2016-07-01

    Objective To investigate the synergistic anti-breast cancer effect of Toll-like receptor 7 agonist T7-ethacrynic acid conjugate (T7-EA) in combination with receptor-tyrosine-kinase-like orphan receptor 1 (ROR1). Methods ROR1 cytotoxic T lymphocyte (CTL) epitope was predicted using Syfpeithi online software. Mouse spleen lymphocytes and bone marrow dendritic cells (DCs) were separately stimulated with 4 μmol/L T7-EA and 4 μmol/L ROR1 alone or in combination. ELISA assay was used to measure the levels of interferon-γ (IFN-γ), interleukin 12 (IL-12) and tumor necrosis factor-α (TNF-α). Xenograft model was established via subcutaneous injection of mouse breast cancer 4T1 cells. The mice were weekly treated through intraperitoneal administration of 3 mg/kg T7-EA, 15 mg/kg ROR1 or the combination of T7-EA and ROR1. After four rounds of treatment, tumor tissues were weighed. Serum level of anti-4T1 tumor protein IgG was measured by ELISA. Specific CTL activity was detected by lactate dehydrogenase (LDH) assay. Results The peptide PYCDETSSV was chosen as an antigen epitope of breast cancer. The T7-EA highly activated in vitro lymphocytes in a dose-dependent manner, which wasn't affected by other relevant peptides. The combination of T7-EA and ROR1 stimulated the secretion of IFN-γ and IL-12 by lymphocytes and TNF-α by bone marrow DCs. The growth of tumor in vivo was significantly inhibited by T7-EA combined with ROR1 compared with T7-EA or ROR1 alone. The specific CTL activity triggered by T7-EA combined with ROR1 was much stronger than that triggered by T7-EA or ROR1 alone. The titer of anti-4T1 tumor protein IgG induced by T7-EA combined with ROR1 was higher than that induced by T7-EA or ROR1. Conclusion The combination of T7-EA and ROR1 has a better killing effect on breast cancer. PMID:27363264

  20. Grafting polyethylenimine with quinoline derivatives for targeted imaging of intracellular Zn(2+) and logic gate operations.

    PubMed

    Pan, Yi; Shi, Yupeng; Chen, Junying; Wong, Chap-Mo; Zhang, Heng; Li, Mei-Jin; Li, Cheuk-Wing; Yi, Changqing

    2016-12-01

    In this study, a highly sensitive and selective fluorescent Zn(2+) probe which exhibited excellent biocompatibility, water solubility, and cell-membrane permeability, was facilely synthesized in a single step by grafting polyethyleneimine (PEI) with quinoline derivatives. The primary amino groups in the branched PEI can increase water solubility and cell permeability of the probe PEIQ, while quinoline derivatives can specifically recognize Zn(2+) and reduce the potential cytotoxicity of PEI. Basing on fluorescence off-on mechanism, PEIQ demonstrated excellent sensing capability towards Zn(2+) in absolute aqueous solution, where a high sensitivity with a detection limit as low as 38.1nM, and a high selectivity over competing metal ions and potential interfering amino acids, were achieved. Inspired by these results, elementary logic operations (YES, NOT and INHIBIT) have been constructed by employing PEIQ as the gate while Zn(2+) and EDTA as chemical inputs. Together with the low cytotoxicity and good cell-permeability, the practical application of PEIQ in living cell imaging was satisfactorily demonstrated, emphasizing its wide application in fundamental biology research. PMID:27612748

  1. New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives.

    PubMed

    Bradbury, R H; Allott, C P; Dennis, M; Fisher, E; Major, J S; Masek, B B; Oldham, A A; Pearce, R J; Rankine, N; Revill, J M

    1992-10-30

    A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 microM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICI D8731, has been selected for clinical evaluation.

  2. Synthesis, photochemistry, DNA cleavage/binding and cytotoxic properties of fluorescent quinoxaline and quinoline hydroperoxides.

    PubMed

    Chowdhury, Nilanjana; Gangopadhyay, Moumita; Karthik, S; Pradeep Singh, N D; Baidya, Mithu; Ghosh, S K

    2014-01-01

    Novel fluorescent quinoxaline and quinoline hydroperoxides were shown to perform dual role as both fluorophores for cell imaging and photoinduced DNA cleaving agents. Photophysical studies of newly synthesized quinoxaline and quinoline hydroperoxides showed that they all exhibited moderate to good fluorescence. Photolysis of quinoxaline and quinoline hydroperoxides in acetonitrile using UV light above 350nm resulted in the formation of corresponding ester compounds via γ-hydrogen abstraction by excited carbonyl chromophore. Single strand DNA cleavage was achieved on irradiation of newly synthesized hydroperoxides by UV light (⩾350nm). Both hydroxyl radicals and singlet oxygen were identified as reactive oxygen species (ROS) responsible for the DNA cleavage. Further, we showed quinoline hydroperoxide binds to ct-DNA via intercalative mode. In vitro biological studies revealed that quinoline hydroperoxide has good biocompatibility, cellular uptake property and cell imaging ability. Finally, we showed that quinoline hydroperoxide can permeate into cells efficiently and may cause cytotoxicity upon irradiation by UV light.

  3. Sensitive and rapid determination of quinoline yellow in drinks using polyvinylpyrrolidone-modified electrode.

    PubMed

    Zhang, Shenghui; Shi, Zhen; Wang, Jinshou

    2015-04-15

    A novel electrochemical sensor using polyvinylpyrrolidone (PVP)-modified carbon paste electrode was developed for the sensitive and rapid determination of quinoline yellow. In 0.1M, pH 6.5 phosphate buffer, an irreversible oxidation wave at 0.97 V was observed for quinoline yellow. PVP exhibited strong accumulation ability to quinoline yellow, and consequently increased the oxidation peak current of quinoline yellow remarkably. The effects of pH value, amount of PVP, accumulation potential and time were studied on the oxidation signals of quinoline yellow. The linear range was from 5×10(-8) to 1×10(-6) M, and the limit of detection was evaluated to be 2.7×10(-8) M. It was used to detect quinoline yellow in different drink samples, and the results consisted with the values that obtained by high-performance liquid chromatography.

  4. Tomato PYR/PYL/RCAR abscisic acid receptors show high expression in root, differential sensitivity to the abscisic acid agonist quinabactin, and the capability to enhance plant drought resistance.

    PubMed

    González-Guzmán, Miguel; Rodríguez, Lesia; Lorenzo-Orts, Laura; Pons, Clara; Sarrión-Perdigones, Alejandro; Fernández, Maria A; Peirats-Llobet, Marta; Forment, Javier; Moreno-Alvero, Maria; Cutler, Sean R; Albert, Armando; Granell, Antonio; Rodríguez, Pedro L

    2014-08-01

    Abscisic acid (ABA) plays a crucial role in the plant's response to both biotic and abiotic stress. Sustainable production of food faces several key challenges, particularly the generation of new varieties with improved water use efficiency and drought tolerance. Different studies have shown the potential applications of Arabidopsis PYR/PYL/RCAR ABA receptors to enhance plant drought resistance. Consequently the functional characterization of orthologous genes in crops holds promise for agriculture. The full set of tomato (Solanum lycopersicum) PYR/PYL/RCAR ABA receptors have been identified here. From the 15 putative tomato ABA receptors, 14 of them could be grouped in three subfamilies that correlated well with corresponding Arabidopsis subfamilies. High levels of expression of PYR/PYL/RCAR genes was found in tomato root, and some genes showed predominant expression in leaf and fruit tissues. Functional characterization of tomato receptors was performed through interaction assays with Arabidopsis and tomato clade A protein phosphatase type 2Cs (PP2Cs) as well as phosphatase inhibition studies. Tomato receptors were able to inhibit the activity of clade A PP2Cs differentially in an ABA-dependent manner, and at least three receptors were sensitive to the ABA agonist quinabactin, which inhibited tomato seed germination. Indeed, the chemical activation of ABA signalling induced by quinabactin was able to activate stress-responsive genes. Both dimeric and monomeric tomato receptors were functional in Arabidopsis plant cells, but only overexpression of monomeric-type receptors conferred enhanced drought resistance. In summary, gene expression analyses, and chemical and transgenic approaches revealed distinct properties of tomato PYR/PYL/RCAR ABA receptors that might have biotechnological implications. PMID:24863435

  5. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  6. Internal loop photo-biodegradation reactor used for accelerated quinoline degradation and mineralization.

    PubMed

    Chang, Ling; Zhang, Yongming; Gan, Lu; Xu, Hua; Yan, Ning; Liu, Rui; Rittmann, Bruce E

    2014-07-01

    Biofilm biodegradation was coupled with ultra-violet photolysis using the internal loop photobiodegradation reactor for degradation of quinoline. Three protocols-photolysis alone (P), biodegradation alone (B), and intimately coupled photolysis and biodegradation (P&B)-were used for degradation of quinoline in batch and continuous-flow experiments. For a 1,000 mg/L initial quinoline concentration, the volumetric removal rate for quinoline was 38 % higher with P&B than with B in batch experiments, and the P&B kinetics were the sum of kinetics from the P and B experiments. Continuous-flow experiments with an influent quinoline concentration of 1,000 mg/L also gave significantly greater quinoline removal in P&B, and the quinoline-removal kinetics for P&B were approximately equal to the sum of the removal kinetics for P and B. P&B similarly increased the rate and extent of quinoline mineralization, for which the kinetics for P&B were nearly equal to the sum of kinetics for P and B. These findings support that the rate-limiting step for mineralization was transformation of quinoline, which was accelerated by the simultaneous action of photolysis and biodegradation. PMID:24488551

  7. Internal loop photo-biodegradation reactor used for accelerated quinoline degradation and mineralization.

    PubMed

    Chang, Ling; Zhang, Yongming; Gan, Lu; Xu, Hua; Yan, Ning; Liu, Rui; Rittmann, Bruce E

    2014-07-01

    Biofilm biodegradation was coupled with ultra-violet photolysis using the internal loop photobiodegradation reactor for degradation of quinoline. Three protocols-photolysis alone (P), biodegradation alone (B), and intimately coupled photolysis and biodegradation (P&B)-were used for degradation of quinoline in batch and continuous-flow experiments. For a 1,000 mg/L initial quinoline concentration, the volumetric removal rate for quinoline was 38 % higher with P&B than with B in batch experiments, and the P&B kinetics were the sum of kinetics from the P and B experiments. Continuous-flow experiments with an influent quinoline concentration of 1,000 mg/L also gave significantly greater quinoline removal in P&B, and the quinoline-removal kinetics for P&B were approximately equal to the sum of the removal kinetics for P and B. P&B similarly increased the rate and extent of quinoline mineralization, for which the kinetics for P&B were nearly equal to the sum of kinetics for P and B. These findings support that the rate-limiting step for mineralization was transformation of quinoline, which was accelerated by the simultaneous action of photolysis and biodegradation.

  8. Gold-catalyzed oxidative cycloadditions to activate a quinoline framework.

    PubMed

    Huple, Deepak B; Ghorpade, Satish; Liu, Rai-Shung

    2013-09-23

    Going for gold! Gold-catalyzed reactions of 3,5- and 3,6-dienynes with 8-alkylquinoline oxides results in an oxidative cycloaddition with high stereospecificity (see scheme; EWG = electron-withdrawing group); this process involves a catalytic activation of a quinoline framework. The reaction mechanism involves the intermediacy of α-carbonyl pyridinium ylides (I) in a concerted [3+2]-cycloaddition with a tethered alkene.

  9. Effects of Chronic Dopamine D2R Agonist Treatment and Polysialic Acid Depletion on Dendritic Spine Density and Excitatory Neurotransmission in the mPFC of Adult Rats

    PubMed Central

    Castillo-Gómez, Esther; Varea, Emilio; Blasco-Ibáñez, José Miguel; Crespo, Carlos; Nacher, Juan

    2016-01-01

    Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist) after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting their inhibitory innervation. Endo-N also reduced the expression of vesicular glutamate transporter-1. These results indicate that D2R and PSA-NCAM are important players in the regulation of the structural plasticity of mPFC excitatory neurons. This is relevant to our understanding of the neurobiological basis of schizophrenia, in which structural alterations of pyramidal neurons and altered expression of D2R and PSA-NCAM have been found. PMID:27110404

  10. Effects of Chronic Dopamine D2R Agonist Treatment and Polysialic Acid Depletion on Dendritic Spine Density and Excitatory Neurotransmission in the mPFC of Adult Rats.

    PubMed

    Castillo-Gómez, Esther; Varea, Emilio; Blasco-Ibáñez, José Miguel; Crespo, Carlos; Nacher, Juan

    2016-01-01

    Dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) are key players in the etiology and therapeutics of schizophrenia. The overactivation of these receptors contributes to mPFC dysfunction. Chronic treatment with D2R agonists modifies the expression of molecules implicated in neuronal structural plasticity, synaptic function, and inhibitory neurotransmission, which are also altered in schizophrenia. These changes are dependent on the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a plasticity-related molecule, but nothing is known about the effects of D2R and PSA-NCAM on excitatory neurotransmission and the structure of mPFC pyramidal neurons, two additional features affected in schizophrenia. To evaluate these parameters, we have chronically treated adult rats with PPHT (a D2R agonist) after enzymatic removal of PSA with Endo-N. Both treatments decreased spine density in apical dendrites of pyramidal neurons without affecting their inhibitory innervation. Endo-N also reduced the expression of vesicular glutamate transporter-1. These results indicate that D2R and PSA-NCAM are important players in the regulation of the structural plasticity of mPFC excitatory neurons. This is relevant to our understanding of the neurobiological basis of schizophrenia, in which structural alterations of pyramidal neurons and altered expression of D2R and PSA-NCAM have been found. PMID:27110404

  11. Agonist-dependent endocytosis of γ-aminobutyric acid type A (GABAA) receptors revealed by a γ2(R43Q) epilepsy mutation.

    PubMed

    Chaumont, Severine; André, Caroline; Perrais, David; Boué-Grabot, Eric; Taly, Antoine; Garret, Maurice

    2013-09-27

    GABA-gated chloride channels (GABAARs) trafficking is involved in the regulation of fast inhibitory transmission. Here, we took advantage of a γ2(R43Q) subunit mutation linked to epilepsy in humans that considerably reduces the number of GABAARs on the cell surface to better understand the trafficking of GABAARs. Using recombinant expression in cultured rat hippocampal neurons and COS-7 cells, we showed that receptors containing γ2(R43Q) were addressed to the cell membrane but underwent clathrin-mediated dynamin-dependent endocytosis. The γ2(R43Q)-dependent endocytosis was reduced by GABAAR antagonists. These data, in addition to a new homology model, suggested that a conformational change in the extracellular domain of γ2(R43Q)-containing GABAARs increased their internalization. This led us to show that endogenous and recombinant wild-type GABAAR endocytosis in both cultured neurons and COS-7 cells can be amplified by their agonists. These findings revealed not only a direct relationship between endocytosis of GABAARs and a genetic neurological disorder but also that trafficking of these receptors can be modulated by their agonist.

  12. Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064.

    PubMed

    Martínez-Fernández, Pilar; Hierro, Loreto; Jara, Paloma; Alvarez, Luis

    2009-05-01

    Farnesoid X receptor (FXR) is a bile acid-sensing nuclear receptor that controls bile acid homeostasis. It has been suggested that downregulation of FXR contributes to the pathogenesis of an inherited disorder of bile secretion caused by mutations in ATP8B1. We have investigated the relationship between ATP8B1 knockdown and FXR downregulation in the human hepatoblastoma cell line HepG2. Transfection of HepG2 cells with ATP8B1 small interfering RNA (siRNA) duplexes led to a 60% reduction in the endogenous levels of ATP8B1 mRNA and protein and a concomitant decrease in FXR mRNA and protein content, as well as in FXR phosphorylation. This decrease was accompanied by a marked reduction in mRNA levels of a subset of FXR targets, such as bile salt export pump (ABCB11), small heterodimer partner, and uridine 5'-diphosphate-glucuronosyltransferase. ATP8B1 inhibition specifically targeted FXR since mRNA expression of other prominent nuclear receptors, such as pregnane X receptor and constitutive androstane receptor, or liver-enriched transcription factors, such as hepatocyte nuclear factor 1alpha (HNF-1alpha) and HNF-4alpha, was not altered. The expression of other key genes involved in bile acid synthesis, detoxification, and transport also remained unchanged upon ATP8B1 knockdown. Supporting the specificity of the effect, siRNA-mediated silencing of ABCB11, whose defect is associated with another inherited disorder of bile secretion, did not affect FXR expression. Treatment with the synthetic FXR agonist GW4064 was able to partially neutralize ATP8B1 siRNA-mediated FXR downregulation and fully counteract inhibition of FXR target genes. Collectively these findings indicate that ATP8B1 knockdown specifically downregulates FXR, and this action can be circumvented by treatment with FXR agonists.

  13. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039).

    PubMed

    Rorick-Kehn, Linda M; Johnson, Bryan G; Burkey, Jennifer L; Wright, Rebecca A; Calligaro, David O; Marek, Gerard J; Nisenbaum, Eric S; Catlow, John T; Kingston, Ann E; Giera, Deborah D; Herin, Marc F; Monn, James A; McKinzie, David L; Schoepp, Darryle D

    2007-04-01

    Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in

  14. Electricity production from and biodegradation of quinoline in the microbial fuel cell.

    PubMed

    Zhang, Cuiping; Liu, Guangli; Zhang, Renduo; Luo, Haiping

    2010-01-01

    Quinoline has become one of the common contaminants in groundwater and soil, discharged from the process of coal tar distillation and creosote wood preservation, as well as fossil fuel facilities. The aim of this study was to investigate the feasibility of electricity production from and biodegradation of quinoline in the microbial fuel cell (MFC). Experiments were conducted in the MFC using an initial 500 mg/L quinoline with different glucose concentrations as substrates. Results showed maximum voltages of 558, 469, and 328 mV for the substrates with ratios of quinoline to glucose of 1:1, 5:3, 5:1, respectively. The MFC accomplished complete quinoline biodegradation within 6 h. Experiments were then conducted using 200 mg/L quinoline only as the MFC fuel, resulting in the maximal voltage of 145 mV and maximal power density of 16.4 mW/m(2). GC/MS analyses showed that 2(1H)quinolinone accumulated in the anode solution and later disappeared. The results clearly demonstrated the feasibility to use quinoline as the MFC fuel to generate electricity and enhance quinoline biodegradation simultaneously.

  15. Flexible modulation of agonist efficacy at the human A3 adenosine receptor by the imidazoquinoline allosteric enhancer LUF6000

    PubMed Central

    Gao, Zhan-Guo; Ye, Kai; Göblyös, Anikó; IJzerman, Adriaan P; Jacobson, Kenneth A

    2008-01-01

    Background A series of 1H-imidazo- [4,5-c]quinolin-4-amine derivatives, represented by LUF6000 (N-(3,4-dichloro-phenyl)-2-cyclohexyl-1H-imidazo [4,5-c]quinolin-4-amine), are allosteric modulators of the human A3 adenosine receptor (AR). Here we studied the modulation by LUF6000 of the maximum effect (Emax) of structurally diverse agonists at the A3 AR stably expressed in CHO cells. Results In an assay of [35S]GTPγS binding, the Emax of the A3 AR agonist Cl-IB-MECA at the A3 AR was lower than that of the non-selective AR agonist NECA. LUF6000 exerted an Emax-enhancing effect at a concentration of 0.1 μM or higher, and was shown to increase the Emax of Cl-IB-MECA and other low-efficacy agonists to a larger extent than that of the high-efficacy agonist NECA. Interestingly, LUF6000 converted a nucleoside A3 AR antagonist MRS542, but not a non-nucleoside antagonist MRS1220, into an agonist. LUF6000 alone did not show any effect. Mathematical modeling was performed to explain the differential effects of LUF6000 on agonists with various Emax. A simple explanation for the observation that LUF6000 has a much stronger effect on Cl-IB-MECA than on NECA derived from the mathematical modeling is that NECA has relatively strong intrinsic efficacy, such that the response is already close to the maximum response. Therefore, LUF6000 cannot enhance Emax much further. Conclusion LUF6000 was found to be an allosteric enhancer of Emax of structurally diverse agonists at the A3 AR, being more effective for low-Emax agonists than for high-Emax agonists. LUF6000 was demonstrated to convert an antagonist into an agonist, which represents the first example in G protein-coupled receptors. The observations from the present study are consistent with that predicted by mathematical modeling. PMID:19077268

  16. Genotoxicity risk assessment of diversely substituted quinolines using the SOS chromotest.

    PubMed

    Duran, Leidy Tatiana Díaz; Rincón, Nathalia Olivar; Galvis, Carlos Eduardo Puerto; Kouznetsov, Vladimir V; Lorenzo, Jorge Luis Fuentes

    2015-03-01

    Quinolines are aromatic nitrogen compounds with wide therapeutic potential to treat parasitic and microbial diseases. In this study, the genotoxicity of quinoline, 4-methylquinoline, 4-nitroquinoline-1-oxide (4-NQO), and diversely functionalized quinoline derivatives and the influence of the substituents (functional groups and/or atoms) on their genotoxicity were tested using the SOS chromotest. Quinoline derivatives that induce genotoxicity by the formation of an enamine epoxide structure did not induce the SOS response in Escherichia coli PQ37 cells, with the exception of 4-methylquinoline that was weakly genotoxic. The chemical nature of the substitution (C-5 to C-8: hydroxyl, nitro, methyl, isopropyl, chlorine, fluorine, and iodine atoms; C-2: phenyl and 3,4-methylenedioxyphenyl rings) of quinoline skeleton did not significantly modify compound genotoxicities; however, C-2 substitution with α-, β-, or γ-pyridinyl groups removed 4-methylquinoline genotoxicity. On the other hand, 4-NQO derivatives whose genotoxic mechanism involves reduction of the C-4 nitro group were strong inducers of the SOS response. Methyl and nitrophenyl substituents at C-2 of 4-NQO core affected the genotoxic potency of this molecule. The relevance of these results is discussed in relation to the potential use of the substituted quinolines. The work showed the sensitivity of SOS chromotest for studying structure-genotoxicity relationships and bioassay-guided quinoline synthesis.

  17. Dietary Effects of Oxidized Eicosapentaenoic Acid (EPA) and Intact EPA on Hepatic Steatosis Induced by a High-sucrose Diet and Liver-X-receptor α Agonist in Mice.

    PubMed

    Furumoto, Hidehiro; Nanthirudjanar, Tharnath; Hirata, Takashi; Sugawara, Tatsuya

    2016-01-01

    Numerous studies have shown that dietary omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA), improve lipid metabolism. The beneficial effects of PUFA-derived oxidation products have been increasingly reported. However, EPA is easily oxidized in food products and in the human body, generating various derivatives of oxidized EPA (oxEPA), such that these oxidation products may partially contribute to EPA's effect. We previously reported that oxEPA was more potent than intact EPA in reducing liver-X-receptor α (LXRα)-induced cellular triacylglycerol (TG) accumulation. However, the in vivo hypolipidemic effects of oxEPA remain unclear. In the present study, we evaluated the effect of oral administration of EPA and oxEPA on hepatic steatosis in mice induced by a high-sucrose diet and a synthetic LXRα agonist, TO-901317. Both EPA and oxEPA reduced TG accumulation in the liver and plasma biomarkers of liver injury. Furthermore, they suppressed the expression of lipogenic genes, but not β-oxidation genes, in a similar pattern as the biomarkers. Our results suggest that oxEPA and intact EPA suppress de novo lipogenesis to ameliorate hepatic steatosis. PMID:26876675

  18. Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones.

    PubMed

    Higuchi, Robert I; Arienti, Kristen L; López, Francisco J; Mani, Neelakhanda S; Mais, Dale E; Caferro, Thomas R; Long, Yun Oliver; Jones, Todd K; Edwards, James P; Zhi, Lin; Schrader, William T; Negro-Vilar, Andrés; Marschke, Keith B

    2007-05-17

    Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.

  19. Synthesis and biological activity of pyrimido [1, 2-a] quinoline moiety and its 2-substituted derivatives

    NASA Astrophysics Data System (ADS)

    Jadhav, A. G.; Halikar, N. K.

    2013-04-01

    2-Amino-3-cyano quinoline (1) and bis (methylthio) methylene malononitrile (2) were refluxed in N,N-dimethyl formamide (DMF) in presence of catalytic amount of anhydrous potassium carbonate to afforded 3, 11-dicyano-4-imino-2-methylthio -4H-pyrimido [1, 2-a] quinoline (3). The latter were further reacted with different substituted aniline, phenol, hetryl amine and compound containing active methyl group. Afforded to 3, 11-dicyano-4-imino -4H-pyrimido [1, 2-a] quinoline and their 2-substuited derivatives (4a-7c). All these newly synthesized compounds were characterized by elemental analysis and spectral data, and screened for their antimicrobial activities.

  20. Structure-Based Design of Human TLR8-Specific Agonists with Augmented Potency and Adjuvanticity

    PubMed Central

    2016-01-01

    Human Toll-like receptor 8 (hTLR8) is expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells. Engagement by TLR8 agonists evokes a distinct cytokine profile which favors the development of type 1 helper T cells. Crystal structures of the ectodomain of hTLR8 cocrystallized with two regioisomers of a dual TLR7/8-agonistic N1-substituted imidazoquinolines showed subtle differences in their interactions in the binding site of hTLR8. We hypothesized that the potency of a previously reported best-in-class pure TLR8 agonist, 3-pentylquinoline-2-amine, could be further enhanced by “designing in” functional groups that would mimic key intermolecular interactions that we had observed in the crystal structures. We performed a focused exploration of decorating the quinoline core with alkylamino groups at all possible positions. These studies have led to the identification of a novel TLR8 agonist that was ∼20-fold more potent than the parent compound and displays prominent adjuvantic activity in a rabbit model of immunization. PMID:26351878

  1. A natural history of "agonist".

    PubMed

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  2. Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors.

    PubMed

    Monn, J A; Valli, M J; Massey, S M; Hansen, M M; Kress, T J; Wepsiec, J P; Harkness, A R; Grutsch, J L; Wright, R A; Johnson, B G; Andis, S L; Kingston, A; Tomlinson, R; Lewis, R; Griffey, K R; Tizzano, J P; Schoepp, D D

    1999-03-25

    As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II m

  3. Microbial degradation of quinoline: Kinetic studies with Comamonas acidovorans DSM 6426

    SciTech Connect

    Miethling, R.; Hecht, V.; Deckwer, W.D. . Dept. of Biochemical Engineering)

    1993-08-20

    The microbial degradation of quinoline by Comamonas acidovorans was studied in a laboratory scale stirred tank reactor. In continuous culture experiments using quinoline as a sole source of carbon and nitrogen, it was shown by means of mass balances that quinoline was converted completely to biomass, carbon dioxide, and ammonia. Degradation rates up to 0.7 g/L h were obtained. Measured yield coefficients Y[sub x/s] for quinoline were about 0.7 g/g, which is in agreement with the theoretical value for complete mineralization. Kinetic constants based on Haldane substrate inhibition were evaluated. The values were [mu][sub max] = 0.48 h[sup [minus]1], K[sub i] = 69 mg/L, and K[sub s]<1.45 mg/L.

  4. Coordination chemistry and biological activity of 5'-OH modified quinoline-B12 derivatives.

    PubMed

    Zelenka, Karel; Brandl, Helmut; Spingler, Bernhard; Zelder, Felix

    2011-10-14

    The consequences of structural modifications at the 5'-OH ribofuranotide moiety of quinoline modified B12 derivatives are discussed in regard of the coordination chemistry, the electrochemical properties and the biological behaviour of the compound.

  5. 4-Hy-droxy-1-methyl-3-phenyl-quinolin-2(1H)-one.

    PubMed

    Kafka, Stanislav; Pevec, Andrej; Proisl, Karel; Kimmel, Roman; Košmrlj, Janez

    2013-02-01

    In the title compound, C(16)H(13)NO(2), the quinoline system is approximately planar with a maximum deviation from the least-squares plane of 0.059 (1) Å for the N atom. The phenyl ring is rotated by 62.16 (4)° with respect to the plane of the quinoline system. In the crystal, O-H⋯O hydrogen bonds link mol-ecules into infinite chains running along the b-axis direction.

  6. Time-of-flight accurate mass spectrometry identification of quinoline alkaloids in honey.

    PubMed

    Rodríguez-Cabo, Tamara; Moniruzzaman, Mohammed; Rodríguez, Isaac; Ramil, María; Cela, Rafael; Gan, Siew Hua

    2015-08-01

    Time-of-flight accurate mass spectrometry (TOF-MS), following a previous chromatographic (gas or liquid chromatography) separation step, is applied to the identification and structural elucidation of quinoline-like alkaloids in honey. Both electron ionization (EI) MS and positive electrospray (ESI+) MS spectra afforded the molecular ions (M(.+) and M+H(+), respectively) of target compounds with mass errors below 5 mDa. Scan EI-MS and product ion scan ESI-MS/MS spectra permitted confirmation of the existence of a quinoline ring in the structures of the candidate compounds. Also, the observed fragmentation patterns were useful to discriminate between quinoline derivatives having the same empirical formula but different functionalities, such as aldoximes and amides. In the particular case of phenylquinolines, ESI-MS/MS spectra provided valuable clues regarding the position of the phenyl moiety attached to the quinoline ring. The aforementioned spectral information, combined with retention times matching, led to the identification of quinoline and five quinoline derivatives, substituted at carbon number 4, in honey samples. An isomer of phenyquinoline was also noticed; however, its exact structure could not be established. Liquid-liquid microextraction and gas chromatography (GC) TOF-MS were applied to the screening of the aforementioned compounds in a total of 62 honeys. Species displaying higher occurrence frequencies were 4-quinolinecarbonitrile, 4-quinolinecarboxaldehyde, 4-quinolinealdoxime, and the phenylquinoline isomer. The Pearson test revealed strong correlations among the first three compounds. PMID:26041455

  7. Quinolines in clothing textiles--a source of human exposure and wastewater pollution?

    PubMed

    Luongo, Giovanna; Thorsén, Gunnar; Ostman, Conny

    2014-05-01

    A production process in which the use of various types of chemicals seems to be ubiquitous makes the textile industry a growing problem regarding both public health as well as the environment. Among several substances used at each stage, the present study focuses on the quinolines, a class of compounds involved in the manufacture of dyes, some of which are skin irritants and/or classified as probable human carcinogens. A method was developed for the determination of quinoline derivatives in textile materials comprising ultrasound-assisted solvent extraction, solid phase extraction cleanup, and final analysis by gas chromatography/mass spectrometry. Quinoline and ten quinoline derivatives were determined in 31 textile samples. The clothing samples, diverse in color, material, brand, country of manufacture, and price, and intended for a broad market, were purchased from different shops in Stockholm, Sweden. Quinoline, a possible human carcinogen, was found to be the most abundant compound present in almost all of the samples investigated, reaching a level of 1.9 mg in a single garment, and it was found that quinoline and its derivatives were mainly correlated to polyester material. This study points out the importance of screening textiles with nontarget analysis to investigate the presence of chemicals in an unbiased manner. Focus should be primarily on clothing worn close to the body. PMID:24604325

  8. Quinoline biodegradation and its nitrogen transformation pathway by a Pseudomonas sp. strain.

    PubMed

    Bai, Yaohui; Sun, Qinghua; Zhao, Cui; Wen, Donghui; Tang, Xiaoyan

    2010-06-01

    A Pseudomonas sp. strain, which can utilize quinoline as its sole carbon, nitrogen and energy source, was isolated from activated sludge in a coking wastewater treatment plant. Quinoline can be degraded via the 8-hydroxycoumarin pathway. We quantified the first two organic intermediates of the biodegradation, 2-hydroxyquinoline and 2,8-dihydroxyquinoline. We tracked the transformation of the nitrogen in quinoline in two media containing different C/N ratios. At least 40.4% of the nitrogen was finally transformed into ammonium when quinoline was the sole C and N source. But addition of an external carbon source like glucose promoted the transformation of N from NH3 into NO3(-), NO2(-), and then to N2. The product analysis and gene characteristics indicated that the isolate accomplished heterotrophic nitrification and aerobic denitrification simultaneously. The study also demonstrated that quinoline and its metabolic products can be eliminated if the C/N ratio is properly controlled in the treatment of quinoline-containing wastewater.

  9. Quinolines in clothing textiles--a source of human exposure and wastewater pollution?

    PubMed

    Luongo, Giovanna; Thorsén, Gunnar; Ostman, Conny

    2014-05-01

    A production process in which the use of various types of chemicals seems to be ubiquitous makes the textile industry a growing problem regarding both public health as well as the environment. Among several substances used at each stage, the present study focuses on the quinolines, a class of compounds involved in the manufacture of dyes, some of which are skin irritants and/or classified as probable human carcinogens. A method was developed for the determination of quinoline derivatives in textile materials comprising ultrasound-assisted solvent extraction, solid phase extraction cleanup, and final analysis by gas chromatography/mass spectrometry. Quinoline and ten quinoline derivatives were determined in 31 textile samples. The clothing samples, diverse in color, material, brand, country of manufacture, and price, and intended for a broad market, were purchased from different shops in Stockholm, Sweden. Quinoline, a possible human carcinogen, was found to be the most abundant compound present in almost all of the samples investigated, reaching a level of 1.9 mg in a single garment, and it was found that quinoline and its derivatives were mainly correlated to polyester material. This study points out the importance of screening textiles with nontarget analysis to investigate the presence of chemicals in an unbiased manner. Focus should be primarily on clothing worn close to the body.

  10. Synthesis and cytotoxic evaluation of certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives.

    PubMed

    Zhao, Yue-Ling; Chen, Yeh-Long; Tzeng, Cherng-Chyi; Chen, I-Li; Wang, Tai-Chi; Han, Chien-Hwa

    2005-02-01

    Certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCIs 60 cancer cell lines. The preliminary results indicated these tricyclic 4-(phenylamino)furo[2,3-b]quinolines were more cytotoxic than their corresponding 2-(furan-2-yl)-4-(phenylamino)quinoline isomers. For the 4-(phenylamino)furo[2,3-b]quinolines, compounds 2a and 3d are two of the most potent with a mean GI50 value of 0.025 microM in each case. Inactivity of 2b and 2c (positional isomers of 2a) indicated that both electronic environment, and the distance between intercalating pharmacophore and H-bond-donating MeO group are important. For the 2-(furan-2-yl)-4-(phenylamino)quinoline isomers, compound 12 (a mean GI50 of 4.36 microM), which bears a para-COMe substituent, is more active than its meta-substituted counterpart 13 (10.5 microM). However, the electron-donating MeO substituent is preferred at the meta-position, and the cytotoxicity for the meta-substituted derivatives decreased in the order: MeO derivative 14b (3.05 microM) > oxime 16 (6.85 microM) > ketone 13 (10.5 microM) > methyl oxime 18 (20.6 microM). PMID:17191973

  11. Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part I: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators

    PubMed Central

    Han, Changho; Chatterjee, Arindam; Noetzel, Meredith J.; Panarese, Joseph D.; Niswender, Colleen; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.

    2014-01-01

    Results from a 2012 high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) against the human muscarinic receptor subtype 1 (M1) for positive allosteric modulators is reported. A content-rich screen utilizing an intracellular calcium mobilization triple-addition protocol allowed for assessment of all three modes of pharmacology at M1, including agonist, positive allosteric modulator, and antagonist activities in a single screening platform. We disclose a dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one hit (DBPQ, CID 915409) and examine N-benzyl pharmacophore/SAR relationships versus previously reported quinolin-3(5H)-ones and isatins, including ML137. SAR and consideration of recently reported crystal structures, homology modeling, and structure-function relationships using point mutations suggests a shared binding mode orientation at the putative common allosteric binding site directed by the pendant N-benzyl substructure. PMID:25435150

  12. Crystal Structure of Sus scrofa Quinolinate Phosphoribosyltransferase in Complex with Nicotinate Mononucleotide

    PubMed Central

    Youn, Hyung-Seop; Kim, Mun-Kyoung; Kang, Gil Bu; Kim, Tae Gyun; Lee, Jung-Gyu; An, Jun Yop; Park, Kyoung Ryoung; Lee, Youngjin; Kang, Jung Youn; Song, Hye-Eun; Park, Inju; Cho, Chunghee; Fukuoka, Shin-Ichi; Eom, Soo Hyun

    2013-01-01

    We have determined the crystal structure of porcine quinolinate phosphoribosyltransferase (QAPRTase) in complex with nicotinate mononucleotide (NAMN), which is the first crystal structure of a mammalian QAPRTase with its reaction product. The structure was determined from protein obtained from the porcine kidney. Because the full protein sequence of porcine QAPRTase was not available in either protein or nucleotide databases, cDNA was synthesized using reverse transcriptase-polymerase chain reaction to determine the porcine QAPRTase amino acid sequence. The crystal structure revealed that porcine QAPRTases have a hexameric structure that is similar to other eukaryotic QAPRTases, such as the human and yeast enzymes. However, the interaction between NAMN and porcine QAPRTase was different from the interaction found in prokaryotic enzymes, such as those of Helicobacter pylori and Mycobacterium tuberculosis. The crystal structure of porcine QAPRTase in complex with NAMN provides a structural framework for understanding the unique properties of the mammalian QAPRTase active site and designing new antibiotics that are selective for the QAPRTases of pathogenic bacteria, such as H. pylori and M. tuberculosis. PMID:23626766

  13. Synthesis of quinoxalines or quinolin-8-amines from N-propargyl aniline derivatives employing tin and indium chlorides.

    PubMed

    Aichhorn, Stefan; Himmelsbach, Markus; Schöfberger, Wolfgang

    2015-09-28

    Pyrazino compounds such as quinoxalines are 1,4-diazines with widespread occurrence in nature. Quinolin-8-amines are isomerically related and valuable scaffolds in organic synthesis. Herein, we present intramolecular main group metal Lewis acid catalyzed formal hydroamination as well as hydroarylation methodology using mono-propargylated aromatic ortho-diamines. The annulations can be conducted utilizing equal aerobic conditions with either stannic chloride or indium(iii) chloride and represent primary examples for main group metal catalyzed 6-exo-dig and 6-endo-dig, respectively, cyclizations in such settings. Both types of reactions can also be utilized in a one-pot manner starting from ortho-nitro N-propargyl anilines using stoichiometric amounts SnCl2·2H2O or In powder. Mechanistic considerations are presented regarding the substituent-depending regioselectivity.

  14. Metal(II) complexes synthesized based on quinoline-2,3-dicarboxylate as electrocatalysts for the degradation of methyl orange.

    PubMed

    Gong, Yun; Zhang, Miao Miao; Qin, Jian Bo; Li, Jian; Meng, Jiang Ping; Lin, Jian Hua

    2014-06-14

    Based on quinoline-2,3-dicarboxylic acid (H2L), two metal(II) complexes formulated as MnL(phen)(H2O)·H2O (phen = 1,10-phenanthroline) (1) and Co(HL)2(PPA)·4H2O (PPA = N(1),N(4)-di(pyridin-4-yl)terephthalamide) (2) were synthesized and structurally characterized by single-crystal X-ray diffraction. Both complexes 1 and 2 exhibit one-dimensional (1D) chain-like structures, in which stable five-membered rings are observed. Different chains are linked by strong π-π stacking interactions into a three-dimensional (3D) supramolecular architecture. Both complexes can increase the degradation rate of methyl orange (MO), which is expected to be associated with their electrocatalytic activities for the H2 evolution reaction from water. PMID:24741675

  15. Cerium(IV) ammonium nitrate is an excellent, general catalyst for the Friedländer and Friedländer-Borsche quinoline syntheses: very efficient access to the antitumor alkaloid luotonin A.

    PubMed

    Sridharan, Vellaisamy; Ribelles, Pascual; Ramos, Ma Teresa; Menéndez, J Carlos

    2009-08-01

    The use of cerium(IV) ammonium nitrate as a catalyst of the Friedländer reaction allows the synthesis of polysubstituted quinoline derivatives in excellent yields, avoiding the traditional harshly basic or acidic conditions. Unlike most other previously known reagents, CAN allows double condensations and is also an excellent catalyst for the Borsche variation of the Friedländer reaction, which has been applied to the very efficient synthesis of the antitumor alkaloid luotonin A.

  16. Novel 2- and 4- Substituted 1H-Imidazo[4,5-c]quinolin-4-amine Derivatives as Allosteric Modulators of the A3 Adenosine Receptor

    PubMed Central

    Kim, Yoonkyung; de Castro, Sonia; Gao, Zhan-Guo; IJzerman, Adriaan P.; Jacobson, Kenneth A.

    2009-01-01

    4-Arylamino and 2- cycloalkyl (including amino substitution) modifications were made in a series of 1H-imidazo-[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the human A3 adenosine receptor (AR). In addition to allosteric modulation of the maximum functional efficacy (in [35S]GTPγS G protein binding assay) of the A3AR agonist Cl-IB-MECA (15), some analogues also weakly inhibited equilibrium radioligand binding at ARs. 4-(3,5-Dichlorophenylamino) (6) or 2-(1-adamantyl) (20) substitution produced allosteric enhancement (twice the maximal agonist efficacy), with minimal inhibition of orthosteric AR binding. 2-(4-Tetrahydropyranyl) substitution abolished allosteric enhancement but preserved inhibition of orthosteric binding. Introduction of nitrogen in the six-membered ring at 2 position, to improve aqueous solubility and provide a derivatization site, greatly reduced the allosteric enhancement. 2-(4-(Benzoylamino)cyclohexyl) analogues 23 and 24 were weak negative A3AR modulators. Thus, consistent with previous findings, the allosteric and orthosteric inhibitory A3AR effects in imidazoquinolines are structurally separable, suggesting the possible design of additional derivatives with enhanced positive or negative allosteric A3AR activity and improved selectivity in comparison to inhibition of orthosteric binding. PMID:19284749

  17. Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 may protect against cognitive impairment in rats of chronic cerebral hypoperfusion via PI3K/AKT signaling.

    PubMed

    Su, Shao-Hua; Wang, Yue-Qing; Wu, Yi-Fang; Wang, Da-Peng; Lin, Qi; Hai, Jian

    2016-10-15

    The present study further investigated the protective effects of cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide hydrolase (FAAH) inhibitor URB597 (URB) on chronic cerebral hypoperfusion (CCH)-induced cognitive impairment in rats. Spatial learning and memory were assessed with the Morris water maze and by measuring Long-term potentiation. The expression of microtubule-associated protein-2 (MAP)-2, growth-associated protein-43 (GAP)-43, synaptophysin, cannabinoid receptor 1 (CB1), brain-derived neurotrophic factor (BDNF), FAAH, N-acylphosphatidylethanolamine phospholipase D(NAPE-PLD) and monoacyl glycerol lipase (MGL) as well as phosphoinositide 3-kinase (PI3K)/AKT signaling pathway molecules and downstream targets including AKT, phosphorylated (p-)AKT, cyclic AMP response element- binding protein (CREB), p-CREB, Bcl-2-associated death protein (BAD), p-BAD, glycogen synthase kinase (GSK)-3β, p-GSK-3β, forkhead box protein (FOXO) 3A and p-FOXO3A was determined by western blotting. WIN and URB treatment improved learning and memory performance, effects that were abolished by co-administration of the PI3K/AKT inhibitor LY294002. Moreover, WIN and URB reversed the decreases in MAP-2 and synaptophysin expression resulting from CCH, and stimulated BDNF and CB1 expression as well as CREB, FOXO3A, GSK-3β, and BAD phosphorylation, confirming that WIN and URB mediate neuroprotection by preventing neuronal apoptosis and improving cognition via PI3K/AKT signaling. These findings suggest that WIN and URB are promising agents for therapeutic management of CCH. PMID:27424778

  18. (+)-Dinapsoline: an efficient synthesis and pharmacological profile of a novel dopamine agonist.

    PubMed

    Sit, Sing-Yuen; Xie, Kai; Jacutin-Porte, Swanee; Taber, Matthew T; Gulwadi, Amit G; Korpinen, Carolyn D; Burris, Kevin D; Molski, Thaddeus F; Ryan, Elaine; Xu, Cen; Wong, Henry; Zhu, Juliang; Krishnananthan, Subramaniam; Gao, Qi; Verdoorn, Todd; Johnson, Graham

    2002-08-15

    A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).

  19. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  20. Regioselective demethylation of quinoline derivatives. A DFT rationalization

    NASA Astrophysics Data System (ADS)

    Belferdi, Fatiha; Merabet, Naima; Belkhiri, Lotfi; Douara, Bachir

    2016-08-01

    Demethylation of compound 2,7-dimethoxyquinoline-3-carbaldehyde 1, is carried out using BBr3. However, all attempts led, either to the starting material or to the regioselective demethylation at position 2 affording the product 4a. The nature (donor or acceptor) and the position of the R (CHO or CN) group is likely to play a role in the preventing the demethylation at position 7. To address this phenomena, the demethylation of 2-chloro-7-methoxyquinoline-3-carbaldehyde 2 and 2,7-dimethoxyquinoline-3-carbaldehyde 3 has been carried out. To support the results obtained, theoretical computations at DFT level (vide infra) have been carried out upon compound 1. The exploration of how the gas-phase demethylation process on Quinoline can be affected at a position 7 center by stepwise substation effects using different electro-donor and attractor groups, show that demethylation process seems to be more favorable when substituent is an electro-donor. This is sustained by bond energy and thermodynamic analyses (vide infra).

  1. Zero Kinetic Energy Photoelectron Spectroscopy of Benzo[h]quinoline.

    PubMed

    Harthcock, Colin; Zhang, Jie; Kong, Wei

    2015-12-17

    We report zero kinetic energy (ZEKE) photoelectron spectroscopy of benzo[h]quinoline (BhQ) via resonantly enhanced multiphoton ionization (REMPI) through the first electronically excited state S1. From the simulated REMPI spectra with and without Herzberg-Teller coupling, we conclude that vibronic coupling plays a minor but observable role in the electronic excitation to the S1 state. We further compare the S1 state of BhQ with the first two electronically excited states of phenanthrene, noticing a similarity of the S1 state of BhQ with the second electronically excited state S2 of phenanthrene. In the ZEKE spectra of BhQ, the vibrational frequencies of the cationic state D0 are consistently higher than those of the intermediate neutral state, indicating enhanced bonding upon ionization. The sparse ZEKE spectra, compared with the spectrum of phenanthrene containing rich vibronic activities, further imply that the nitrogen atom has attenuated the structural change between S1 and D0 states. We speculate that the nitrogen atom can withdraw an electron in the S1 state and donate an electron in the D0 state, thereby minimizing the structural change during ionization. The origin of the first electronically excited state is determined to be 29,410 ± 5 cm(-1), and the adiabatic ionization potential is determined to be 65,064 ± 7 cm(-1). PMID:26039927

  2. UV action spectroscopy of protonated PAH derivatives. Methyl substituted quinolines

    NASA Astrophysics Data System (ADS)

    Klærke, B.; Holm, A. I. S.; Andersen, L. H.

    2011-08-01

    Aims: We investigate the production of molecular photofragments upon UV excitation of PAH derivatives, relevant for the interstellar medium. Methods: The action absorption spectra of protonated gas-phase methyl-substituted quinolines (CH3 - C9H7NH+) have been recorded in the 215-338 nm spectral range using the electrostatic storage ring ELISA, an electrospray ion source and 3 ns UV laser pulses. Results: It is shown that the absorption profile is both redshifted and broadened when moving the methyl group from the heterocycle containing nitrogen to the homoatomic ring. The absorption profiles are explained by TD-DFT calculations. The dissociation time of the studied molecules is found to be of several milliseconds at 230 nm and it is shown that after redistribution of the absorbed energy the molecules dissociate in several channels. The dissociation time found is an order of magnitude faster than the estimated IR relaxation time. Photophysical properties of both nitrogen containing and methyl-substituted PAHs are interesting in an astrophysical context in connection with identifying the aromatic component of the interstellar medium.

  3. Antimalarial quinolines and artemisinin inhibit endocytosis in Plasmodium falciparum.

    PubMed

    Hoppe, Heinrich C; van Schalkwyk, Donelly A; Wiehart, Ursula I M; Meredith, Sandra A; Egan, Joanne; Weber, Brandon W

    2004-07-01

    Endocytosis is a fundamental process of eukaryotic cells and fulfills numerous functions, most notably, that of macromolecular nutrient uptake. Malaria parasites invade red blood cells and during their intracellular development endocytose large amounts of host cytoplasm for digestion in a specialized lysosomal compartment, the food vacuole. In the present study we have examined the effects of artemisinin and the quinoline drugs chloroquine and mefloquine on endocytosis in Plasmodium falciparum. By using novel assays we found that mefloquine and artemisinin inhibit endocytosis of macromolecular tracers by up to 85%, while the latter drug also leads to an accumulation of undigested hemoglobin in the parasite. During 5-h incubations, chloroquine inhibited hemoglobin digestion but had no other significant effect on the endocytic pathway of the parasite, as assessed by electron microscopy, the immunofluorescence localization of hemoglobin, and the distribution of fluorescent and biotinylated dextran tracers. By contrast, when chloroquine was added to late ring stage parasites, followed by a 12-h incubation, macromolecule endocytosis was inhibited by more than 40%. Moreover, there is an accumulation of transport vesicles in the parasite cytosol, possibly due to a disruption in vacuole-vesicle fusion. This fusion block is not observed with mefloquine, artemisinin, quinine, or primaquine but is mimicked by the vacuole alkalinizing agents ammonium chloride and monensin. These results are discussed in the light of present theories regarding the mechanisms of action of the antimalarials and highlight the potential use of drugs in manipulating and studying the endocytic pathway of malaria parasites.

  4. Antiglycation activity of quinoline derivatives- a new therapeutic class for the management of type 2 diabetes complications.

    PubMed

    Bano, Bilquees; Abbasi, Sanaullah; Khan, Jalaluddin A J; Hussain, Shafqat; Rasheed, Saima; Perveen, Shahnaz; Khan, Khalid Mohammed; Choudhary, M Iqbal

    2014-01-01

    We report here a new class of compounds, quinoline derivatives, as potential inhibitors of in vitro bovine serum albumin-methylglyoxal glycation. Among compounds 1-19, compound 14 was found to be the most active analog with IC₅₀ of 282.98 ± 8.4 µM. Compounds 12 (IC₅₀ = 661.78 ± 8.7 µM) and 15 (IC₅₀ = 629.43 ± 7.85 7 µM) were also identified as modest inhibitors, in comparison to the standard inhibitor, rutin (IC₅₀ = 294.50 ± 1.5 µM). When evaluated for antioxidant activity through in vitro DPPH radical scavenging assay, compounds 3 (IC₅₀ = 2.19 ± 0.27 µM), 6 (IC₅₀ = 7.35 ± 2.27 µM), 11 (IC₅₀ = 8.96 ± 0.56 µM), and 12 (IC₅₀ = 10.11 ± 2.03 µM), and 15 (IC₅₀ = 7.01 ± 3.87 µM) were found to be more active than the standard i.e. gallic acid (IC₅₀ = 23.34 ± 0.43 µM). These compounds were also evaluated for cytotoxicity against rat fibroblast cell line (3T3 cell line). All compounds were found to be non-toxic in cellular model. This study identifies quinoline derivatives as a new class of inhibitors of protein glycation in vitro, along with antioxidant and non-toxic nature. These properties make them interesting leads for further studies as potential anti-diabetic agents. PMID:24875825

  5. When Indolizine Meets Quinoline: Diversity-Oriented Synthesis of New Polyheterocycles and Their Optical Properties.

    PubMed

    Park, Sujin; Kwon, Dah In; Lee, Jeeyeon; Kim, Ikyon

    2015-08-10

    Fluorescence-based technologies play a pivotal role in various biomedical applications. Here we report an efficient route to a new class of fluorophores, indolizino[3,2-c]quinolines, via the oxidative Pictet-Spengler cyclization strategy. The condensation of several 2-methylpyridines with 2-bromo-2'-nitroacetophenone allowed for the rapid assembly of indolizines with a 2-nitrophenyl group at the C2 position. The subsequent reduction of the nitro group under mild conditions followed by oxidative Pictet-Spengler cyclization with various aryl aldehydes in the presence of a catalytic amount of FeCl3 furnished the indolizino[3,2-c]quinolines in good overall yields. We also examined the photophysical properties of this new series of polyheterocyclic compounds. Several indolizino[3,2-c]quinolines were found to have unique and desirable optical properties, suggesting that these compounds may be suitable for use as prospective fluorescent probes in aqueous systems. PMID:26203781

  6. Synthesis and evaluation of antioxidant activity of new quinoline-2-carbaldehyde hydrazone derivatives: bioisosteric melatonin analogues.

    PubMed

    Puskullu, M Orhan; Shirinzadeh, Hanif; Nenni, Merve; Gurer-Orhan, Hande; Suzen, Sibel

    2016-01-01

    Overproduction of reactive oxygen species results in oxidative stress that can cause fatal damage to vital cell structures. It is known that the use of antioxidants could be beneficial in the prevention or delay of numerous diseases associated with oxidative stress. Melatonin (MLT) is known as a powerful free-radical scavenger and antioxidant. It was found that indole ring of MLT can be employed by bioisosteric replacement by other aromatic rings. Quinoline derivatives constitute an important class of compounds for new drug development. Owing to quinoline and hydrazones appealing physiological properties and are mostly found in numerous biologically active compounds a series of quinoline-2-carbaldehyde hydrazone derivatives were synthesized as bioisosteric analogues of MLT, characterized and in vitro antioxidant activity was investigated by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Cytotoxicity potential of all compounds was investigated both by lactate dehydrogenase leakage assay and by MTT assay.

  7. A New One-Pot Synthesis of Quinoline-2-carboxylates under Heterogeneous Conditions.

    PubMed

    Gabrielli, Serena; Giardinieri, Alessandra; Sampaolesi, Susanna; Ballini, Roberto; Palmieri, Alessandro

    2016-01-01

    Quinoline-2-carboxylates are an important subclass of quinoline derivatives largely present in a variety of biologically active molecules, as well as useful ligands in metal-catalyzed reactions. Herein, we present a new one-pot protocol for synthesizing this class of derivatives starting from β-nitroacrylates and 2-aminobenzaldehydes. In order to optimize the protocol, we investigated several reaction conditions, obtaining the best results using the 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) as solid base, in acetonitrile. Finally, we demonstrated the generality of our approach over several substrates which led to synthesize a plethora of functionalized quinolines-2-carboxylate derivatives in good overall yields.

  8. Design, evaluation, and comparison of ghrelin receptor agonists and inverse agonists as suitable radiotracers for PET imaging.

    PubMed

    Chollet, Constance; Bergmann, Ralf; Pietzsch, Jens; Beck-Sickinger, Annette G

    2012-04-18

    Ghrelin agonist and inverse agonist radiotracers, suitable for positron emission tomography (PET), were developed to study the behavior of ghrelin receptor ligands in vivo and for further design of druggable peptides. The target peptides were synthesized on solid support and conjugated to the bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga(3+). Complexation with (68)Ga could be achieved under mild conditions and led to radiotracers with high radiochemical purity and specific activity. The biological activity of the radiotracers was evaluated in vitro by an inositol phosphate turnover assay. Pharmacokinetic profile and metabolic stability of the (68)Ga-NODAGA-radiotracers were investigated by small animal PET in rodent. Ghrelin derived agonists presented very high kidney accumulation, negligible tissue distribution, fast blood clearance, and poor stability in blood. Contrarily, the inverse agonist radiotracer exhibited very high stability in blood, large diffusion in tissues, reasonable kidney and liver metabolism, and slow blood clearance. This pharmacokinetic profile makes the ghrelin inverse agonist motif KwFwLL-CONH(2) suitable for further development of radiotracers and a promising lead to design peptide-based therapeutics against obesity. PMID:22372770

  9. Human Toll-like receptor 8-selective agonistic activities in 1-alkyl-1H-benzimidazol-2-amines.

    PubMed

    Beesu, Mallesh; Malladi, Subbalakshmi S; Fox, Lauren M; Jones, Cassandra D; Dixit, Anshuman; David, Sunil A

    2014-09-11

    Toll-like receptor (TLR)-8 agonists strongly induce the production of T helper 1-polarizing cytokines and may therefore serve as promising candidate vaccine adjuvants, especially for the very young and the elderly. Earlier structure-based ligand design led to the identification of 3-pentyl-quinoline-2-amine as a novel, human TLR8-specific agonist. Comprehensive structure-activity relationships in ring-contracted 1-alkyl-1H-benzimidazol-2-amines were undertaken, and the best-in-class compound, 4-methyl-1-pentyl-1H-benzo[d]imidazol-2-amine, was found to be a pure TLR8 agonist, evoking strong proinflammatory cytokine and Type II interferon responses in human PBMCs, with no attendant CD69 upregulation in natural lymphocytic subsets. The 1-alkyl-1H-benzimidazol-2-amines represent a novel, alternate chemotype with pure TLR8-agonistic activities and will likely prove useful not only in understanding TLR8 signaling but also perhaps as a candidate vaccine adjuvant. PMID:25102141

  10. Convergent Synthesis of 2-Aryl-Substituted Quinolines by Gold-Catalyzed Cascade Reaction.

    PubMed

    Ueda, Hirofumi; Yamaguchi, Minami; Tokuyama, Hidetoshi

    2016-01-01

    Gold-catalyzed auto-tandem catalysis has been developed for synthesizing 2-aryl-substituted quinolines. The reaction of an aniline bearing an acetal moiety with an aryl alkyne proceeded via formal [4+2]-cycloaddition, which involved the addition of gold acetylide to an oxonium ion to give amino alkyne intermediate and sequential 6-endo-dig cyclization of amino alkyne intermediate by attacking of nitrogen to alkyne moiety activated by gold catalyst. The cationic gold catalyst promoted two different processes by enhancing the nucleophilicity and electrophilicity of alkyne. This convergent synthetic methodology enabled the synthesis of a variety of 2-aryl-substituted quinolines. PMID:27373638

  11. Synthesis of substituted quinolines via allylic amination and intramolecular Heck-coupling.

    PubMed

    Murru, Siva; McGough, Brandon; Srivastava, Radhey S

    2014-12-01

    A new catalytic approach for the synthesis of substituted quinolines via C-N and C-C bond formation using 2-haloaryl hydroxylamines and allylic C-H substrates is described. Fe-catalyzed allylic C-H amination followed by Pd-catalyzed intramolecular Heck-coupling and aerobic dehydrogenation deliver the valuable quinoline and naphthyridine heterocycles in good to excellent overall yields. In this process, Pd(OAc)2 plays a dual role in catalyzing Heck coupling as well as aerobic dehydrogenation of dihydroquinolines. PMID:25247637

  12. 2-(Anthracen-9-yl)-10-meth-oxy-benzo[h]quinoline acetone hemisolvate.

    PubMed

    Dong, Zhenming; Liu, Bo; Cui, Xinxin; Liu, Yufang

    2012-08-01

    The asymmetric unit of the title structure, C(28)H(19)NO·0.5C(3)H(6)O, comprises one 2-(anthracen-9-yl)-10-meth-oxy-benzo[h]-quinoline mol-ecule and an acteone mol-ecule with an occupany of 0.5. The solvent mol-ecule is disordered around a centre of symmetry. Its occupancy was determined from NMR data and kept fixed during the refinement. The two conjugated ring systems of the mol-ecule are almost perpendicular to each other; the inter-planar angle between the anthracene and quinoline ring systems is 84.9 (2)°. PMID:22904968

  13. Vibronic Spectroscopy of a Structural Isomer of Quinoline: -

    NASA Astrophysics Data System (ADS)

    Mehta-Hurt, Deepali N.; Korn, Joseph A.; Zwier, Timothy S.

    2013-06-01

    This talk will present results of a gas phase, jet-cooled vibronic spectroscopy study of (Z)-phenylvinylnitrile ((Z)-C_6H_5-CH=CH-C=N, (Z)-PVN). With a substituent locked into a cis conformation with respect to the aromatic ring, (Z)-PVN is postulated to be a molecule with an ideal functionality to isomerize to quinoline upon photoexcitation. As such, (Z)-PVN is particularly relevant to Titan's nitrile-containing atmosphere, where much of the chemistry is photochemically driven. As a first step towards such photochemical studies, a fluorescence excitation spectrum of a mixture of (E)- and (Z)-PVN was collected spanning the range 33,300-35,580 cm^{-1} (300.0-281.0 nm). Previous investigations in the Zwier group pertaining to the vibronic spectroscopy of (E)-PVN allowed for the identification of peaks in the (E)- and (Z)-PVN composite spectrum that were solely due to (Z)-PVN, and the S_0-S_1 origin of (Z)-PVN was identified as a dominant band that occurs at 33,706 cm^{-1}. For additional confirmation, ultraviolet depletion spectroscopy (UVD) was used to obtain an isomer specific spectrum of (Z)-PVN as well as search for non-radiative transitions. Dispersed fluorescence spectra that characterize the vibronic activity have also been acquired. A comparison between the vibronic spectroscopy of (Z)-PVN with both (E)-PVN and (Z)-phenylvinylacetylene ((Z)-PVA), the hydrocarbon analog of (Z)-PVN, will be made in this talk.

  14. Peripherally mediated antinociception of the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) after subcutaneous and oral administration in rats with carrageenan-induced hindpaw inflammation.

    PubMed

    Bileviciute-Ljungar, Indre; Spetea, Mariana; Guo, Yan; Schütz, Johannes; Windisch, Petra; Schmidhammer, Helmut

    2006-04-01

    Opioids induce analgesia by activating opioid receptors not only within the central nervous system but also on peripheral sensory neurons. This study investigated peripherally mediated antinociception produced by the mu-opioid receptor agonist 2-[(4,5alpha-epoxy-3-hydroxy-14beta-methoxy-17-methylmorphinan-6beta-yl)amino]acetic acid (HS-731) after s.c. and oral administration in rats with carrageenan-induced hindpaw inflammation. Antinociceptive effects after s.c. administration were assessed 3 h after intraplantar carrageenan injection and compared with those of centrally acting mu-opioid agonists 14-methoxymetopon and morphine. Opioid agonists caused dose-dependent increases in inflamed paw withdrawal latencies to mechanical and thermal stimulation. The time course of action was different, in that HS-731 (20 microg/kg s.c.) produced significant long-lasting effects up to 4 h after administration, whereas 14-methoxymetopon (20 microg/kg) and morphine (2 mg/kg) reached their peak of action at 10 to 30 min, and their effect declined rapidly thereafter. Subcutaneous administration of the peripherally selective opioid antagonist naloxone methiodide inhibited antinociception elicited by HS-731 (20 microg/kg s.c.), whereas it was ineffective against 14-methoxymetopon (20 microg/kg s.c.). Moreover, the antinociception produced by 100 microg/kg s.c. HS-731 was dose-dependently reversed by s.c. naloxone methiodide. This indicates that HS-731 preferentially activates peripheral opioid receptors, whereas 14-methoxymetopon mediates analgesia via central mechanisms. Orally administered HS-731 significantly reduced hyperalgesia in the inflamed paw induced by carrageenan, which was reversible by s.c. administered naloxone methiodide. These results show that systemic (s.c. and oral) treatment with the mu-opioid agonist HS-731 produces potent and long-lasting antinociception through peripheral mechanisms in rats with carrageenan-induced hindpaw inflammation.

  15. Synthesis and structure of interaction products of quinoline-2(1H)-thione with molecular iodine.

    PubMed

    Chernov'yants, Margarita S; Starikova, Zoya A; Kolesnikova, Tatiana S; Karginova, Anastasia O; Lyanguzov, Nikolay V

    2015-03-15

    The behavior of quinoline-2(1H)-thione, which is a potential antithyroid drug toward molecular iodine, was investigated. The ability of quinoline-2(1H)-thione to form the outer-sphere charge-transfer complex C9H7NS·I2 with iodine molecular in dilute chloroform solution has been studied by UV-vis spectroscopy (lgβ=3.85). The crystal structure of the new salt 2-(quinoline-2-yldisulfanyl)quinolinium triiodide - product of irreversible oxidation of quinoline-2(1H)-thione was determined by X-ray diffraction. The 2-(quinoline-2-yldisulfanyl)quinolinium cations form dimers through π-π-stacking interaction between quinoline rings. Strong intramolecular interactions are observed between iodine - sulfur atoms and iodine - hydrogen atoms with shortened contacts (less of sum of van der Waals contacts). It is noteworthy that two perfectly centrosymmetrical anions I3(-) form a very short contact I(3)⋯I(3') 3.7550(5) so we can state the formation of the dianion I(6)(2-). Therefore the formation and topology of polyiodide species depend on the characteristics, such as shape, size and charge, etc., of the counter cation, 2-(quinoline-2-yldisulfanyl)quinolinium, which is considered as templating agent. PMID:25579655

  16. Effect of starvation on induction of quinoline degradation for a subsurface bacterium in a continuous-flow column

    SciTech Connect

    Truex, M.J.; Brockman, F.J.; Fredrickson, J.K. ); Johnstone, D.L. )

    1992-08-01

    Differences in the induction response and the initial two reactions of quinoline degradation between short-term and long-term starved cells of a subsurface Pseudomonas cepacia strain were examined by using continuous-flow columns. The ability of bacteria that are indigenous to oligotrophic environments to respond to a contaminant was assessed by using long-term starvation to induce a cell physiology that stimulates the in situ physiology of the bacteria. With quinoline concentrations of 39 and 155 [mu]M, long-term-starved cells converted quinoline to degradation products more efficiently than did short-term-starved cells. Quinoline concentrations of 155 [mu]M and, to a greater extent, 775 [mu]M had an inhibitory effect on induction in long-term-starved cells. However, only the length of the induction process was affected with these quinoline concentrations; degradation of quinoline at the steady state for long-term-starved cells was equal to or better than that for short-term-starved cells. The induction time for short-term-starved cells did not increase progressively with increasing quinoline concentration. Experiments with starved cells are important for the development of accurate predictive models of contaminant transport in the subsurface because starvation, which induces a cell physiology that stimulates the in situ physiology of many bacteria, may affect the induction process.

  17. Synthesis and structure of interaction products of quinoline-2(1H)-thione with molecular iodine.

    PubMed

    Chernov'yants, Margarita S; Starikova, Zoya A; Kolesnikova, Tatiana S; Karginova, Anastasia O; Lyanguzov, Nikolay V

    2015-03-15

    The behavior of quinoline-2(1H)-thione, which is a potential antithyroid drug toward molecular iodine, was investigated. The ability of quinoline-2(1H)-thione to form the outer-sphere charge-transfer complex C9H7NS·I2 with iodine molecular in dilute chloroform solution has been studied by UV-vis spectroscopy (lgβ=3.85). The crystal structure of the new salt 2-(quinoline-2-yldisulfanyl)quinolinium triiodide - product of irreversible oxidation of quinoline-2(1H)-thione was determined by X-ray diffraction. The 2-(quinoline-2-yldisulfanyl)quinolinium cations form dimers through π-π-stacking interaction between quinoline rings. Strong intramolecular interactions are observed between iodine - sulfur atoms and iodine - hydrogen atoms with shortened contacts (less of sum of van der Waals contacts). It is noteworthy that two perfectly centrosymmetrical anions I3(-) form a very short contact I(3)⋯I(3') 3.7550(5) so we can state the formation of the dianion I(6)(2-). Therefore the formation and topology of polyiodide species depend on the characteristics, such as shape, size and charge, etc., of the counter cation, 2-(quinoline-2-yldisulfanyl)quinolinium, which is considered as templating agent.

  18. Mono- and multimeric ferrocene congeners of quinoline-based polyamines as potential antiparasitics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A series of mono- and multimeric polyamine-containing ferrocenyl complexes bearing a quinoline motif were prepared. The complexes were characterised by standard techniques. The molecular structure of the monomeric salicylaldimine derivative was elucidated using single crystal X-ray diffraction and w...

  19. Solvent-free Povarov reaction for synthesizing ferrocenyl quinolines: antioxidant abilities deriving from ferrocene moiety.

    PubMed

    Xi, Gao-Lei; Liu, Zai-Qun

    2014-10-30

    Twenty-two 2-phenyl-4-ferrocenylquinolines are synthesized by Povarov three-component-reaction (3CR) among the substituted anilines, benzaldehydes, and ferrocenylacetylene with Ce(OTf)3 being catalyst in the absence of solvents. The antioxidative effects of the obtained quinolines are estimated by quenching 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+·)), 2,2'-diphenyl-1-picrylhydrazyl (DPPH), and galvinoxyl radicals, and by inhibiting Cu(2+)/glutathione (GSH)-, hydroxyl radical (·OH)-, and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidations of DNA. It is found that the ferrocenyl group instead of hydroxyl group generates the antioxidative effect for quinoline to quench radicals and to protect DNA against radical-induced oxidations. The antioxidative effect generated by ferrocenyl group can be further increased by the electron-donating moieties such as furan, -N(CH3)2, -OCH3, and ferrocenyl group, while the electron-withdrawing groups such as -NO2 and -Cl are not beneficial for quinolines to be antioxidants. The ferrocenyl group in quinoline exhibits higher antioxidant activity than hydroxyl group in Trolox.

  20. Self-Assembly of a Library of Polyborate Chiral Anions for Asymmetric Catalytic Quinoline Reduction

    PubMed Central

    Desai, Aman A.; Guan, Yong; Odom, Aaron L.; Majumder, Supriyo; Wulff, William D.

    2015-01-01

    The ‘template’ polyborate BOROX catalysts are shown to mediate the asymmetric transfer hydrogenation of 2-quinolines. The rapid and simple generation of a large family of BOROX catalysts with significantly altered asymmetric pockets is described. A transition state model that explains the enantioselectivity is proposed. PMID:26034335

  1. The role of the characteristics of humic substances in binding with benzo[h]quinoline.

    PubMed

    Hsieh, Ping-Chieh; Brimblecombe, Peter; Lee, Chon-Lin; Hsu, Shih-Han

    2012-02-01

    The binding constants (K(DOC)) of the mixture of benzo[h]quinoline and its protonated analog, benzo[h]quinolinium, to four types of humic substances obtained from the International Humic Substances Society were determined by the fluorescence quenching method. A simple mixing model was used to eliminate the fluorescent interference from the minor analog in the solution and to deduce K(mix), which represents the overall binding as the sum of that for the individual analogs. The characteristics of humic substances, especially their hydrophobicity and aromaticity, established by principal component analysis of structural and elemental compositions, were the main determinants of the binding affinity with both benzo[h]quinoline and benzo[h]quinolinium (K(BQ) and K (BQH+) across a range of pH values. The strongest overall affinity of benzo[h]quinoline for humic substances is observed near pH 4 and with more hydrophobic humic substances, which suggests possible choices in attempts at remediation of benzo[h]quinoline containing particles with humic substances. PMID:22065405

  2. Fast regioselective sulfonylation of pyridine/quinoline N-oxides induced by iodine.

    PubMed

    Wang, Ruijia; Zeng, Zebing; Chen, Chuang; Yi, Niannian; Jiang, Jun; Cao, Zhong; Deng, Wei; Xiang, Jiannan

    2016-06-21

    Fast sulfonylation of pyridine/quinoline N-oxides induced by iodine is demonstrated herein. The regioselective protocol occurs under metal-free conditions in a short reaction time (10 min), exhibiting high efficiency (up to 92% yield) and good compatibility (up to 33 examples). A gram-scale reaction was conducted with only a slight loss of production. PMID:27219641

  3. Microbial hydroxylation of quinoline in contaminated groundwater: evidence for incorporation of the oxygen atom of water.

    USGS Publications Warehouse

    Pereira, W.E.; Rostad, C.E.; Leiker, T.J.; Updegraff, D.M.; Bennett, J.L.

    1988-01-01

    Studies conducted in an aquifer contaminated by creosote suggest that quinoline is converted to 2(1H)quinolinone by an indigenous consortium of microorganisms. Laboratory microbial experiments using H218O indicate that water is the source of the oxygen atom for this hydroxylation reaction under aerobic and anaerobic conditions.

  4. Optimized quinoline amino alcohols as disruptors and dispersal agents of Vibrio cholerae biofilms

    PubMed Central

    León, Brian; Jake Haeckl, F. P.; Linington, Roger G.

    2015-01-01

    The biofilm state is an integral part of the lifecycle of many bacterial pathogens. Identifying inhibitors as molecular probes against bacterial biofilms has numerous potential biomedical applications. Here we report quinoline amino alcohol 20 as a highly potent disruptor of V. cholerae biofilms. Additionally, 20 was able to disperse preformed biofilms, an activity exhibited by few compounds with biofilm inhibiting activity. PMID:26156292

  5. Structural evaluation of three 2-phenylpyrazolo[4,3-c]quinolin-3-one monohydrates

    NASA Astrophysics Data System (ADS)

    Ferreira, Vitor F.; Leal, Katia Z.; Lindgren, Eric B.; de Oliveira, Mara R. P.; de Souza, Maria Celia B. V.; Vasconcelos, Thatyana R. A.; Wardell, James L.; Wardell, Solange M. S. V.; Yoneda, Julliane D.

    2013-11-01

    A single crystal X-ray diffraction and theoretical study has been carried out on mono hydrates of three 2H-pyrazolo[4,3-c]quinolin-3(5H)-one derivatives, namely 6-methyl-2-phenylpyrazolo[4,3-c]quinolin-3-one, 3, 6-methyl-2-(4-chlorophenyl)pyrazolo[4,3-c]quinolin-3-one, 4, and 8-methyl-2-(4-nitrophenyl)pyrazolo[4,3-c]quinolin-3-one, 5. The monohydrates were obtained on recrystallization from moist solvents. While there are three tautomeric forms possible for such pyrazolo[4,3-c]quinolin-3-one molecules, the sole form isolated in the solid [(X)ṡ(H2O)] (X = 3, 4 and 5) compounds was the quinoloid form - the one calculated to be the most stable at the M06-2X/6-311++G(d,p) level of theory. Excellent agreement was found between the calculated and X-ray determined structures. Molecule 5 in [(5)ṡ(H2O)] is very near planar while both molecules 3 and 4 in their respective hydrates are much less so as a consequence of angles about 24° between the two aromatic rings. In each hydrate, the pyrazolo[4,3-c]quinolin-3-one molecule is bonded to three water molecules and each water molecule is likewise H-bonded to three pyrazolo[4,3-c]quinolin-3-one molecules. While the water molecules are H-bonded to 3 and 4 via the pyridinyl N and 2x the carbonyl O atoms, in [(5)ṡ(H2O)] the H-bonds are to pyridinyl N, carbonyl O and a nitro O atoms. Calculations indicated that the found arrangement in [(5)ṡ(H2O)] is more stable than one using the connections as found in [(3)ṡ(H2O)] and [(4)ṡ(H2O)]. While each of the hydrates possess strong Nsbnd H⋯O and Osbnd H⋯O hydrogen bonds, and weaker Csbnd H⋯π and π⋯π interactions, the supramolecular arrays are very different.

  6. The washout effect during laundry on benzothiazole, benzotriazole, quinoline, and their derivatives in clothing textiles.

    PubMed

    Luongo, Giovanna; Avagyan, Rozanna; Hongyu, Ren; Östman, Conny

    2016-02-01

    In two previous papers, the authors have shown that benzothiazole, benzotriazole, quinoline, and several of their derivatives are widespread in clothing textile articles. A number of these compounds exhibit allergenic and irritating properties and, due to their octanol-water partition coefficient, are prone to be absorbed by the skin. Moreover, they are slightly soluble in water, which could make washing of clothes a route of emission into the environment. In the present study, the washout effect of benzothiazole, benzotriazole, quinoline, and some of their derivatives has been investigated. Twenty-seven textile samples were analyzed before, as well as after five and ten times of washing. The most abundant analyte was found to be benzothiazole, which was detected in 85 % of the samples with an average concentration of 0.53 μg/g (median 0.44 μg/g), followed by quinoline, detected in 81 % of the samples with an average concentration of 2.42 μg/g (median 0.21 μg/g). The average decrease in concentration for benzothiazoles was 50 % after ten times washing, while it was around 20 % for quinolines. The average emission to household wastewater of benzothiazoles and quinolines during one washing (5 kg of clothes made from polyester materials) was calculated to 0.5 and 0.24 g, respectively. These results strongly indicate that laundering of clothing textiles can be an important source of release of these compounds to household wastewater and in the end to aquatic environments. It also demonstrates a potential source of human exposure to these chemicals since considerable amounts of the compounds remain in the clothes even after ten times of washing.

  7. The washout effect during laundry on benzothiazole, benzotriazole, quinoline, and their derivatives in clothing textiles.

    PubMed

    Luongo, Giovanna; Avagyan, Rozanna; Hongyu, Ren; Östman, Conny

    2016-02-01

    In two previous papers, the authors have shown that benzothiazole, benzotriazole, quinoline, and several of their derivatives are widespread in clothing textile articles. A number of these compounds exhibit allergenic and irritating properties and, due to their octanol-water partition coefficient, are prone to be absorbed by the skin. Moreover, they are slightly soluble in water, which could make washing of clothes a route of emission into the environment. In the present study, the washout effect of benzothiazole, benzotriazole, quinoline, and some of their derivatives has been investigated. Twenty-seven textile samples were analyzed before, as well as after five and ten times of washing. The most abundant analyte was found to be benzothiazole, which was detected in 85 % of the samples with an average concentration of 0.53 μg/g (median 0.44 μg/g), followed by quinoline, detected in 81 % of the samples with an average concentration of 2.42 μg/g (median 0.21 μg/g). The average decrease in concentration for benzothiazoles was 50 % after ten times washing, while it was around 20 % for quinolines. The average emission to household wastewater of benzothiazoles and quinolines during one washing (5 kg of clothes made from polyester materials) was calculated to 0.5 and 0.24 g, respectively. These results strongly indicate that laundering of clothing textiles can be an important source of release of these compounds to household wastewater and in the end to aquatic environments. It also demonstrates a potential source of human exposure to these chemicals since considerable amounts of the compounds remain in the clothes even after ten times of washing. PMID:26429136

  8. Development of 2′-substituted (2S,1′R,2′S)-2-(carboxycyclopropyl)glycine analogues as potent N-methyl-d-aspartic acid receptor agonists

    PubMed Central

    Risgaard, Rune; Nielsen, Simon D.; Hansen, Kasper B.; Jensen, Christina M.; Nielsen, Birgitte; Traynelis, Stephen F.; Clausen, Rasmus P.

    2013-01-01

    A series of 2′-substituted analogues of the selective NMDA receptor ligand (2S,1′R,2′S)-2-(carboxycyclopropyl)glycine ((S)-CCG-IV) have been designed, synthesized and pharmacologically characterized. The design was based on a docking study hypothesizing that substituents in the 2′-position would protrude into a region where differences among the NMDA receptor GluN2 subunits exist. Various synthetic routes were explored, and two different routes provided a series of alkyl-substituted analogues. Pharmacological characterization revealed that these compounds are NMDA receptor agonists and that potency decreases with increasing size of the alkyl groups. Variations in agonist activity are observed at the different recombinant NMDA receptor subtypes. This study demonstrates that it is possible to introduce substituents in the 2′-position of (S)-CCG-IV while maintaining agonist activity and that variation among NMDA receptor subtypes may be achieved by probing this region of the receptor. PMID:23614571

  9. Quinoline-Substituted 10-(naphthalene-7-yl)anthracene Derivatives for Blue Fluorescent Organic Light-Emitting Diodes.

    PubMed

    Kim, Chanwoo; Park, Soo Na; Lee, Seul Bee; Kim, Young Seok; Lee, Ho Won; Kim, Young Kwan; Yoon, Seung Soo

    2016-02-01

    In this study, we have designed and synthesized blue emitters based on quinoline-substituted 10-(naphthalene-7-yl)anthracene. Particularly, a material exhibited highly efficient blue electroluminescence with CIE coordinates of (0.15, 0.18).

  10. Hydrogen-bis[2-(4-dimethylaminostyryl)-quinoline-1-oxide]dichlorocuprate (I) from X-ray study

    NASA Astrophysics Data System (ADS)

    Ekimova, T. A.; Tafeenko, V. A.; Aleshina, L. A.; Basalaev, R. S.; Andreev, V. P.; Nizhnik, Ya. P.

    2013-03-01

    X-ray diffraction data on powder and single-crystal samples were used to determine the crystal structure of hydrogen-bis[2-(4-dimethylaminostyryl)-quinoline-1-oxide]dichlorocuprate (I): monoclinic system, sp. gr. P21/ n, and Z = 2. Two molecules of N oxide of 2-(4-dimethylaminostyryl)quinoline are bound through a hydrogen atom located at the center of symmetry, thus forming a complex cation.

  11. Hydrogen-bis[2-(4-dimethylaminostyryl)-quinoline-1-oxide]dichlorocuprate (I) from X-ray study

    SciTech Connect

    Ekimova, T. A.; Tafeenko, V. A.; Aleshina, L. A.; Basalaev, R. S.; Andreev, V. P.; Nizhnik, Ya. P.

    2013-03-15

    X-ray diffraction data on powder and single-crystal samples were used to determine the crystal structure of hydrogen-bis[2-(4-dimethylaminostyryl)-quinoline-1-oxide]dichlorocuprate (I): monoclinic system, sp. gr. P2{sub 1}/n, and Z = 2. Two molecules of N oxide of 2-(4-dimethylaminostyryl)quinoline are bound through a hydrogen atom located at the center of symmetry, thus forming a complex cation.

  12. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  13. Ecotoxicity of quinoline and hydroxylated derivatives and their occurrence in groundwater of a tar-contaminated field site.

    PubMed

    Neuwoehner, Judith; Reineke, Anne-Kirsten; Hollender, Juliane; Eisentraeger, Adolf

    2009-03-01

    In the groundwater of a timber impregnation site higher concentrations of hydroxylated quinolines compared to their parent compounds quinoline and isoquinoline were found. Studying the toxicity of parent compounds and metabolites, genotoxicity was found with metabolic activation in the SOS-Chromotest and Ames fluctuation test only for quinoline. An adverse effect on algae was observed only for the parent compounds quinoline and isoquinoline, while in the Daphnia magna immobilization assay most hydroxylated quinoline derivatives showed toxicity. The highest ecotoxic potential was observed in the Vibrio fischeri luminescence-inhibition assay. Comparing experimental EC50-values with QSAR predicted ones, for all compounds apart from isoquinoline and 2(1H)-quinolinone in the V. fischeri test baseline toxicity or polar nacrosis is indicated. In conclusion, the hydroxylation of quinoline leads to a detoxification of the genotoxic potential, while taken additive mixture toxicity and a safety factor into account parent compounds and metabolites are found of ecotoxicological relevance in the groundwater. PMID:18550163

  14. Interactive effects involving different classes of excitatory amino acid receptors and the survival of cerebellar granule cells in culture.

    PubMed

    Balázs, R; Hack, N; Jørgensen, O S

    1990-01-01

    Differentiating granule cells develop survival requirements in culture which can be met by treatment with high K+ or N-methyl-D-aspartate (NMDA) and, according to our recent findings, also with low concentrations of kainic acid (KA, 50 microM). We have now attempted to elucidate the mechanism(s) underlying the trophic effect of KA. KA rescue of cells was completely suppressed by blockers of voltage-sensitive calcium channels, such as nifedipine in low concentrations (5 x 10(-7) M), indicating that the promotion of cell survival is mediated through the activation of these channels by membrane depolarization. Thus the trophic influences of KA and NMDA share a common mechanism, increased Ca2+ influx (albeit through different routes), a conclusion that is supported by the observation that the effects of these agonists at concentrations causing maximal promotion of cell survival were not additive. Interactive effects involving different classes of excitatory amino acid receptors were revealed by the potentiation of the KA rescue of cells by the NMDA receptor antagonists, 2-amino 5-phosphonovalerate (APV) or (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine hydrogen maleate (MK-801), which on their own failed to promote, but rather reduced cell survival. The potentiation of the KA effect by the competitive NMDA antagonist APV was counteracted by the weak NMDA agonist, quinolinic acid. These observations suggest that KA alone has both trophic and toxic effects, the latter being mediated secondarily through an NMDA-like glutamate receptor, which is distinct from the conventional NMDA, KA and quisqualate preferring subtypes.

  15. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

    PubMed

    Zaware, Pandurang; Shah, Shailesh R; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V V M; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. PMID:21195611

  16. Crystal Structures of Quinolinate Synthase in Complex with a Substrate Analogue, the Condensation Intermediate, and Substrate-Derived Product.

    PubMed

    Volbeda, Anne; Darnault, Claudine; Renoux, Oriane; Reichmann, Debora; Amara, Patricia; Ollagnier de Choudens, Sandrine; Fontecilla-Camps, Juan C

    2016-09-14

    The enzyme NadA catalyzes the synthesis of quinolinic acid (QA), the precursor of the universal nicotinamide adenine dinucleotide (NAD) cofactor. Here, we report the crystal structures of complexes between the Thermotoga maritima (Tm) NadA K219R/Y107F variant and (i) the first intermediate (W) resulting from the condensation of dihydroxyacetone phosphate (DHAP) with iminoaspartate and (ii) the DHAP analogue and triose-phosphate isomerase inhibitor phosphoglycolohydroxamate (PGH). In addition, using the TmNadA K219R/Y21F variant, we have reacted substrates and obtained a crystalline complex between this protein and the QA product. We also show that citrate can bind to both TmNadA K219R and its Y21F variant. The W structure indicates that condensation causes dephosphorylation. We propose that catalysis by the K219R/Y107F variant is arrested at the W intermediate because the mutated protein is unable to catalyze its aldo-keto isomerization and/or cyclization that ultimately lead to QA formation. Intriguingly, PGH binds to NadA with its phosphate group at the site where the carboxylate groups of W also bind. Our results shed significant light on the mechanism of the reaction catalyzed by NadA. PMID:27545412

  17. 2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors—Synthesis, Radiolabeling and Biodistribution

    PubMed Central

    Szymański, Paweł; Lázničková, Alice; Lázniček, Milan; Bajda, Marek; Malawska, Barbara; Markowicz, Magdalena; Mikiciuk-Olasik, Elżbieta

    2012-01-01

    In the present study we describe the synthesis and biological assessment of new tacrine analogs in the course of inhibition of acetylcholinesterase. The obtained molecules were synthesized in a condensation reaction between activated 6-BOC-hydrazinopyridine-3-carboxylic acid and 8-aminoalkyl derivatives of 2,3-dihydro-1H-cyclopenta[b]quinoline. Activities of the newly synthesized compounds were estimated by means of Ellman’s method. Compound 6h (IC50 = 3.65 nM) was found to be most active. All obtained novel compounds present comparable activity to that of tacrine towards acetylcholinesterase (AChE) and, simultaneously, lower activity towards butyrylcholinesterase (BChE). Apart from 6a, all synthesized compounds are characterized by a higher affinity for AChE and a lower affinity for BChE in comparison with tacrine. Among all obtained molecules, compound 6h presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling showed that all compounds demonstrated a similar binding mode with AChE and interacted with catalytic and peripheral sites of AChE. Also, a biodistribution study of compound 6a radiolabeled with 99mTc was performed. PMID:22949848

  18. Regioselective introduction of heteroatoms at the C-8 position of quinoline N-oxides: remote C-H activation using N-oxide as a stepping stone.

    PubMed

    Hwang, Heejun; Kim, Jinwoo; Jeong, Jisu; Chang, Sukbok

    2014-07-30

    Reported herein is the metal-catalyzed regioselective C-H functionalization of quinoline N-oxides at the 8-position: direct iodination and amidation were developed using rhodium and iridium catalytic systems, respectively. Mechanistic study of the amidation revealed that the unique regioselectivity is achieved through the smooth formation of N-oxide-chelated iridacycle and that an acid additive plays a key role in the rate-determining protodemetalation step. While this approach of remote C-H activation using N-oxide as a directing group could readily be applied to a wide range of heterocyclic substrates under mild conditions with high functional group tolerance, an efficient synthesis of zinquin ester (a fluorescent zinc indicator) was demonstrated.

  19. Simultaneous Determination of Potassium Sorbate, Sodium Benzoate, Quinoline Yellow and Sunset Yellow in Lemonades and Lemon Sauces by HPLC Using Experimental Design.

    PubMed

    Dinç Zor, Şule; Aşçı, Bürge; Aksu Dönmez, Özlem; Yıldırım Küçükkaraca, Dilek

    2016-07-01

    In this study, development and validation of a HPLC method was described for simultaneous determination of potassium sorbate, sodium benzoate, quinoline yellow and sunset yellow. A Box-Behnken design using three variables at three levels was employed to determine the optimum conditions of chromatographic separation: pH of mobile phase, 6.0-7.0; flow rate, 0.8-1.2 mL min(-1) and the ratio of mobile phase composed of a 0.025 M sodium acetate/acetic acid buffer, 80-90%. Resolution was chosen as a response. The optimized method was validated for linearity, the limits of detection and quantification, accuracy, precision and stability. All the validation parameters were within the acceptance range. The applicability of the developed method to the determination of these food additives in commercial lemonade and lemon sauce samples was successfully demonstrated. PMID:26951541

  20. Series of coordination polymers based on 4-(5-sulfo-quinolin-8-yloxy) phthalate and bipyridinyl coligands: Structure diversity and properties

    NASA Astrophysics Data System (ADS)

    Feng, Xun; Liu, Jing; Li, Jin; Ma, Lu-Fang; Wang, Li-Ya; Ng, Seik-Weng; Qin, Guo-Zhan

    2015-10-01

    Reactions between later metal salts and conjugational N-hetrocyclic sulfonate/ carboxylic acid under the presence of bipyridyl auxiliary ligands afforded a series of manganese, nickel, zinc, silver, cadmium coordination polymers bearing with phenyl pendant arm attached to quinoline skeletons, and they have been characterized by elements analysis, thermogravimetry, infrared spectroscopy and single-crystal X-ray diffraction studying. The series of polymers show interesting structural diversity in coordination environment, dimensions and topologies. They are all built from 2-D networks constructed from metal cluster through sulfonate or carboxylate groups, as the secondary building unit (SBU). The thermalgravimetric analyses show that they display framework stabilities in solid state. Variable-temperature magnetic susceptibility studies reveal the existence of antiferromagnetic interactions between adjacent Mn (II) ions in 1, and ferromagnetic interactions between Ni(II) ions for 2, respectively. The photo-luminescence properties of 3-5 have also been investigated systemically.

  1. Synthesis and Cytotoxicity Study of New Cyclopenta [b] quinoline-1,8-dione Derivatives

    PubMed Central

    Miri, Ramin; Firuzi, Omidreza; Peymani, Payam; Nazarian, Zohreh; Shafiee, Abbas

    2011-01-01

    DNA intercalators belong to aromatic heterocyclic compounds interacting reversibly with DNA. These compounds have been used extremely as cytotoxic agents against cancer. In this study, the synthesis and biological activity of some novel derivatives of cyclopenta [b] quinoline-1, 8-dione as new intercalating agent were investigated. Twenty novel derivatives of cyclopenta [b] quinoline-1, 8-dione were synthesized by molecular condensation of equivalent amount of 3-imino cyclopentanone, corresponding aldehyde and cyclohexane-1, 3-dione. Then, their cytotoxic activity was evaluated against HeLa, LS180, MCF-7 and Raji cancer cell lines by MTT assay. The results of cytotoxic activity evaluation indicate that the most of synthesized compounds show weak cytotoxic effect on the different cell lines (IC50 of these compounds is higher than 50 or 100 µ ). According to previous studies, in the case of compounds with the weak biological activity, it is more suitable to use IC15 and IC30 instead of IC50 as the indicator of biological activity. Since most of compounds have weak cytotoxic effect, we also calculated IC15 and IC30 for evaluating the cytotoxic activity of synthesized compounds. The most potent compound, 6 h (9-(3-Bromo-phenyl)-4-pheny l-2, 3, 5, 6, 7, 9-hexahydro-4H-cyclopenta [b] quinoline-1, 8-dione), containing bromophenyl moiety and phenyl substitute on nitrogen of central quinoline ring, show significant cytotoxic activity especially in Raji and HeLa cell lines (IC30: 82 and 24.4 μ M respectively) comparing to other compounds. Although the results of cytotoxic activity evaluation demonstrated that the in-vitro anti-cancer effect of synthesized compounds are mainly low, it seems that this structure can be used as a novel cytotoxic scaffold for further modification and design of novel potent compounds. PMID:24250380

  2. Synthesis and biological activities of new di- and trimeric quinoline derivatives.

    PubMed

    Broch, Sidonie; Hénon, Hélène; Debaud, Anne-Laure; Fogeron, Marie-Laure; Bonnefoy-Bérard, Nathalie; Anizon, Fabrice; Moreau, Pascale

    2010-10-01

    The synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The ability of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivative of this new series (compound A) inhibited Bcl-x(L)/Bak, Bcl-x(L)/Bax and Bcl-x(L)/Bid interactions with IC(50) values around 25 μM.

  3. Proton reduction by a nickel complex with an internal quinoline moiety for proton relay.

    PubMed

    Majee, Karunamay; Patel, Jully; Rai, Surabhi; Das, Babulal; Panda, Binata; Padhi, Sumanta Kumar

    2016-08-21

    The complex Ni(DQPD) (where DQPD = deprotonated N(2),N(6)-di(quinolin-8-yl)pyridine-2,6-dicarboxamide (DQPDH2)) behaves as a visible light driven active catalyst to reduce protons from water when employed with the photosensitizer fluorescein (Fl) and triethylamine (TEA) as the sacrificial electron donor. The photocatalytic system shows very high activity, attaining 2160 turnovers and an initial turnover rate of 0.032 s(-1) with respect to the catalyst. The proposed electrocatalytic mechanism is of the CECE type (C is a chemical step protonation and E is the electrochemical step reduction), where the Ni(DQPD) catalyst undergoes rapid protonation at the non-coordinating nitrogen atom of the quinoline before undergoing reduction. The location of the pendant base is a key factor such that the N-H resulting from the protonation of the non-coordinating nitrogen atom of the quinoline is properly located to interact with the Ni-H hydride leading to heterocoupling between protons and hydrides. Theoretical calculations for the catalytic system were carried out using the density functional level of theory (DFT) and are consistent with a mechanism for catalysis in a polypyridine nickel system. This is the first report of a polypyridine based nickel catalyst where the pendant base is responsible for the internal proton relay towards the metal center through the heterocoupling between protons and hydrides to generate hydrogen. PMID:27432223

  4. Identification of Quinolines that Inhibit Melanogenesis by Altering Tyrosinase Family Trafficking

    PubMed Central

    Ni-Komatsu, Li; Tong, ChunXiang; Chen, Guangming; Brindzei, Nelya; Orlow, Seth J.

    2009-01-01

    A series of quinolines, including chloroquine and quinine, were identified as potent pigmentation inhibitors through screening a compound library in murine melanocytes. Structure-activity relationship analysis indicated that 4-substituted amino groups with a tertiary amine side chain, such as chloroquine, were associated with robust inhibitory activity. In contrast to many previously identified pigmentation inhibitors, these newly identified inhibitors had no effect on either the level or the enzymatic activity of tyrosinase, the rate-limiting enzyme in melanin production. Rather, our results showed that these quinolines inhibited melanogenesis by disrupting the intracellular trafficking of tyrosinase-related proteins and lysosome-associated membrane protein 1 (Lamp-1). In treated melanocytes, tyrosinase and tyrosinase-related protein 1 accumulated in Lamp-1-positive perinuclear organelles instead of melanosomes, thus preventing melanogenesis. The depigmenting abilities of chloroquine and quinine salicylate were assessed in a human skin equivalent model (MelanoDerm). Both compounds were considerably more effective than arbutin, a widely used lightening agent. Our results indicate that quinolines may be useful agents for “cosmeceutical” skin lightening and treatment of hyperpigmentation disorders. PMID:18801917

  5. Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORγ) inverse agonist.

    PubMed

    Fauber, Benjamin P; René, Olivier; Deng, Yuzhong; DeVoss, Jason; Eidenschenk, Céline; Everett, Christine; Ganguli, Arunima; Gobbi, Alberto; Hawkins, Julie; Johnson, Adam R; La, Hank; Lesch, Justin; Lockey, Peter; Norman, Maxine; Ouyang, Wenjun; Summerhill, Susan; Wong, Harvey

    2015-07-01

    Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced δ-sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of 27 in preclinical studies. PMID:26061388

  6. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  7. Characterization of the Antiallergic Drugs 3-[2-(2-Phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic Acid and Ethyl 3-Hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl]propanoate as Full Aryl Hydrocarbon Receptor Agonists

    PubMed Central

    Morales, José Luis; Krzeminski, Jacek; Amin, Shantu; Perdew, Gary H.

    2008-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates most of the toxic effects of numerous chlorinated (e.g., TCDD) and nonchlorinated polycyclic aromatic compounds (e.g., benzo[a]pyrene). Studies in AhR null mice suggested that this receptor may also play a role in the modulation of immune responses. Recently, two drugs, namely, M50354 and M50367 (ethyl ester derivative of M50354), were described as AhR ligands with high efficacy toward reducing atopic allergic symptoms in an AhR-dependent manner by skewing T helper cell differentiation toward a TH1 phenotype [Negishi et al. (2005) J. Immunol. 175 (11), 7348–7356]. Surprisingly, these drugs were shown to have minimal activity toward inducing classical dioxin responsive element-driven AhR-mediated CYP1A1 transcription. We synthesized and reevaluated the ability of these drugs to regulate AhR activity. In contrast to previously published data, both M50354 and M50367 were found to be potent inducers of several AhR target genes, namely, CYP1A1, CYP1B1, and UGT1A2. M50367 was a more effective agonist than M50354, perhaps accounting for its higher bioavailability in vivo. However, M50354 was capable of displacing an AhR-specific radioligand more effectively than M50367. This is consistent with M50354 being the active metabolite of M50367. In conclusion, two selective inhibitors of TH2 differentiation are full AhR agonists. PMID:18179178

  8. Hydrodenitrogenation of benzo(f)quinoline and benzo(h)quinoline over a sulfided NiO-MoO sub 3 /. gamma. -Al sub 2 O sub 3 catalyst

    SciTech Connect

    Moreau, C.; Durand, R.; Zmimita, N.; Geneste, P. )

    1988-08-01

    The hydroprocessing of benzo(f)quinoline and benzo(h)quinoline was studied by a batch method at 340{degree}C and 70 bar H{sub 2} over a commercial sulfide NiO-MoO{sub 3}/{gamma}-Al{sub 2}O{sub 3} catalyst. The hydrogenation of the N ring occurs at similar rates for the two isomeric benzoquinolines but is slower than the hydrogenation of the N ring of quinoline. On the other hand, an important and unusual percentage of C{sub sp{sup 2}}-N bond cleavage is observed from the two intermediates 1,2,3,4-tetrahydrobenzo(f)quinoline and 1,2,3,4-tetrahydrobenzo(h)quinoline. These two main reactions, hydrogenation of N rings and cleavage of C-N bonds, are then discussed in terms of aromaticity; a decrease in aromaticity favors both the hydrogenation of N rings and the cleavage of C{sub sp{sup 2}}-N bonds.

  9. Effects of peripherally restricted κ opioid receptor agonists on pain-related stimulation and depression of behavior in rats.

    PubMed

    Negus, S Stevens; O'Connell, Robert; Morrissey, Ember; Cheng, Kejun; Rice, Kenner C

    2012-03-01

    κ opioid receptor agonists that do not readily cross the blood-brain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted κ agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral κ receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central κ receptors. The present study used assays of pain-related stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted κ agonists [the tetrapeptide D-Phe-D-Phe-D-Ile-D-Arg-NH(2) (ffir) and the nonpeptidic compound ((R,S)-N-[2-(N-methyl-3,4-dichlorophenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride (ICI204448)], 2) a centrally penetrating κ agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal anti-inflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted κ agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted κ agonists had little effect, and salvinorin A exacerbated acid-induced depression of ICSS. These results suggest that peripherally restricted κ agonists may be safer than centrally penetrating κ agonists but less efficacious than NSAIDS or μ opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with κ agonists capable of greater peripheral selectivity are warranted.

  10. Effects of μ-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of μ-agonist efficacy and noxious stimulus intensity.

    PubMed

    Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens

    2015-02-01

    Pain is associated with stimulation of some behaviors and depression of others, and μ-opioid receptor agonists are among the most widely used analgesics. This study used parallel assays of pain-stimulated and pain-depressed behavior in male Sprague-Dawley rats to compare antinociception profiles for six μ-agonists that varied in efficacy at μ-opioid receptors (from highest to lowest: methadone, fentanyl, morphine, hydrocodone, buprenorphine, and nalbuphine). Intraperitoneal injection of diluted lactic acid served as an acute noxious stimulus to either stimulate stretching or depress operant responding maintained by electrical stimulation in an intracranial self-stimulation (ICSS). All μ-agonists blocked both stimulation of stretching and depression of ICSS produced by 1.8% lactic acid. The high-efficacy agonists methadone and fentanyl were more potent at blocking acid-induced depression of ICSS than acid-stimulated stretching, whereas lower-efficacy agonists displayed similar potency across assays. All μ-agonists except morphine also facilitated ICSS in the absence of the noxious stimulus at doses similar to those that blocked acid-induced depression of ICSS. The potency of the low-efficacy μ-agonist nalbuphine, but not the high-efficacy μ-agonist methadone, to block acid-induced depression of ICSS was significantly reduced by increasing the intensity of the noxious stimulus to 5.6% acid. These results demonstrate sensitivity of acid-induced depression of ICSS to a range of clinically effective μ-opioid analgesics and reveal distinctions between opioids based on efficacy at the μ-receptor. These results also support the use of parallel assays of pain-stimulated and -depressed behaviors to evaluate analgesic efficacy of candidate drugs. PMID:25406170

  11. Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039).

    PubMed

    Fell, Matthew J; Svensson, Kjell A; Johnson, Bryan G; Schoepp, Darryle D

    2008-07-01

    (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) is a potent and selective group II metabotropic glutamate [(mGlu)2 and mGlu3] receptor agonist for which its prodrug LY2140023 [(1R,4S,5S,6S)-2-thiabicyclo[3.1.0]-hexane-4,6-dicarboxylic acid,4-[(2S)-2-amino-4-(methylthio)-1-oxobutyl]amino-, 2,2-dioxide monohydrate] has recently been shown to have efficacy in the treatment of the positive and negative symptoms of schizophrenia. In this article, we use mGlu receptor-deficient mice to investigate the relative contribution of mGlu2 and mGlu3 receptors in mediating the antipsychotic profile of LY404039 in the phencyclidine (PCP) and d-amphetamine (AMP) models of psychosis. To further explore the mechanism of action of LY404039, we compared the drugs' ability to block PCP-induced hyperlocomotion to that of atypical antipsychotics in wild-type and mice lacking mGlu2/3 receptors. In wild-type animals, LY404039 (3-30 mg/kg i.p.) significantly reversed AMP (5 mg/kg, i.p.)-induced increases in ambulations, distance traveled, and reduced time spent at rest. LY404039 reversed PCP (7.5 mg/kg i.p.)-evoked behaviors at 10 mg/kg. The antipsychotic-like effects of LY404039 (10 mg/kg i.p.) on PCP and AMP-evoked behavioral activation were absent in mGlu2 and mGlu2/3 but not in mGlu3 receptor-deficient mice, indicating that the activation of mGlu2 and not mGlu3 receptors is responsible for the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039. In contrast, the atypical antipsychotic drugs clozapine and risperidone inhibited PCP-evoked behaviors in both wild-type and mGlu2/3 receptor-deficient mice. These data demonstrate that the antipsychotic-like effects of the mGlu2/3 receptor agonist LY404039 in psychostimulant models of psychosis are mechanistically distinct from those of atypical antipsychotic drugs and are dependent on functional mGlu2 and not mGlu3 receptors. PMID:18424625

  12. Bioaugmentation and adsorption treatment of coking wastewater containing pyridine and quinoline using zeolite-biological aerated filters.

    PubMed

    Bai, Yaohui; Sun, Qinghua; Sun, Renhua; Wen, Donghui; Tang, Xiaoyan

    2011-03-01

    Bioaugmented zeolite-biological aerated filters (Z-BAFs), i.e. adding isolated degrading bacteria into the BAFs with zeolite as fillings, were designed to treat coking wastewater containing high concentrations of pyridine and quinoline and to explore the bacterial community of biofilm on the zeolite surface. The investigation was carried out for 91 days of column operation and the treatment of pyridine, quinoline, total organic carbon (TOC), and ammonium was shown to be highly efficient by bioaugmentation and adsorption. Biomass determination and bacterial diversity detection based on 16S rDNA and rRNA techniques supported the treatment data and indicated that bioaugmentation could recover the bacterial richness and diversity from pyridine and quinoline loading shocks. However, bioaugmentation accelerated the shift of the bacterial community structure resulting in a more distinct difference from the starting community. Clone library analysis revealed that pyridine and quinoline were more harmful to Bacterodietes among all ingenious bacteria, and bioaugmentation promoted the growth of Planctomycetes in the biofilm. Moreover, the introduced bacteria did not remain dominant in the bioaugmented biofilm, indicating the indigenous degrading bacteria played the most significant role in the treatment. This bioaugmented Z-BAF method was shown to be an alternative technology for the treatment of wastewater containing pyridine and quinoline or other N-heterocyclic aromatic compounds.

  13. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  14. Copper-Promoted Tandem Reaction of Azobenzenes with Allyl Bromides via N═N Bond Cleavage for the Regioselective Synthesis of Quinolines.

    PubMed

    Yi, Xiangli; Xi, Chanjuan

    2015-12-01

    A copper-promoted tandem reaction of a variety of azobenzenes and allyl bromides via N═N bond cleavage to regioselectively construct quinoline derivatives has been developed. The azobenzenes act as not only construction units but also an oxidant for quinoline formation.

  15. Copper-Promoted Tandem Reaction of Azobenzenes with Allyl Bromides via N═N Bond Cleavage for the Regioselective Synthesis of Quinolines.

    PubMed

    Yi, Xiangli; Xi, Chanjuan

    2015-12-01

    A copper-promoted tandem reaction of a variety of azobenzenes and allyl bromides via N═N bond cleavage to regioselectively construct quinoline derivatives has been developed. The azobenzenes act as not only construction units but also an oxidant for quinoline formation. PMID:26580318

  16. Quinoline-degrading strain Pseudomonas aeruginosa KDQ4 isolated from coking activated sludge is capable of the simultaneous removal of phenol in a dual substrate system.

    PubMed

    Zhang, Panhong; Jia, Rong; Zhang, Yuxiu; Shi, Peili; Chai, Tuanyao

    2016-11-01

    Quinoline is a refractory organic compound in the treatment of coking wastewater. The isolation of high efficiency quinoline-degrading bacteria from activated sludge and the evaluation of their degradation characteristics in the presence of phenol or in the actual coking wastewater are important for the improvement of effluent quality. The novel bacterial strain Pseudomonas aeruginosa KDQ4 was isolated from a quinoline enrichment culture obtained from the activated sludge of a coking wastewater treatment plant. The optimum temperature and initial pH for quinoline degradation were 33-38°C and 8-9, respectively. KDQ4 completely degraded 400 mg/L of quinoline within 24 h and 800 mg/L of phenol within 30 h. In the dual-substrate system, the removal efficiencies of quinoline and phenol at the same initial concentration (200 mg/L) by KDQ4 were 89% and 100% within 24 h, respectively, indicating that KDQ4 could simultaneously and quickly degrade quinoline and phenol in a coexistence system. Moreover, KDQ4 was able to adapt to actual coking wastewater containing high quinoline and phenol concentrations and rapidly remove them. KDQ4 also exhibited heterotrophic nitrification and aerobic denitrification potential under aerobic conditions. These results suggested a potential bioaugmentation role for KDQ4 in the removal of nitrogen-heterocyclic compounds and phenolics from coking wastewater. PMID:27458688

  17. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency.

  18. Lepidozenolide from the liverwort Lepidozia fauriana acts as a farnesoid X receptor agonist.

    PubMed

    Lin, Hsiang-Ru

    2015-01-01

    Lepidozenolide is a sesquiterpenoid isolated from the liverwort Lepidozia fauriana and its possible bioactivity is unclear. The farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that has been widely targeted for developing treatments for chronic liver disease and hyperglycemia. In this study, whether lepidozenolide may act as a FXR agonist was determined. Indeed, in mammalian one-hybrid and transient transfection reporter assays, lepidozenolide transactivated FXR to modulate promoter action including GAL4, CYP7A1, and PLTP promoters in a dose-dependent manner, while it exhibited slightly less agonistic activity than chenodeoxycholic acid, an endogenous FXR agonist. Through the molecular modeling docking studies lepidozenolide was shown to bind to FXR ligand binding pocket fairly well. All these results indicate that lepidozenolide acts as a FXR agonist. PMID:25315435

  19. Thrombin receptor agonist Peptide immobilized in microspheres stimulates reparative processes in rats with gastric ulcer.

    PubMed

    Rusanova, A V; Makarova, A M; Strukova, S M; Markvicheva, E A; Gorbachyova, L R; Stashevskaya, K S; Vasil'eva, T V; Sidorova, E I; Bespalova, Zh D; Grandfils, Ch

    2006-07-01

    The effect of synthetic thrombin receptor (PAR1) agonist peptide encapsulated in microspheres made of lactic and glycolic acid copolymer on tissue reparation was studied in rats with acetate-induced ulcer. PAR1 agonist peptide was immobilized in biodegraded lactic and glycolic acid microspheres by double emulgation, the kinetics of peptide release was analyzed, and the dynamics of ulcer healing was studied in experimental (administration of microspheres with the peptide into the stomach) and two control groups (administration of saline or spheres without peptide). Thrombin receptor agonist peptide gradually released from lactic and glycolic acid microspheres into the stomach shortened the inflammation phase and shifted the proliferation phase to the earlier period, thus accelerating healing of experimental ulcers in rats. PMID:17369897

  20. Molecular characterization of quinolinate phosphoribosyltransferase (QPRtase) in Nicotiana.

    PubMed

    Sinclair, S J; Murphy, K J; Birch, C D; Hamill, J D

    2000-11-01

    Quinolate acid phosphoribosyltransferase (QPRTase), a key enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, also plays an important role in ensuring nicotinic acid is available for the synthesis of defensive pyridine alkaloids in Nicotiana species. In this study, cDNAs for QPRTase were characterized from N. rustica and N. tabacum. Deduced proteins from both cDNAs are almost identical and contain a 24 amino acid N-terminal extension, not reported in other QPRTases, that has characteristics of a mitochondrial targeting sequence. In N. tabacum and N. sylvestris, both of which contain nicotine as the major pyridine alkaloid, QPRTase transcript was detected in roots, the site of nicotine synthesis, but not in leaves. QPRTase transcript levels increased markedly in roots of both species 12-24 h after damage to aerial tissues, with a concomitant rise in transcript levels of putrescine N-methyltransferase (PMT), another key enzyme in nicotine biosynthesis. In N. glauca, however, in which anabasine represents the major pyridine alkaloid, QPRTase transcript was detected in both leaf and root tissues. Moreover, wound induction of QPRTase but not PMT was observed in leaf tissues, and not in roots, 12-24 h after wounding. Southern analysis of genomic DNA from the Nicotiana species noted above, and also several others from within the genus, suggested that QPRTase is encoded by a small gene family in all the species investigated. PMID:11198422

  1. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  2. Formation of α-SF5-Enolate Enables Preparation of 3-SF5-Quinolin-2-ones, 3-SF5-Quinolines, and 3-SF5-Pyridin-2-ones: Evaluation of their Physicochemical Properties.

    PubMed

    Joliton, Adrien; Plancher, Jean-Marc; Carreira, Erick M

    2016-02-01

    This study describes, for the first time, the generation of a SF5 -substituted ester enolate from benzyl SF5 -acetate under soft enolization conditions, which in turn participates in aldol addition reactions in high yield. The reaction was applied in the synthesis of 3-SF5 -quinolin-2-ones, 3-SF5 -quinolines, and 3-SF5 -pyridin-2-ones, none of which have previously been reported. To provide guidelines for their use in drug discovery, the physicochemical properties of these building blocks were determined and compared with those of their CF3 - and t-Bu-analogues. PMID:26732047

  3. GAS PHASE SYNTHESIS OF (ISO)QUINOLINE AND ITS ROLE IN THE FORMATION OF NUCLEOBASES IN THE INTERSTELLAR MEDIUM

    SciTech Connect

    Parker, Dorian S. N.; Kaiser, Ralf I.; Kostko, Oleg; Troy, Tyler P.; Ahmed, Musahid; Mebel, Alexander M.; Tielens, Alexander G. G. M.

    2015-04-20

    Nitrogen-substituted polycyclic aromatic hydrocarbons (NPAHs) have been proposed to play a key role in the astrochemical evolution of the interstellar medium, yet the formation mechanisms of even their simplest prototypes—quinoline and isoquinoline—remain elusive. Here, we reveal a novel concept that under high temperature conditions representing circumstellar envelopes of carbon stars, (iso)quinoline can be synthesized via the reaction of pyridyl radicals with two acetylene molecules. The facile gas phase formation of (iso)quinoline in circumstellar envelopes defines a hitherto elusive reaction class synthesizing aromatic structures with embedded nitrogen atoms that are essential building blocks in contemporary biological-structural motifs. Once ejected from circumstellar shells and incorporated into icy interstellar grains in cold molecular clouds, these NPAHs can be functionalized by photo processing forming nucleobase-type structures as sampled in the Murchison meteorite.

  4. Polyamine quinoline rhodium complexes: synthesis and pharmacological evaluation as antiparasitic agents against Plasmodium falciparum and Trichomonas vaginalis.

    PubMed

    Stringer, Tameryn; Taylor, Dale; Guzgay, Hajira; Shokar, Ajit; Au, Aaron; Smith, Peter J; Hendricks, Denver T; Land, Kirkwood M; Egan, Timothy J; Smith, Gregory S

    2015-09-01

    A series of mono- and bis-salicylaldimine ligands and their corresponding Rh(i) complexes were prepared. The compounds were characterised using standard spectroscopic techniques including NMR, IR spectroscopy and mass spectrometry. The salicylaldimine ligands and complexes were screened for antiparasitic activity against two strains of Plasmodium falciparum i.e. the NF54 CQ-sensitive and K1 CQ-resistant strain as well as against the G3 isolate of Trichomonas vaginalis. The monomeric salicylaldimine quinolines exhibited good activity against the NF54 strain and the dimeric salicylaldimine quinolines exhibited no cross resistance across the two strains. The binuclear 5-chloro Rh(i) complex displayed the best activity against the Trichomonas vaginalis parasite, possibly a consequence of its enhanced lipophilicity. The compounds were also screened for cytotoxicity in vitro against WHCO1 oesophageal cancer cells. The monomeric salicylaldimine quinolines exhibited high selectivity towards malaria parasites compared to cancer cells, while the dimeric compounds were less selective.

  5. [Screening of a Highly Efficient Quinoline-degrading Strain and Its Enhanced Biotreatment on Coking Waste Water].

    PubMed

    Li, Jing; Li, Wen-ying

    2015-04-01

    A bacterial strain, which could utilize quinoline as the sole carbon, nitrogen and energy source, was isolated from the activated sludge in a coking wastewater treatment plant. According to the 16S rRNA gene sequence analysis, the strain was identified as Acidovorax sp. Taken into consideration of both the growth and the quinoline degradation of the strain, the optimized degradation conditions were acquired as following: 10% inoculum, pH value of 8.0-10.0, 35 degrees C and 150 r x min(-1). The process of its growth was simulated by Haldane kinetic model under different initial quinoline concentrations, the fitted curve had a good correlation with test measured values. Furthermore, coking wastewater was bioaugmented by the mixed strains of DQS-01 and D2 with enhanced process in a moving bed biofilm reactor, and the COD degradation rate was 87.4% within 72 h.

  6. Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

    SciTech Connect

    Li, Jun; Kennedy, Lawrence J.; Shi, Yan; Tao, Shiwei; Ye, Xiang-Yang; Chen, Stephanie Y.; Wang, Ying; Hernndez, Andrs S.; Wang, Wei; Devasthale, Pratik V.; Chen, Sean; Lai, Zhi; Zhang, Hao; Wu, Shung; Smirk, Rebecca A.; Bolton, Scott A.; Ryono, Denis E.; Zhang, Huiping; Lim, Ngiap-Kie; Chen, Bang-Chi; Locke, Kenneth T.; O’Malley, Kevin M.; Zhang, Litao; Srivastava, Rai Ajit; Miao, Bowman; Meyers, Daniel S.; Monshizadegan, Hossain; Search, Debra; Grimm, Denise; Zhang, Rongan; Harrity, Thomas; Kunselman, Lori K.; Cap, Michael; Kadiyala, Pathanjali; Hosagrahara, Vinayak; Zhang, Lisa; Xu, Carrie; Li, Yi-Xin; Muckelbauer, Jodi K.; Chang, Chiehying; An, Yongmi; Krystek, Stanley R.; Blanar, Michael A.; Zahler, Robert; Mukherjee, Ranjan; Cheng, Peter T.W.; Tino, Joseph A.

    2010-04-12

    An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and 410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

  7. [Electricity generation and quinoline degradation of pure strains and mixed strains in the microbial fuel cell].

    PubMed

    Chen, Shan-Shan; Zhang, Cui-Ping; Liu, Guang-Li; Zhang, Ren-Duo; Li, Ming-Chen; Quan, Xiang-Chun

    2010-09-01

    Microbial flora composition of microbial fuel cells (MFC) is important to the electricity generation. Four bacterium strains Q1, b, c and d which represent all different morphology of culturable bacterium were isolated from a MFC using 200 mg x L(-1) quinoline as the fuel and operating for at least 210 days. Strains Q1, c and d were Pseudomonas sp. based on 16S rDNA sequence analysis, while strain b was Burkholderia sp. Double-chamber MFCs using 200 mg x L(-1) quinoline and 300 mg x L(-1) glucose as the fuel and potassium ferricyanide as the electron acceptor were constructed. Results showed that strain b, c and d were non-electrogenesis. The electrical charges of MFC inoculated electrogenesis strain Q1 with non-electrogenesis strain b, c and d respectively were 3.00, 3.57 and 5.13C, and the columbic efficiency were 3.85%, 4.59% and 6.58%, which were all lower than that inoculated with pure Q1, because of the interspecific competition of electrogenesis and non-electrogenesis bacteria. Combinations of Q1 with the other three strains respectively resulted in 100% of quinoline degradation rates within 24h, which is better than pure cultures, that is, mixed microbial populations perform better in MFC when complex organics are used as the fuel. GC/MS analyses showed that only 2(1H)-quinolinone and phenol existed in the effluent of the MFC, which was inoculated with only Q1 or mixed bacteria.

  8. Synthesis of C-glycosyl triazolyl quinoline-based fluorescent sensors for the detection of mercury ions.

    PubMed

    Wang, Linfang; Jin, Jianzhong; Zhao, Linwei; Shen, Hongyun; Shen, Chao; Zhang, Pengfei

    2016-10-01

    A series of novel C-glycosyl triazolyl quinoline-based fluorescent sensors have been synthesized via click chemistry. It was found that novel sensors exhibited good selectivity for Hg(2+) over many other metal ions. The glucose framework was introduced to increase the water-solubility of the fluorescent sensors and broaden its application for the detection of Hg(II) in the water-solubility biological systems. The mechanism of the chemodosimetric behavior of the sensors has been attributed to a binding mode of triazolyl quinoline with Hg(2+) which has been characterized by a number of spectroscopic techniques.

  9. Thermo-optical properties of 1H[3,4-b] quinoline films used in electroluminescent devices

    NASA Astrophysics Data System (ADS)

    Jaglarz, Janusz; Kępińska, Mirosława; Sanetra, Jerzy

    2014-06-01

    Electroluminescence cells with H[3,4-b] quinoline layers are promising devices for a blue light emitting EL diode. This work measured the optical reflectance as a function of temperature in copolymers PAQ layers deposited on Si crystalline substrate. Using the extended Cauchy dispersion model of the film refractive index we determined the thermo-optical coefficients for quinoline layers in the temperature range of 76-333 K from combined ellipsometric and spectrofotometric studies. The obtained values of thermo-optical coefficients of thin PAQ film, were negative and ranged in 5-10 × 10-4 [1/K].

  10. (+)- and (-)-Spiroreticulatine, A Pair of Unusual Spiro Bisheterocyclic Quinoline-imidazole Alkaloids from the South China Sea Sponge Fascaplysinopsis reticulata.

    PubMed

    Wang, Qi; Tang, Xuli; Luo, Xiangchao; de Voogd, Nicole J; Li, Pinglin; Li, Guoqiang

    2015-07-17

    A pair of novel bisheterocyclic quinoline-imidazole alkaloids, (+)- and (-)-spiroreticulatine (1), were isolated from the South China Sea sponge Fascaplysinopsis reticulata. The structures and absolute configurations were elucidated by comprehensive spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculation methods. Spiroreticulatine is the first example of a sponge-derived natural spiro quinoline-imidazole alkaloid that may derive from tryptophan and 1,3-dimethylurea. Compound 1 showed inhibitory activity on IL-2 production but inactive against normal tumor cell lines.

  11. Novel Schiff base copper complexes of quinoline-2 carboxaldehyde as proteasome inhibitors in human prostate cancer cells.

    PubMed

    Adsule, Shreelekha; Barve, Vivek; Chen, Di; Ahmed, Fakhara; Dou, Q Ping; Padhye, Subhash; Sarkar, Fazlul H

    2006-11-30

    We report the synthesis of novel 1:1 Schiff base copper complexes of quinoline-2-carboxaldehyde showing dose-dependent, antiproliferative, and proapoptotic activity in PC-3 and LNCaP prostate cancer cells. We found that quinoline thiosemicarbazone 2 (FPA-137) was the most potent and inhibited proteosome activity in intact human prostate cancer PC-3 and LNCaP cells (IC50 of 4 and 3.2 microM, respectively) compared to clioquinol and pyrrolidine dithiocarbamate (IC50 of 10 and 20 microM), supporting the novelty of 2. PMID:17125278

  12. Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates.

    PubMed

    Youngsaye, Willmen; Vincent, Benjamin; Hartland, Cathy L; Morgan, Barbara J; Buhrlage, Sara J; Johnston, Stephen; Bittker, Joshua A; MacPherson, Lawrence; Dandapani, Sivaraman; Palmer, Michelle; Whitesell, Luke; Lindquist, Susan; Schreiber, Stuart L; Munoz, Benito

    2011-09-15

    The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.

  13. A highly selective quinoline-based fluorescent sensor for Zn(II)

    NASA Astrophysics Data System (ADS)

    Kim, Hyun; Kang, Juhye; Kim, Kyung Beom; Song, Eun Joo; Kim, Cheal

    2014-01-01

    A quinoline-based simple receptor (bis(2-quinolinylmethyl)benzylamine = 1) as a Zn2+ selective fluorescent chemosensor showed a large fluorescent enhancement with a blue shift in the presence of Zn2+ which is attributed to a chelation enhanced fluorescence (CHEF) effect with inhibition of a photoinduced electron transfer (PET) process of 1. In particular, this receptor could clearly distinguish Zn2+ from Cd2+. The binding mode of 1 and Zn2+ was found to be a 1:1 and confirmed by Job plot, 1H NMR titration and ESI-mass spectrometry analysis.

  14. 2-(3,4-Dichloro-phen-yl)-4-phenyl-benzo[h]quinoline.

    PubMed

    Wu, Nan; Xu, Zhou

    2011-11-01

    In the title compound, C(25)H(15)Cl(2)N, the benzo[h]quinoline system exhibits an approximately planar conformation with an r.m.s. deviation of 0.0202Å and a maximum deviation of 0.039 (1) Å. The aryl group at position 2 is nearly coplanar with the parent ring [dihedral angle = 6.68 (7)°] while the parent ring and the phenyl subsitituent at position 4 form a dihedral angle of 67.11 (4)°. Inter-molecular C-H⋯π inter-actions stabilize the crystal packing. PMID:22219893

  15. 7-[(Morpholin-4-yl)(phen-yl)meth-yl]quinolin-8-ol.

    PubMed

    Novina, J Josephine; Vasuki, G; Muthukumar, C; Sabastiyan, A; Crochet, A; Fromm, K M

    2013-01-01

    In the title compound, C20H20N2O2, the quinoline ring system makes dihedral angles of 81.05 (4) and 61.16 (5)° with the mean planes of the benzene and morpholine rings, respectively; the mean planes of the latter two rings make a dihedral angle of 83.59 (4)°. In the crystal, pairs of O-H⋯N hydrogen bonds link neighbouring mol-ecules related by a twofold rotation axis, generating R2(2)(10) motifs. PMID:23476429

  16. 3,4-Di­methyl­phenyl quinoline-2-carboxyl­ate

    PubMed Central

    Fazal, E.; Kaur, Manpreet; Sudha, B. S.; Nagarajan, S.; Jasinski, Jerry P.

    2013-01-01

    In the title compound, C18H15NO2, the dihedral angle between the mean planes of the quinoline ring system and the phenyl ring is 48.1 (5)°. The mean plane of the carboxyl­ate group is twisted from the mean planes of the latter by 19.8 (8) and 64.9 (5)°, respectively. The crystal packing features weak C—H⋯O inter­actions, which form chains along [010]. PMID:24454268

  17. The evolution of beta2-agonists.

    PubMed

    Sears, M R

    2001-08-01

    Beta-agonists have been widely used in the treatment of asthma for many years Although concerns have been expressed over their safety based largely upon epidemics of increased mortality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterol in the 1970s and 1980s, the specific beta2-agonists are vital drugs in asthma management. The short-acting beta2-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting beta2-agonists and regular or frequent use can increase the severity of the condition. The development of beta2-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting beta-agonists, such as prolonged bronchodilation, reduced day- and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting beta2-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater mprovement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.

  18. Structure of the agonist-bound neurotensin receptor.

    PubMed

    White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard

    2012-10-25

    Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

  19. Identification of a novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674), that produces marked changes in serum lipids and apolipoprotein A-1 expression.

    PubMed

    Singh, Jai Pal; Kauffman, Raymond; Bensch, William; Wang, Guoming; McClelland, Pam; Bean, James; Montrose, Chahrzad; Mantlo, Nathan; Wagle, Asavari

    2005-09-01

    Low high-density lipoprotein-cholesterol (HDL-c) is an important risk factor of coronary artery disease (CAD). Optimum therapy for raising HDL-c is still not available. Identification of novel HDL-raising agents would produce a major impact on CAD. In this study, we have identified a potent (IC50 approximately 24 nM) and selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonist, 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoic acid (LY518674). In human apolipoprotein A-1 (apoA-1) transgenic mice, LY518674 produced a dose-dependent increase in serum HDL-c, resulting in 208 +/- 15% elevation at optimum dose. A new synthesis of apoA-1 contributed to the increase in HDL-c. LY518674 increased apoA-1 mRNA levels in liver. Moreover, liver slices from animals treated with LY518674 secreted 3- to 6-fold more apoA-1 than control liver slices. In cultured hepatocytes, LY518674 produced 50% higher apoA-1 secretion, which was associated with increase in radiolabeled methionine incorporation in apoA-1. Thus, LY518674 is a potent and selective PPARalpha agonist that produced a much greater increase in serum HDL-c than the known fibrate drugs. The increase in HDL-c was associated with de novo synthesis of apoA-1. PMID:15933217

  20. Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.

    PubMed

    Monn, James A; Prieto, Lourdes; Taboada, Lorena; Hao, Junliang; Reinhard, Matthew R; Henry, Steven S; Beadle, Christopher D; Walton, Lesley; Man, Teresa; Rudyk, Helene; Clark, Barry; Tupper, David; Baker, S Richard; Lamas, Carlos; Montero, Carlos; Marcos, Alicia; Blanco, Jaime; Bures, Mark; Clawson, David K; Atwell, Shane; Lu, Frances; Wang, Jing; Russell, Marijane; Heinz, Beverly A; Wang, Xushan; Carter, Joan H; Getman, Brian G; Catlow, John T; Swanson, Steven; Johnson, Bryan G; Shaw, David B; McKinzie, David L

    2015-09-24

    Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo. PMID:26313429

  1. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(α-phenylethylamino)-2-thiazoline BPAT 2-(β-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane PMID:15841226

  2. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  3. The Effect of PPARα, PPARδ, PPARγ, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice

    PubMed Central

    Harrington, W. Wallace; S. Britt, Christy; G. Wilson, Joan; O. Milliken, Naphtali; G. Binz, Jane; C. Lobe, David; R. Oliver, William; C. Lewis, Michael; M. Ignar, Diane

    2007-01-01

    Activation of peroxisome proliferator-activated receptor (PPAR) α, δ, and γ subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARγ agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARα agonist, GW0742, a PPARδ agonist, GW7845, a PPARγ agonist), combination of PPARα and δ agonists, and PPARpan (PPARα/γ/δ) activators (GW4148 or GW9135) on body weight (BW), body composition, food consumption, fatty acid oxidation, and serum chemistry of diet-induced obese AKR/J mice. PPARα or PPARδ agonist treatment induced a slight decrease in fat mass (FM) while a PPARγ agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARα and δ agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPARδ, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARα and PPARδ activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPARγ agonist while either maintaining weight or producing weight loss. PMID:17710237

  4. The Effect of PPARalpha, PPARdelta, PPARgamma, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice.

    PubMed

    Harrington, W Wallace; S Britt, Christy; G Wilson, Joan; O Milliken, Naphtali; G Binz, Jane; C Lobe, David; R Oliver, William; C Lewis, Michael; M Ignar, Diane

    2007-01-01

    Activation of peroxisome proliferator-activated receptor (PPAR) alpha, delta, and gamma subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARgamma agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARalpha agonist, GW0742, a PPARdelta agonist, GW7845, a PPARgamma agonist), combination of PPARalpha and delta agonists, and PPARpan (PPARalpha/gamma/delta) activators (GW4148 or GW9135) on body weight (BW), body composition, food consumption, fatty acid oxidation, and serum chemistry of diet-induced obese AKR/J mice. PPARalpha or PPARdelta agonist treatment induced a slight decrease in fat mass (FM) while a PPARgamma agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARalpha and delta agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPARdelta, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARalpha and PPARdelta activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPARgamma agonist while either maintaining weight or producing weight loss.

  5. Discovery of a potent and selective GPR120 agonist.

    PubMed

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond

    2012-05-10

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

  6. RXR partial agonist produced by side chain repositioning of alkoxy RXR full agonist retains antitype 2 diabetes activity without the adverse effects.

    PubMed

    Kawata, Kohei; Morishita, Ken-ichi; Nakayama, Mariko; Yamada, Shoya; Kobayashi, Toshiki; Furusawa, Yuki; Arimoto-Kobayashi, Sakae; Oohashi, Toshitaka; Makishima, Makoto; Naitou, Hirotaka; Ishitsubo, Erika; Tokiwa, Hiroaki; Tai, Akihiro; Kakuta, Hiroki

    2015-01-22

    We previously reported RXR partial agonist CBt-PMN (1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid: 5, EC50 = 143 nM, Emax = 75%), which showed a potent glucose-lowering effect without causing serious adverse effects. However, it remains important to elucidate the structural requirements for RXR efficacy and the glucose-lowering effect because RXR-permissive heterodimers such as PPAR/RXR or LXR/RXR are reported to be activated differently depending upon the chemical structure of RXR agonists. In this work, we show that an RXR partial agonist, NEt-4IB (6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: 8b, EC50 = 169 nM, Emax = 55%), can be obtained simply by repositioning the side chains (interchanging the isobutoxy and isopropoxy groups) at the hydrophobic moiety of the RXR full agonist NEt-3IB (6-[ethyl-(3-isobutoxy-4-isopropylphenyl)amino]pyridine-3-carboxylic acid: 7b, EC50 = 19 nM). NEt-4IB (8b) showed antitype 2 diabetes activity without the above side effects upon repeated oral administration to mice at 10 mg/kg/day, similarly to 5. PMID:25486327

  7. Alpha/sub 1/ receptor coupling events initiated by methoxy-substituted tolazoline partial agonists

    SciTech Connect

    Wick, P.; Keung, A.; Deth, R.

    1986-03-01

    A series of mono- and dimethyoxy substituted tolazoline derivatives, known to be partial agonists at the alpha/sub 1/ receptor, were compared with the ..cap alpha../sub 1/ selective full agonist phenylephrine (PE) on isolated strips of rabbit aorta Agonist activity was evaluated in contraction, /sup 45/Ca influx, /sup 45/Ca efflux, and /sup 32/P-Phospholipid labelling studies. Maximum contractile responses for the 2-, 3-, and 3, 5- methoxy substituted tolazoline derivatives (10/sup -5/M) were 53.8, 67.6 and 99.7% of the PE (10/sup -5/M) response respectively. These same partial agonists caused a stimulation of /sup 45/Ca influx to the extent of 64, 86, and 95% of the PE response respectively. In /sup 45/Ca efflux studies, (a measure of the intracellular Ca/sup +2/ release) the tolazolines caused: 30%, 63%, and 78% of the PE stimulated level. /sup 32/P-Phosphatidic acid (PA) labelling was measured as an index of PI turnover after ..cap alpha../sub 1/ receptor stimulation. Compared to PE, the 2-, 3-, and 3,5- methoxy substituted tolazoline derivatives caused 22, 46, and 72% PA labelling. The above values are all in reasonable accord with the rank order or agonist activity shown in maximum contractile responses. The results of this investigation suggest that partial agonists stimulate ..cap alpha.. receptor coupling events at a level which is quantitatively comparable to their potencies in causing contraction of arterial smooth muscle.

  8. One-pot Sequential Reactions Featuring a Copper-catalyzed Amination Leading to Pyrido[2',1':2,3]imidazo[4,5-c]quinolines and Dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines.

    PubMed

    Fan, Xue-Sen; Zhang, Ju; Li, Bin; Zhang, Xin-Ying

    2015-06-01

    Tetracyclic skeletons combining an imidazo[1,2-a]pyridine moiety with a quinoline framework such as pyrido[2',1':2,3]imidazo[4,5-b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative compounds. In this paper, we report a novel methodology for the synthesis of pyrido[2',1':2,3]imidazo[4,5-c]quinolines through one-pot sequential reactions of commercially available or readily obtainable 2-aminopyridines, 2-bromophenacyl bromides, aqueous ammonia, and aldehydes. Moreover, dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines could also be obtained in a similar manner by using various ketones as the substrates in place of aldehydes. Notably, the whole procedure combines condensation/amination/cyclization reactions in one pot to give complex compounds in a simple and practical manner. Compared with literature methods, the synthetic strategy reported herein has the advantages of readily available starting materials, structural diversity of products, good functional group tolerance, and obviation of step-by-step operations. PMID:25865134

  9. One-pot Sequential Reactions Featuring a Copper-catalyzed Amination Leading to Pyrido[2',1':2,3]imidazo[4,5-c]quinolines and Dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines.

    PubMed

    Fan, Xue-Sen; Zhang, Ju; Li, Bin; Zhang, Xin-Ying

    2015-06-01

    Tetracyclic skeletons combining an imidazo[1,2-a]pyridine moiety with a quinoline framework such as pyrido[2',1':2,3]imidazo[4,5-b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative compounds. In this paper, we report a novel methodology for the synthesis of pyrido[2',1':2,3]imidazo[4,5-c]quinolines through one-pot sequential reactions of commercially available or readily obtainable 2-aminopyridines, 2-bromophenacyl bromides, aqueous ammonia, and aldehydes. Moreover, dihydropyrido[2',1':2,3]imidazo[4,5-c]quinolines could also be obtained in a similar manner by using various ketones as the substrates in place of aldehydes. Notably, the whole procedure combines condensation/amination/cyclization reactions in one pot to give complex compounds in a simple and practical manner. Compared with literature methods, the synthetic strategy reported herein has the advantages of readily available starting materials, structural diversity of products, good functional group tolerance, and obviation of step-by-step operations.

  10. Label-Free Cell Phenotypic Identification of D-Luciferin as an Agonist for GPR35.

    PubMed

    Hu, Heidi; Deng, Huayun; Fang, Ye

    2016-01-01

    D-Luciferin (also known as beetle or firefly luciferin) is one of the most widely used bioluminescent reporters for monitoring in vitro or in vivo luciferase activity. The identification of several natural phenols and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as agonists for GPR35, an orphan G protein-coupled receptor, had motivated us to examine the pharmacological activity of D-Luciferin, given that it also contains phenol and carboxylic acid moieties. Here, we describe label-free cell phenotypic assays that ascertain D-Luciferin as a partial agonist for GPR35. The agonistic activity of D-Luciferin at the GPR35 shall evoke careful interpretation of biological data when D-Luciferin or its analogues are used as probes. PMID:27424891

  11. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  12. Mono- and multimeric ferrocene congeners of quinoline-based polyamines as potential antiparasitics.

    PubMed

    Stringer, Tameryn; De Kock, Carmen; Guzgay, Hajira; Okombo, John; Liu, Jenny; Kanetake, Sierra; Kim, Jihwan; Tam, Christina; Cheng, Luisa W; Smith, Peter J; Hendricks, Denver T; Land, Kirkwood M; Egan, Timothy J; Smith, Gregory S

    2016-09-14

    A series of mono- and multimeric polyamine-containing ferrocenyl complexes containing a quinoline motif were prepared. The complexes were characterised by standard techniques. The molecular structure of the monomeric salicylaldimine derivative was elucidated using single crystal X-ray diffraction and was consistent with the proposed structure. The antiplasmodial activity of the compounds were evaluated in vitro against both the NF54 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains of Plasmodium falciparum. The polyamine derivatives exhibit good resistance index values suggesting that these systems are beneficial in overcoming the resistance experienced by chloroquine. Mechanistic studies suggest that haemozoin formation may be the target of these quinoline complexes in the parasite. Some of the complexes exhibit moderate to high cytotoxicity against WHCO1 oesophageal cancer cells in vitro. The monomeric ferrocenyl-amine complexes exhibit potent activity against this particular cell line. The complexes were also screened against the G3 strain of Trichomonas vaginalis and the salicylaldimine complexes demonstrated promising activity at the tested concentration. All of these compounds show no inhibitory effect on several common normal flora bacteria, indicative of their selectivity for eukaryotic pathogens and cancer. PMID:27485032

  13. Benzanilide–Biphenyl Replacement: A Bioisosteric Approach to Quinoline Carboxamide-Type ABCG2 Modulators

    PubMed Central

    2013-01-01

    Recently reported compounds such as UR-COP78 (6) are among the most potent and selective ABCG2 modulators known so far but are prone to rapid enzymatic cleavage at the central benzanilide moiety. In search for more stable analogues, according to a bioisosteric approach, a series of N-(biphenyl-3-yl)quinoline carboxamides was prepared by solid phase and solution phase synthesis. The biphenyl moiety was constructed by Suzuki coupling. Inhibition of ABCB1 and ABCG2 was determined in a calcein-AM and a Hoechst 33342 microplate assay, respectively. Most synthesized compounds selectively inhibited the ABCG2 transporter at submicromolar concentrations with a maximal inhibitory effect (Imax) over 90% (e.g., UR-COP228 (22a), IC50 591 nM, Imax 109%; UR-COP258 (31), IC50 544 nM, Imax 112%), though with lower potency and selectivity than 6. The biphenyl analogues are considerably more stable and demonstrate that the benzanilide core is not a crucial structural feature of quinoline carboxamide-type ABCG2 modulators. PMID:24900683

  14. New quinoline alkaloid from Ruta graveolens aerial parts and evaluation of the antifertility activity.

    PubMed

    Salib, Josline Y; El-Toumy, Sayed A; Hassan, Emad M; Shafik, Nabila H; Abdel-Latif, Sally M; Brouard, Ignacio

    2014-01-01

    Bioassay-guided isolation of methanol extract of Ruta graveolens L. leaves yielded a new quinoline alkaloid, (4S) 1,4-dihydro-4-methoxy-1,4-dimethyl-3-(3-methylbut-2-enyl)quinoline 2,7-diol, and nine phenolic compounds including rutin as a major compound. Structures of the isolated compounds were determined by using chromatography, UV, HR-ESI-MS and 1D/2D (1)H/(13)C NMR spectroscopy. The uterotonic activity of methanol extract fractions (ethyl acetate, n-butanol and aqueous fraction) as well as the isolated major compounds was tested in the isolated mouse uterus in vitro. The n-butanol-soluble fraction was found to demonstrate the most potent uterotonic activity in a dose-dependent manner, also the major isolated compound rutin revealed the occurrence of an uterotonic response, which was maximum at a concentration level of 0.25 mg/mL, accounting for 68.7% of that exhibited by the chosen concentration of oxytocin.

  15. Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors.

    PubMed

    Mantoani, Susimaire P; Chierrito, Talita P C; Vilela, Adriana F L; Cardoso, Carmen L; Martínez, Ana; Carvalho, Ivone

    2016-02-05

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization.

  16. Effect of the electronic structure of quinoline and its derivatives on the capacity for intermolecular interactions

    SciTech Connect

    Privalova, N.Yu.; Sokolova, I.V.

    1985-05-01

    Calculations of the ground and excited states of quinoline and its 20H-, 70H-, 7NH2-, 7N(CH3)2-, and 7N(C2H5)2- substituted derivatives were undertaken by the INDO method, and the effect of intramolecular proton transfer (IPT) on their electronic structure was studied. The proton-accepting capacity of the compounds for intermolecular interactions was estimated by the molecular electrostatic potential method. It was shown that the proton-accepting capacity with respect to intermolecular interactions increases during the tautomeric transformation of the enolic form of 2-OH-quinoline to its keto form. The change in the basicity of the two forms of the molecules is affected by the orbital nature, and the multiplicity of the state is also important for the keto form. Substitution by electron-donating groups leads to increase in the proton-accepting capacity of both forms of the compounds in the S0, S/sub */, and T/sub */ states.

  17. Interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX, a solid state spectroscopy study.

    PubMed

    Asghari-Khiavi, Mehdi; Vongsvivut, Jitraporn; Perepichka, Inna; Mechler, Adam; Wood, Bayden R; McNaughton, Don; Bohle, D Scott

    2011-12-01

    To investigate the nature of binding of quinoline antimalarial drugs to heme and to extract experimental evidence for this binding, the interaction of ferriprotoporphyrin IX (FP) with chloroquine and quinacrine (both of which have a similar side chain) and quinoline methanol antimalarials quinine and mefloquine has been studied using IR and NIR-Raman spectroscopy in the solid state. Attenuated total reflectance infrared spectroscopic data clearly show that heme in chloroquine-FP complex is not μ-oxo dimeric indicating that the hypothesis that chloroquine binds to FP μ-oxo dimer with a stoichiometry of 1 chloroquine:2 μ-oxo dimers is not valid in the solid state. Moreover, the first vibrational spectroscopy evidence is presented for the formation of hydrogen bonding between a propionate group of heme and the tertiary amino nitrogen of chloroquine and quinacrine. Raman spectroscopy data does not provide any evidence to support the formation of a similar salt bridge in the complexes of FP with quinine and mefloquine; however, it suggests that the interaction of these drugs with FP happens through coordination of the Fe(III) center of the porphyrin to the 9-hydroxy group of the drug.

  18. Application of Porous Nickel-Coated TiO2 for the Photocatalytic Degradation of Aqueous Quinoline in an Internal Airlift Loop Reactor

    PubMed Central

    Zhu, Suiyi; Yang, Xia; Yang, Wu; Zhang, Leilei; Wang, Jian; Huo, Mingxin

    2012-01-01

    P25 film, prepared by a facile dip-coating method without any binder, was further developed in a recirculating reactor for quinoline removal from synthetic wastewater. Macroporous foam Ni, which has an open three-dimensional network structure, was utilized as a substrate to make good use of UV rays. Field emission scanning electron microscopy and X-ray diffraction analysis showed that the coated/calcinated P25 films consisted of two crystal phases, and had a number of uniform microcracks on the surface. The effects of initial quinoline concentration, light intensity, reaction temperature, aeration, and initial pH were studied. Increased reaction time, light intensity, environmental temperature, and gas aeration were found to significantly improve the quinoline removal efficiency. The aeration effect of oxygen dependency on the quinoline degradation had the trend pure oxygen > air > no gas > pure nitrogen with free O2. The solution pH crucially affected quinoline photodegradation; the high electrostatic adsorption of quinoline molecules on the TiO2 surface was strongly pH dependent. 2-Pyridine-carboxaldehyde, 3-pyridinecarboxaldehyde, and 2(1H)-quinolinone were identified as the major intermediates of quinoline degradation. Based on these intermediates, a primary degradation mechanism was proposed. This reusable P25 film benefits the photodegradation of water contaminants and has potential in other various applications. PMID:22470309

  19. Biodegradation characterization and immobilized strains' potential for quinoline degradation by Brevundimonas sp. K4 isolated from activated sludge of coking wastewater.

    PubMed

    Wang, Chunrong; Zhang, Mengru; Cheng, Fanglin; Geng, Qi

    2015-01-01

    A novel quinoline-degrading strain, named K4, was isolated from activated sludge of a coking wastewater treatment plant and identified as Brevundimonas sp. on the basis of its 16s rDNA gene sequence analysis. Its optimum temperature and pH for quinoline degradation were 30 °C and pH 9.0, respectively, and during the biodegradation process, at 100 mg/L initial quinoline concentration, an inoculation amount of 8% (OD600 of 0.23) was the optimal strain concentration. In addition, the kinetics of free K4 strains for quinoline degradation showed that it followed a zero-order equation. Furthermore, compared with free K4 strains, immobilized K4 strains' potential for quinoline degradation was investigated by adding both of them into SBR reactors for actual coking wastewater treatment on operation over 15 days. The results showed that bioaugmentation by both free and immobilized K4 strains enhanced quinoline removal efficiency, and especially, the latter could reach its stable removal after a shorter accommodation period, with 94.8% of mean quinoline removal efficiency.

  20. The effect of ((-)-2-oxa-4-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY379268), an mGlu2/3 receptor agonist, on EEG power spectra and coherence in ketamine model of psychosis.

    PubMed

    Fujáková, Michaela; Páleníček, Tomáš; Brunovský, Martin; Gorman, Ingmar; Tylš, Filip; Kubešová, Anna; Řípová, Daniela; Krajča, Vladimír; Horáček, Jiří

    2014-07-01

    In the present study we investigated the potential antipsychotic effects of the mGlu2/3 agonist LY379268 on changes in EEG power spectra and coherence in the ketamine model of psychosis. In order to use behaviorally active drug doses, experiments detecting changes in locomotor activity and sensorimotor gating were also conducted. In EEG experiments, adult male Wistar rats were injected with ketamine 30 mg/kg i.p. and LY379268 3 mg/kg i.p. Cortical EEG was recorded from twelve (2 × 6) electrodes placed homolaterally on each hemisphere. To avoid interference with the behavioral hyperactivity of ketamine challenge, the behavioral activity of animals was simultaneously registered at the time of recording. Subsequent power spectral and coherence analyses were assessed in epochs corresponding to behavioral inactivity. Analysis of segments with behavioral activity compared to inactivity was also performed. The effects of LY379268 3 mg/kg i.p. on the deficits in sensorimotor processing and on hyperlocomotion induced by ketamine were evaluated in the test of prepulse inhibition of acoustic startle reaction (PPI ASR) and in the open field. LY379268 reversed the ketamine-induced hyperlocomotion but had no effect on ketamine-induced PPI deficits. In EEG epochs corresponding to behavioral inactivity ketamine decreased the power in the delta band, induced a power increase in the high frequency bands and globally decreased EEG coherence. Pretreatment with the LY379268 completely reversed the ketamine-induced power increase in high frequency bands and had a partial effect on EEG coherence. LY379268 alone induced a decrease of beta, high beta and low-gamma power, and an increase in coherence in high frequency bands. Additional analysis revealed that behavioral activity increases power as well as coherence in most frequency bands. In conclusion, agonism of mGlu2/3 receptors was effective in reversing most of the changes induced by ketamine, however due to the lack of effectiveness

  1. Dopamine receptor partial agonists and addiction.

    PubMed

    Moreira, Fabricio A; Dalley, Jeffrey W

    2015-04-01

    Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction.

  2. PPAR Agonists and Cardiovascular Disease in Diabetes.

    PubMed

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  3. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  4. Efficient metal-free synthesis of various pyrido[2',1':2,3]imidazo- [4,5-b]quinolines.

    PubMed

    Arnould, Mathieu; Hiebel, Marie-Aude; Massip, Stéphane; Léger, Jean Michel; Jarry, Christian; Berteina-Raboin, Sabine; Guillaumet, Gérald

    2013-09-01

    Dancing with diversity: The synthesis of diverse pyrido[2',1':2,3]imidazo[4,5-b]quinolines bearing several substitution patterns was developed based on combining a multicomponent reaction (Groebke-Blackburn-Bienaymé reaction) with an original cyclization as a secondary transformation (see scheme; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene).

  5. Intramolecular 1,3-dipolar cycloaddition reactions in the synthesis of complex annelated quinolines, α-carbolines and coumarins.

    PubMed

    Majumder, Swarup; Borah, Pallabi; Bhuyan, Pulak J

    2012-05-01

    In this study, we report the synthesis of several novel dihydroisoxazole-, tetrahydroisoxazole- and dihydropyrazole-fused pyrido[2,3-b]quinolines, α-carbolines, and pyrido[2,3-c]coumarins, respectively, from simple precursors and by exploring intramolecular 1,3-dipolar cycloaddition reactions involving nitrile oxides, nitrones, and nitrile imines as 1,3-dipoles. PMID:22374452

  6. Quinoline-Substituted 10-(naphthalene-7-yl)anthracene Derivatives for Blue Fluorescent Organic Light-Emitting Diodes.

    PubMed

    Kim, Chanwoo; Park, Soo Na; Lee, Seul Bee; Kim, Young Seok; Lee, Ho Won; Kim, Young Kwan; Yoon, Seung Soo

    2016-02-01

    In this study, we have designed and synthesized blue emitters based on quinoline-substituted 10-(naphthalene-7-yl)anthracene. Particularly, a material exhibited highly efficient blue electroluminescence with CIE coordinates of (0.15, 0.18). PMID:27433688

  7. Copper-catalyzed intermolecular dehydrogenative amidation/amination of quinoline N-oxides with lactams/cyclamines.

    PubMed

    Li, Gang; Jia, Chunqi; Sun, Kai

    2013-10-18

    C-H, N-H dehydrogenative coupling of quinoline N-oxides with lactams/cyclamines has been achieved in the presence of the Cu(OAc)2 catalyst to give good to excellent yields. This study provides a new strategy for the construction of a 2-aminoquinoline skeleton via direct functionalization of aryl C-H bonds. PMID:24093556

  8. Base catalysed intermolecular cyclisation of N-protected o-amino benzaldehyde/acetophenone with phosphorus/sulphur based allenes: facile synthesis of substituted quinolines.

    PubMed

    Anitha, Mandala; Gangadhararao, G; Kumara Swamy, K C

    2016-04-14

    Reaction of N-Bz protected o-aminobenzaldehyde or acetophenone with allenylphosphonates in the presence of a simple base leads to quaternary carbon substituted phosphono-quinolines which undergo thermal rearrangement to O-phosphorylated quinolines. The present one-pot reaction involves intermolecular cyclisation, dehydration, and benzoyl group rearrangement followed by a novel phosphoryl group migration. The migration was less facile/not observed in the reactions using allenylphosphine oxides and sulphur based allenes wherein only substituted quinolines were obtained in good yields. X-ray structures have been determined for the key products. PMID:26976203

  9. Effect of different beta-adrenergic agonists on the intestinal absorption of galactose and phenylalanine.

    PubMed

    Díez-Sampedro, A; Pérez, M; Cobo, M T; Martínez, J A; Barber, A

    1998-08-01

    Nutrient transport across the mammalian small intestine is regulated by several factors, including intrinsic and extrinsic neural pathways, paracrine modulators, circulating hormones and luminal agents. Because beta-adrenoceptors seem to regulate gastrointestinal functions such as bicarbonate and acid secretion, intestinal motility and gastrointestinal mucosal blood flow, we have investigated the effects of different beta-adrenergic agonists on nutrient absorption by the rat jejunum in-vitro. When intestinal everted sacs were used the beta2-agonist salbutamol had no effect either on galactose uptake by the tissue or mucosal-to-serosal flux whereas mixed beta1- and beta2-agonists (isoproterenol and orciprenaline) and beta3-agonists (BRL 35135, Trecadrine, ICI 198157 and ZD 7114) inhibited galactose uptake and transfer of D-galactose from the mucosal-to-serosal media across the intestinal wall (although the inhibiting effects of isoproterenol and Trecadrine were not statistically significant). In intestinal everted rings both Trecadrine and BRL 35135 clearly reduced galactose uptake, the effect being a result of inhibition of the phlorizin-sensitive component. Total uptake of phenylalanine by the intestinal rings was also reduced by those beta3-adrenergic agonists. These results suggest that beta1- and beta3-adrenergic receptors could be involved in the regulation of intestinal active transport of sugars and amino acids. PMID:9751456

  10. Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum

    PubMed Central

    2010-01-01

    Background The aim of the present work was to assess the in vitro cross-resistance of pyronaridine with other quinoline drugs, artesunate and several other commonly used anti-malarials and to evaluate whether decreased susceptibility to pyronaridine could be associated with genetic polymorphisms in genes involved in reduced quinoline susceptibility, such as pfcrt, pfmdr1, pfmrp and pfnhe. Methods The in vitro chemosusceptibility profiles of 23 strains of Plasmodium falciparum were analysed by the standard 42-hour 3H-hypoxanthine uptake inhibition method for pyronaridine, artesunate, chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine and doxycycline. Genotypes were assessed for pfcrt, pfmdr1, pfnhe-1 and pfmrp genes. Results The IC50 values for pyronaridine ranged from 15 to 49 nM (geometric mean = 23.1 nM). A significant positive correlation was found between responses to pyronaridine and responses to artesunate (r2 = 0.20; P = 0.0317) but too low to suggest cross-resistance. No significant correlation was found between pyronaridine IC50 and responses to other anti-malarials. Significant associations were not found between pyronaridine IC50 and polymorphisms in pfcrt, pfmdr1, pfmrp or pfnhe-1. Conclusion There was an absence of cross-resistance between pyronaridine and quinolines, and the IC50 values for pyronaridine were found to be unrelated to mutations in the transport protein genes pfcrt, pfmdr1, pfmrp or pfnhe-1, known to be involved in quinoline resistance. These results confirm the interest and the efficacy of the use of a combination of pyronaridine and artesunate in areas in which parasites are resistant to quinolines. PMID:21108786

  11. PPARγ agonist from Chromolaena odorata.

    PubMed

    Zhang, Man-Li; Irwin, Dianne; Li, Xiao-Ning; Sauriol, Françoise; Shi, Xiao-Wei; Wang, Yu-Fang; Huo, Chang-Hong; Li, Li-Geng; Gu, Yu-Cheng; Shi, Qing-Wen

    2012-12-28

    A phytochemical investigation of Chromolaena odorata resulted in the isolation of five new compounds, 5aα,6,9,9aβ,10-pentahydro-10β-hydroxy-7-methylanthra[1,2-d][1,3]dioxol-5-one (1), 1,2-methylenedioxy-6-methylanthraquinone (2), 3-hydroxy-1,2,4-trimethoxy-6-methylanthraquinone (3), 3-hydroxy-1,2-dimethoxy-6-methylanthraquinone (4), and 7-methoxy-7-epi-medioresinol (5), together with 12 known compounds, odoratin (6), 3β-acetyloleanolic acid (7), ursolic acid (8), ombuin (9), 4,2'-dihydroxy-4',5',6'-trimethoxychalcone (10), (-)-pinoresinol (11), austrocortinin (12), tianshic acid (13), cleomiscosin D (14), (-)-medioresinol (15), (-)-syringaresinol (16), and cleomiscosin A (17). All the compounds were evaluated for their PPARγ transactivation activity, and compound 6 showed moderate activity with an EC(50) value of 3.10 μM.

  12. Series of coordination polymers based on 4-(5-sulfo-quinolin-8-yloxy) phthalate and bipyridinyl coligands: Structure diversity and properties

    SciTech Connect

    Feng, Xun; Liu, Jing; Li, Jin; Ma, Lu-Fang; Wang, Li-Ya; Ng, Seik-Weng; Qin, Guo-Zhan

    2015-10-15

    Reactions between later metal salts and conjugational N-hetrocyclic sulfonate/ carboxylic acid under the presence of bipyridyl auxiliary ligands afforded a series of manganese, nickel, zinc, silver, cadmium coordination polymers bearing with phenyl pendant arm attached to quinoline skeletons, and they have been characterized by elements analysis, thermogravimetry, infrared spectroscopy and single-crystal X-ray diffraction studying. The series of polymers show interesting structural diversity in coordination environment, dimensions and topologies. They are all built from 2-D networks constructed from metal cluster through sulfonate or carboxylate groups, as the secondary building unit (SBU). The thermalgravimetric analyses show that they display framework stabilities in solid state. Variable-temperature magnetic susceptibility studies reveal the existence of antiferromagnetic interactions between adjacent Mn (II) ions in 1, and ferromagnetic interactions between Ni(II) ions for 2, respectively. The photo-luminescence properties of 3-5 have also been investigated systemically. - Highlights: • A series of coordination polymers based on later transition metal ions have been obtained. • They contain conjugational N-hetrocyclic sulfonate-carboxylic acid and bipyridyl auxiliary ligands. • They have been characterized systemically. • They exhibit structure diversity and interesting properties.

  13. Quinoline and derivatives at a tar oil contaminated site: hydroxylated products as indicator for natural attenuation?

    SciTech Connect

    Anne-Kirsten Reineke; Thomas Goeen; Alfred Preiss; Juliane Hollender

    2007-08-01

    LC-MS-MS analysis of groundwater of a tar oil contaminated site (a former coal mine and coking plant in Castrop-Rauxel, Germany) showed the occurrence of the N-heterocycles quinoline and isoquinoline as well as their hydroxylated and hydrogenated metabolites. The concentrations of the hydroxylated compounds, 2(1H)-quinolinone and 1(2H)-isoquinolinone, were significantly higher than those of the nonsubstituted parent compounds. Therefore, exclusive quantification of the parent compounds leads to an underestimation of the amount of N-heterocycles present in the groundwater. Microbial degradation experiments of quinoline and isoquinoline with aquifer material of the site as inocculum showed the formation of hydroxylated and hydrogenated products under sulfate-reducing conditions, the prevailing conditions in the field. However, since analyses of seven tar products showed that these compounds are also primary constituents, their detection in groundwater is found to be a nonsufficient indicator for the occurrence of biological natural attenuation processes. Instead, the ratio of hydroxylated to parent compound (R{sub metabolite}) is proposed as a useful indicator. We found that 65-83% of all groundwater samples showed R{sub metabolite} for 2(1H)-quinolinone, 1(2H)-isoquinolinone, 3,4-dihydro-2(1H)-quinolinone, and 3,4-dihydro-1(2H)-isoquinolinone, which was higher than the highest ratio found in tar products. With respect to the observed partition coefficient between tar oil and water of 3.5 for quinoline and isoquinoline and 0.3 for 2(1H)-quinolinone and 1(2H)-isoquinolinone, the ratio in groundwater would be approximately 10 times higher than the ratio in tar oil. When paying attention to these two parameters, 19-31% of groundwater samples exceed the highest tar oil ratio. This indicates that biological processes take place in the aquifer of the site and R{sub metabolite} is an applicable indicator for natural attenuation. 42 refs., 6 figs., 2 tabs.

  14. Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea.

    PubMed

    Sato, Hiroyuki; Genet, Cédric; Strehle, Axelle; Thomas, Charles; Lobstein, Annelise; Wagner, Alain; Mioskowski, Charles; Auwerx, Johan; Saladin, Régis

    2007-11-01

    Olive tree (Olea europeaea) leaves are well known for their effect on metabolism in particular as a traditional anti-diabetic and anti-hypertensive herbal drug. These properties are until now only attributed to oleuropein, the major secoiridoid of olive leaves. Here we describe the isolation and the identification of another constituent implicated in the anti-diabetic effect of this plant, i.e. oleanolic acid. We show that this triterpene is an agonist for TGR5, a member of G-protein coupled receptor activated by bile acids and which mediates some of their various cellular and physiological effect. Oleanolic acid lowers serum glucose and insulin levels in mice fed with a high fat diet and it enhances glucose tolerance. Our data suggest that both oleuropein and oleanolic acid are involved in the anti-diabetic effect of olive leaves and further emphasize the potential role of TGR5 agonists to improve metabolic disorders.

  15. The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist

    PubMed Central

    Kumar, Naresh; Solt, Laura A.; Conkright, Juliana J.; Wang, Yongjun; Istrate, Monica A.; Busby, Scott A.; Garcia-Ordonez, Ruben D.; Burris, Thomas P.

    2010-01-01

    Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiological processes including hepatic gluconeogenesis, lipid metabolism, circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both RORα and RORγ. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of RORα and RORγ but not RORβ. T0901317 was found to directly bind to RORα and RORγ with high affinity (Ki = 132 and 51 nM, respectively), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed RORα/γ-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by RORα at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compound's LXR activity. In summary, T0901317 represents a novel chemical probe to examine RORα/γ function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small molecules can be used to target the RORs for therapeutic intervention in metabolic and immune disorders. PMID:19887649

  16. Time and space profiling of NMDA receptor co-agonist functions.

    PubMed

    Mothet, Jean-Pierre; Le Bail, Matildé; Billard, Jean-Marie

    2015-10-01

    The N-Methyl D-Aspartic acid (NMDA) receptors (NMDAR) are key tetrameric ionotropic glutamate receptors that transduce glutamatergic signals throughout the central nervous system (CNS) and spinal cord. Although NMDARs are diverse in their subunit composition, subcellular localization, and biophysical and pharmacological properties, their activation always requires the binding of a co-agonist that has long been thought to be glycine. However, intense research over the last decade has challenged this classical model by showing that another amino acid, d-serine, is the preferential co-agonist for a subset of synaptic NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses at work is emerging where both glycine and d-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. The purpose of this review was to highlight the particular role of each co-agonist in modulating NMDAR-dependent activities in healthy and diseased brains. We have herein integrated our most advanced knowledge of how glycine and d-serine may orchestrate synapse dynamics and drive neuronal network activity in a time- and synapse-specific manner and how changes in synaptic availability of these amino acids may contribute to cognitive impairments such as those associated with healthy aging, epilepsy, and schizophrenia. The N-Methyl D-Aspartic acid (NMDA) subtype of glutamate receptors are central to many physiological functions and are linked to brain disorders. Their functions require glutamate and a co-agonist d-serine or glycine. After years of intense research and controversy on the identity of the amino acid that serves as the right co-agonist, we are just entering a new era of consensus where glycine and d-serine are teaming up to regulate the function of different subsets of NMDA receptors and at different synapses during different time windows of brain development. PMID:26088787

  17. Copper-catalyzed synthesis of substituted quinolines via C–N coupling/condensation from ortho-acylanilines and alkenyl iodides.

    PubMed

    Kong, Lingkai; Zhou, Yuanyuan; Huang, He; Yang, Yang; Liu, Yuanyuan; Li, Yanzhong

    2015-01-16

    An efficient cascade copper-catalyzed intermolecular Ullmann-type C–N coupling/enamine condensation reaction is described, in which ortho-acylanilines and alkenyl iodides converted to multisubstituted quinolines in good to excellent yields.

  18. [UV-spectrophotometry in drug control. 33. New drugs with benzene, pyridine, quinoline and phenanthrene chromophores in the molecule. 6. The effect of substitution and solvents].

    PubMed

    Krácmar, J; Krácmarová, J; Stejskal, Z

    1987-01-01

    UV-spectra of 14 new substances with benzene, pyridine, quinoline and phenanthrene chromophores as well as influences of substitutes and solvents on shifts of the bands E, K, B and R are discussed. PMID:2953035

  19. Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists.

    PubMed

    Makadia, Pankaj; Shah, Shailesh R; Pingali, Harikishore; Zaware, Pandurang; Patel, Darshit; Pola, Suresh; Thube, Baban; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Giri, Suresh; Trivedi, Chitrang; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.

  20. Agonistic interactions, cuticular and hemolymphatic lipid variations during the foraging period in spider females Brachypelma albopilosa (Theraphosidae).

    PubMed

    Trabalon, Marie

    2011-06-01

    Agonistic behaviour and lipid state were examined in tarantula Brachypelma albopilosa females during the foraging period. Modulation of the agonistic behaviour of females was not connected to their body size. Results show that the agonistic pattern of females differed significantly from the predation pattern at the behavioural and lipid levels. Aggressive-foraging females had low predation behaviour. Quantitative lipid changes were observed in relation to agonistic behaviour and predation. The total lipid index was studied by colorimetric methods, and lipid compounds were analyzed by gas chromatography-mass spectrometry in cuticle and hemolymph of females. The lipid components were free fatty acids, methyl esters, cholesterol, and long-chain aliphatic hydrocarbons. Methyl esters were much more abundant in cuticular lipids; unsaturated free fatty acids (linoleic and oleic acids) and methyl esters (methyl linoleate and methyl stearate) predominated in the hemolymph. Spider aggression was positively correlated with lipid concentration (cholesterol, fatty acids, methyl esters and hydrocarbons) in the hemolymph and the levels of cuticular fatty acids. Lipid levels are hypothesized to have evolved as a regulatory factor of predation and agonistic behaviours in tarantula females. PMID:21338607

  1. A Rhodium Nanoparticle-Lewis Acidic Ionic Liquid Catalyst for the Chemoselective Reduction of Heteroarenes.

    PubMed

    Karakulina, Alena; Gopakumar, Aswin; Akçok, İsmail; Roulier, Bastien L; LaGrange, Thomas; Katsyuba, Sergey A; Das, Shoubhik; Dyson, Paul J

    2016-01-01

    We describe a catalytic system composed of rhodium nanoparticles immobilized in a Lewis acidic ionic liquid. The combined system catalyzes the hydrogenation of quinolines, pyridines, benzofurans, and furan to access the corresponding heterocycles, important molecules present in fine chemicals, agrochemicals, and pharmaceuticals. The catalyst is highly selective, acting only on the heteroaromatic ring, and not interfering with other reducible functional groups.

  2. Fluorescence in complexes based on quinolines-derivatives: a search for better fluorescent probes.

    PubMed

    Mecca, Carolina Z P; Fonseca, Fernando L A; Bagatin, Izilda A

    2016-11-01

    Quinoline-derived fluorescent complexes were designed; synthesized by the reaction of 5-nitro-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline with Al(3+), Mg(2+), Zn(2+), and Cd(2+) salts (1-8); and characterized. The (1)H NMR spectra of complexes 1 and 5, containing Al(3+), were consistent with an octahedral structure having approximate D3 symmetry, and the results supported the favored facial isomer (fac). Data for complexes 2-4 and 6-8 supported the formation of tetrahedral structures. Intense luminescence was detected for complexes 5-8, even with the naked eye, as indicated by quantum yield values of 0.087, 0.094, 0.051, and 0.021, respectively. Furthermore, in contrast to 5-nitro-8-hydroxyquinoline, the 5-chloro-8-hydroxyquinoline ligand exhibited bands at different energies depending on the coordinated metal, which supported its potential application in ionic and biological probes, as well as in cell imaging. PMID:27288961

  3. Fluorescence in complexes based on quinolines-derivatives: a search for better fluorescent probes.

    PubMed

    Mecca, Carolina Z P; Fonseca, Fernando L A; Bagatin, Izilda A

    2016-11-01

    Quinoline-derived fluorescent complexes were designed; synthesized by the reaction of 5-nitro-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline with Al(3+), Mg(2+), Zn(2+), and Cd(2+) salts (1-8); and characterized. The (1)H NMR spectra of complexes 1 and 5, containing Al(3+), were consistent with an octahedral structure having approximate D3 symmetry, and the results supported the favored facial isomer (fac). Data for complexes 2-4 and 6-8 supported the formation of tetrahedral structures. Intense luminescence was detected for complexes 5-8, even with the naked eye, as indicated by quantum yield values of 0.087, 0.094, 0.051, and 0.021, respectively. Furthermore, in contrast to 5-nitro-8-hydroxyquinoline, the 5-chloro-8-hydroxyquinoline ligand exhibited bands at different energies depending on the coordinated metal, which supported its potential application in ionic and biological probes, as well as in cell imaging.

  4. Novel thiophene derivatives with sulfonamide, isoxazole, benzothiazole, quinoline and anthracene moieties as potential anticancer agents.

    PubMed

    Ghorab, Mostafa M; Bashandy, Mahmoud S; Alsaid, Mansour S

    2014-12-01

    A novel series of thiophenes having biologically active sulfonamide 2-11, 3-methylisoxazole 12, 4-methoxybenzo[d] thiazole 13, quinoline 14, 15, benzoylphenylamino 16, and anthracene-9,10-dione 17 moieties were prepared. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. All newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Most of the screened compounds showed cytotoxic activities compared to doxorubicin as a positive control. Compounds 6, 7, 9 and 13 (IC50 values 10.25, 9.70, 9.55 and 9.39 μmol L-1) revealed higher cytotoxic activities than that of doxorubicin (IC50 = 32.00 μmol L-1). Also, compounds 5, 8 and 10 were found nearly as active as doxorubicin (IC50 28.85, 23.48 and 27.51 μmol L-1).

  5. Second-order optical effects in several pyrazolo-quinoline derivatives

    NASA Astrophysics Data System (ADS)

    Makowska-Janusik, M.; Gondek, E.; Kityk, I. V.; Wisła, J.; Sanetra, J.; Danel, A.

    2004-11-01

    Using optical poling of several pyazolo-quinoline (PAQ) derivatives we have found an existence of sufficiently high second order optical susceptibility at wavelength 1.76 μm varying in the range 0.9-2.8 pm/V. The performed quantum chemical simulations of the UV-absorption for isolated, solvated and incorporated into the polymethacrylate (PMMA) polymer films have shown that the PM3 method is the best among the semi-empirical ones to simulate the optical properties. The calculations of the hyperpolarizabilites have shown a good correlation with experimentally measured susceptibilities obtained from the optical poling. We have found that experimental susceptibility depends on linear molecular polarizability and photoinducing changes of the molecular dipole moment. It is clearly seen for the PAQ4-PAQ6 molecules possessing halogen atoms with relatively large polarizabilities.

  6. Second-generation substituted quinolines as anticancer drugs for breast cancer.

    PubMed

    Heiniger, Brian; Gakhar, Gunjan; Prasain, Keshar; Hua, Duy H; Nguyen, Thu A

    2010-10-01

    Cancer cells have reduced capacity for gap junctional inter-cellular communication (GJIC). One feasible approach to reduce growth of cancer cells is to enhance GJIC. This report shows that a second-generation substituted quinoline, PQ7, has anti-tumor effect. Scrape load/dye transfer and colony growth assays were performed to measure GJIC and tumor formation of T47D breast cancer cells. PQ7 at 500 nM induced a 16-fold increase in the GJIC in T47D cells. In addition to an increase in GJIC, a 50% decrease of colony growth was observed with 100 nM of PQ7. PQ7-treated nu/nu mice showed a 100% regression of xenograft tumor growth of T47D cells. The results show that PQ7 has a promising role in exerting anti-tumor activity in human breast cancer cells.

  7. 8-Hy­droxy-5,7-dimethyl­quinolin-1-ium hydrogen sulfate

    PubMed Central

    Thanigaimani, Kaliyaperumal; Khalib, Nuridayanti Che; Arshad, Suhana; Razak, Ibrahim Abdul

    2013-01-01

    The quinoline ring system of the title salt, C11H12NO+·HSO4 −, is essentially planar, with a maximum deviation of 0.054 (2) Å for all non H atoms. In the crystal, the cations and anions are linked via N—H⋯O, O—H⋯O and weak C—H⋯O hydrogen bonds, and are stacked respectively in columns along the a axis. π–π stacking inter­actions, with centroid–centroid distances of 3.5473 (12) and 3.6926 (12) Å, are also observed. The crystal studied was an inversion twin with refined components of 0.43 (7):0.57 (7). PMID:23476427

  8. 8-Hy­droxy-5,7-dimethyl­quinolin-1-ium chloride dihydrate

    PubMed Central

    Thanigaimani, Kaliyaperumal; Khalib, Nuridayanti Che; Arshad, Suhana; Razak, Ibrahim Abdul

    2013-01-01

    In the title hydrated salt, C11H12NO+·Cl−·2H2O, the quinoline ring system is essentially planar, with a maximum deviation of 0.005 (1) Å for all non-H atoms. In the crystal, the three components are linked by O—H⋯O, N—H⋯O, O—H⋯Cl and weak C—H⋯O hydrogen bonds, forming a layer structure parallel to the ac plane. The crystal structure is further stabilized by π–π stacking inter­actions, with centroid–centroid distances of 3.5213 (6) and 3.7176 (6) Å. PMID:23476428

  9. Study on the interaction of food colourant quinoline yellow with bovine serum albumin by spectroscopic techniques.

    PubMed

    Shahabadi, Nahid; Maghsudi, Maryam; Rouhani, Shohre

    2012-12-01

    The interaction of a food colourant, quinoline yellow (Qy), and bovine serum albumin (BSA) was investigated by spectrophotometry, spectrofluorometry, FT-IR and circular dichroism (CD) techniques. The experimental results indicated that the quenching mechanism of BSA by the dye was a static procedure. Various binding parameters were evaluated. The negative value of ΔH, negative value of ΔS and the negative value of ΔG indicated that van der Waals force and hydrogen bonding play major roles in the binding of Qy and BSA. Based on Forster's theory of non-radiation energy transfer, the binding distance, r, between the donor (BSA) and acceptor (Qy) was evaluated. The results of CD and UV-vis spectroscopy showed that this dye could bind to BSA and the conformation of BSA changed.

  10. Fluorescence in complexes based on quinolines-derivatives: a search for better fluorescent probes

    NASA Astrophysics Data System (ADS)

    Mecca, Carolina Z. P.; Fonseca, Fernando L. A.; Bagatin, Izilda A.

    2016-11-01

    Quinoline-derived fluorescent complexes were designed; synthesized by the reaction of 5-nitro-8-hydroxyquinoline and 5-chloro-8-hydroxyquinoline with Al3+, Mg2+, Zn2+, and Cd2+ salts (1-8); and characterized. The 1H NMR spectra of complexes 1 and 5, containing Al3+, were consistent with an octahedral structure having approximate D3 symmetry, and the results supported the favored facial isomer (fac). Data for complexes 2-4 and 6-8 supported the formation of tetrahedral structures. Intense luminescence was detected for complexes 5-8, even with the naked eye, as indicated by quantum yield values of 0.087, 0.094, 0.051, and 0.021, respectively. Furthermore, in contrast to 5-nitro-8-hydroxyquinoline, the 5-chloro-8-hydroxyquinoline ligand exhibited bands at different energies depending on the coordinated metal, which supported its potential application in ionic and biological probes, as well as in cell imaging.

  11. Iodine-Mediated Intramolecular Dehydrogenative Coupling: Synthesis of N-Alkylindolo[3,2-c]- and -[2,3-c]quinoline Iodides.

    PubMed

    Volvoikar, Prajesh S; Tilve, Santosh G

    2016-03-01

    An I2/TBHP-mediated intramolecular dehydrogenative coupling reaction is developed for the synthesis of a library of medicinally important 5,11-dialkylindolo[3,2-c]quinoline salts and 5,7-dimethylindolo[2,3-c]quinoline salts. The annulation reaction is followed by aromatization to yield tetracycles in good yield. This protocol is also demonstrated for the synthesis of the naturally occurring isocryptolepine in salt form. PMID:26866309

  12. Iodine-Mediated Intramolecular Dehydrogenative Coupling: Synthesis of N-Alkylindolo[3,2-c]- and -[2,3-c]quinoline Iodides.

    PubMed

    Volvoikar, Prajesh S; Tilve, Santosh G

    2016-03-01

    An I2/TBHP-mediated intramolecular dehydrogenative coupling reaction is developed for the synthesis of a library of medicinally important 5,11-dialkylindolo[3,2-c]quinoline salts and 5,7-dimethylindolo[2,3-c]quinoline salts. The annulation reaction is followed by aromatization to yield tetracycles in good yield. This protocol is also demonstrated for the synthesis of the naturally occurring isocryptolepine in salt form.

  13. Elucidation of the biochemical basis for a clinical drug-drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha.

    PubMed

    Kalgutkar, Amit S; Chen, Danny; Varma, Manthena V; Feng, Bo; Terra, Steven G; Scialis, Renato J; Rotter, Charles J; Frederick, Kosea S; West, Mark A; Goosen, Theunis C; Gosset, James R; Walsky, Robert L; Francone, Omar L

    2013-11-01

    1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778875 (1.0 mg QD) on days 5-12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778875. Subjects in group B (n = 29) received CP-778875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5-12. 3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778875. CP-778875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4.  Inhibition of organic anion transporting polypeptide 1B1 by CP-778875 (IC50 = 2.14 ± 0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.

  14. Polymorphs and salts of 4-nitro-N-(quinolin-8-yl)benzamide

    NASA Astrophysics Data System (ADS)

    Khakhlary, Prithiviraj; Baruah, Jubaraj B.

    2014-12-01

    Three polymorphs (I-III) of 4-nitro-N-(quinolin-8-yl)benzamide (L) arising from differences in their packing patterns are characterized. Out of the three polymorphs, two polymorphs (I and II) have extended chain of R22(10) type of hydrogen bonds involving oxygen atom of carbonyl and nitro group through C-H⋯O interactions. These two polymorphs have head to head arrangements of molecules in their respective crystal lattice. One polymorph has two layers of molecules which are held by π⋯π interactions; whereas another polymorph is devoid of π-interactions. The third polymorph (III) has head to tail arrangement of molecules and have C-H⋯O interactions involving carbonyl groups of amides. The polymorph I shows two melting points resembling liquid crystalline property. The powder X-ray diffraction studies performed on the crystals obtained from solutions of different mixed solvents showed the independent role of each solvent to guide crystallization of mixture of polymorphs. The structure of the salts of L having ethylsulphate (IV), bromide (V) and nitrate (VI) anions were determined and conformational differences are established. The nitrate salt is an isomorphic desolvate, which has a porous structure, with voids of dimension 114.8 Å3 (13.5%) per unit cell having volume of 853.4 Å3. It is found that the projection of carbonyl group with respect to the nitrogen atom of the quinoline in LH+ part in the structure of ethylsulphate salt (IV) with respect to bromide salt (V) is opposite.

  15. Selective α4β2 nicotinic acetylcholine receptor agonists target epigenetic mechanisms in cortical GABAergic neurons.

    PubMed

    Maloku, Ekrem; Kadriu, Bashkim; Zhubi, Adrian; Dong, Erbo; Pibiri, Fabio; Satta, Rosalba; Guidotti, Alessandro

    2011-06-01

    Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic α(4)β(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)β(2) and a lower affinity full agonist at α(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to α(4)β(2) but has negligible affinity for α(3)β(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)β(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists.

  16. Agonist self-inhibition at the nicotinic acetylcholine receptor a nonspecific action

    SciTech Connect

    Forman, S.A.; Firestone, L.L.; Miller, K.W.

    1987-05-19

    Agonist concentration-response relationships at nicotinic postsynaptic receptors were established by measuring /sup 86/Rb/sup +/ efflux from acetylcholine receptor rich native Torpedo membrane vesicles under three different conditions: (1) integrated net ion efflux (in 10 s) from untreated vesicles, (2) integrated net efflux from vesicles in which most acetylcholine sites were irreversibly blocked with ..cap alpha..-bungarotoxin, and (3) initial rates of efflux (5-100 ms) from vesicles that were partially blocked with ..cap alpha..-bungarotoxin. Exposure to acetylcholine, carbamylcholine, suberyldicholine, phenyltrimethylammonium, or (-)-nicotine over 10/sup 8/-fold concentration ranges results in bell-shaped ion flux response curves due to stimulation of acetylcholine receptor channel opening at low concentrations and inhibition of channel function at 60-2000 times higher concentrations. Concentrations of agonists that inhibit their own maximum /sup 86/Rb/sup +/ efflux by 50% (K/sub B/ values) are 110, 211, 3.0, 39, and 8.9 mM, respectively, for the agonists listed above. For acetylcholine and carbamylcholine, K/sub B/ values determined from both 10-s and 15-ms efflux measurements are the same, indicating that the rate of agonist-induced desensitization increases to maximum at concentrations lower than those causing self-inhibition. For all partial and full agonists studied, Hill coefficients for self-inhibition are close to 1.0. Concentrations of agonists up to 8 times K/sub B/ did not change the order parameter reported by a spin-labeled fatty acid incorporated in Torpedo membranes. The authors conclude that agonist self-inhibition cannot be attributed to a general nonspecific membrane perturbation. Instead, these results are consistent with a saturable site of action either at the lipid-protein interface or on the acetylcholine receptor protein itself.

  17. Identification of a New Type of Covalent PPARγ Agonist using a Ligand-Linking Strategy.

    PubMed

    Ohtera, Anna; Miyamae, Yusaku; Yoshida, Kotaro; Maejima, Kazuhiro; Akita, Toru; Kakizuka, Akira; Irie, Kazuhiro; Masuda, Seiji; Kambe, Taiho; Nagao, Masaya

    2015-12-18

    Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that plays an important role in adipogenesis and glucose metabolism. The ligand-binding pocket (LBP) of PPARγ has a large Y-shaped cavity with multiple subpockets where multiple ligands can simultaneously bind and cooperatively activate PPARγ. Focusing on this unique property of the PPARγ LBP, we describe a novel two-step cell-based strategy to develop PPARγ ligands. First, a combination of ligands that cooperatively activates PPARγ was identified using a luciferase reporter assay. Second, hybrid ligands were designed and synthesized. For proof of concept, we focused on covalent agonists, which activate PPARγ through a unique activation mechanism regulated by a covalent linkage with the Cys285 residue in the PPARγ LBP. Despite their biological significance and pharmacological potential, few covalent PPARγ agonists are known except for endogenous fatty acid metabolites. With our strategy, we determined that plant-derived cinnamic acid derivatives cooperatively activated PPARγ by combining with GW9662, an irreversible antagonist. GW9662 covalently reacts with the Cys285 residue. A docking study predicted that a cinnamic acid derivative can bind to the open cavity in GW9662-bound PPARγ LBP. On the basis of the putative binding mode, structures of both ligands were linked successfully to create a potent PPARγ agonist, which enhanced the transactivation potential of PPARγ at submicromolar levels through covalent modification of Cys285. Our approach could lead to the discovery of novel high-potency PPARγ agonists.

  18. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  19. Identification of dual PPARα/γ agonists and their effects on lipid metabolism.

    PubMed

    Gao, Quanqing; Hanh, Jacky; Váradi, Linda; Cairns, Rose; Sjöström, Helena; Liao, Vivian W Y; Wood, Peta; Balaban, Seher; Ong, Jennifer Ai; Lin, Hsuan-Yu Jennifer; Lai, Felcia; Hoy, Andrew J; Grewal, Thomas; Groundwater, Paul W; Hibbs, David E

    2015-12-15

    The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50μM and 100μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes. PMID:26616289

  20. Agonists-induced platelet activation varies considerably in healthy male individuals: studies by flow cytometry.

    PubMed

    Panzer, Simon; Höcker, Lisa; Koren, Daniela

    2006-02-01

    Flow cytometric evaluation of platelet function extends our understanding of platelets' role in various clinical conditions associated with either bleeding disorders, thrombosis, or monitoring of antiplatelet therapy. The use of suboptimal concentrations of various agonists may allow assessing the "activatability" of platelets. We determined platelet responsiveness to thrombin-receptor-activating peptide-6, arachidonic acid, adenosine 5c-diphosphate (ADP), epinephrine, collagen, and ristocetin at suboptimal concentrations by determination of P-selectin expression and binding of PAC-1 in 26 healthy male individuals. The response varied considerably from one individual to the next. However, within individuals, responses to all agonists except collagen correlated strongly (p<0.05), suggesting a global variability of platelet responses. Moreover, P-selectin expression and PAC-1 binding were strongly correlated (p<0.05). Interestingly, with epinephrine, PAC-1 positive events outnumbered P-selectin positive events, while this was not seen with the other agonists. Thus, epinephrine may specifically affect the conformational switch mechanism and receptor clustering. Our data indicate that the in vitro response to suboptimal concentrations of agonists varies, but individuals with selective platelet defects may still be identified based on data obtained with the various agonists. PMID:16283308

  1. Phospholipase D and its product, phosphatidic acid, mediate agonist-dependent raf-1 translocation to the plasma membrane and the activation of the mitogen-activated protein kinase pathway.

    PubMed

    Rizzo, M A; Shome, K; Vasudevan, C; Stolz, D B; Sung, T C; Frohman, M A; Watkins, S C; Romero, G

    1999-01-01

    The primary known function of phospholipase D (PLD) is to generate phosphatidic acid (PA) via the hydrolysis of phosphatidylcholine. However, the functional role of PA is not well understood. We report here evidence that links the activation of PLD by insulin and the subsequent generation of PA to the activation of the Raf-1-mitogen-activated protein kinase (MAPK) cascade. Brefeldin A (BFA), an inhibitor of the activation of ADP-ribosylation factor proteins, inhibited insulin-dependent production of PA and MAPK phosphorylation. The addition of PA reversed the inhibition of MAPK activation by BFA. Overexpression of a catalytically inactive variant of PLD2, but not PLD1, blocked insulin-dependent activation of PLD and phosphorylation of MAPK. Real time imaging analysis showed that insulin induced Raf-1 translocation to cell membranes by a process that was inhibited by BFA. PA addition reversed the effects of BFA on Raf-1 translocation. However, PA did not activate Raf-1 in vitro or in vivo, suggesting that the primary function of PA is to enhance the recruitment of Raf-1 to the plasma membrane where other factors may activate it. Finally, we found that the recruitment of Raf-1 to the plasma membrane was transient, but Raf-1 remained bound to endocytic vesicles.

  2. Crystal Structures and Phase Relationships of 2 Polymorphs of 1,4-Diazabicyclo[3.2.2]nonane-4-Carboxylic Acid 4-Bromophenyl Ester Fumarate, A Selective α-7 Nicotinic Receptor Partial Agonist.

    PubMed

    Robert, Benoît; Perrin, Marc-Antoine; Barrio, Maria; Tamarit, Josep-Lluis; Coquerel, Gérard; Ceolin, René; Rietveld, Ivo B

    2016-01-01

    Two polymorphs of the 1:1 fumarate salt of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester, developed for the treatment of cognitive symptoms of schizophrenia and Alzheimer disease, have been characterized. The 2 crystal structures have been solved, and their phase relationships have been established. The space group of form I is P2₁/c with a unit-cell volume of 1811.6 (5) Å(3) with Z = 4. The crystals of form I were 2-component nonmerohedral twins. The space group of form II is P2₁/n with a unit-cell volume of 1818.6 (3) Å(3) with Z = 4. Relative stabilities have been inferred from experimental and topological P-T diagrams exhibiting an overall enantiotropic relationship between forms I and II although the solid-solid transition has never been observed. The slope of the I-II equilibrium in the P-T diagram is negative, form II is the stable phase below the solid-solid transition temperature of 371 K, and form I exhibits a stable melting equilibrium. The I-II transition temperature has been obtained from the intersection of the sublimation curves of the 2 solid forms. PMID:26852840

  3. Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues.

    PubMed

    Martins, Carla; Carreiras, M Carmo; León, Rafael; de los Ríos, Cristóbal; Bartolini, Manuela; Andrisano, Vincenza; Iriepa, Isabel; Moraleda, Ignacio; Gálvez, Enrique; García, Manuela; Egea, Javier; Samadi, Abdelouhaid; Chioua, Mourad; Marco-Contelles, José

    2011-12-01

    The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1-11 and 12-16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines1-11 and pyrrolotacrine13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC(50) (eqBuChE)=2.9 ± 0.4 μM; IC(50) (hBuChE)=119 ± 15 μM]. Conversely, pyrrolotacrines 12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC(50) (EeAChE)=0.61 ± 0.04 μM; IC(50) (eqBuChE)=0.074 ± 0.009 μM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Aβ-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer's disease. PMID:22000936

  4. Recent advances in the development of farnesoid X receptor agonists

    PubMed Central

    Carey, Elizabeth J.; Lindor, Keith D.

    2015-01-01

    Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing. PMID:25705637

  5. Acinetobacter calcoaceticus genes involved in biosynthesis of the coenzyme pyrrolo-quinoline-quinone: nucleotide sequence and expression in Escherichia coli K-12.

    PubMed Central

    Goosen, N; Horsman, H P; Huinen, R G; van de Putte, P

    1989-01-01

    Synthesis of the coenzyme pyrrolo-quinoline-quinone (PQQ) from Acinetobacter calcoaceticus requires the products of at least four different genes. In this paper we present the nucleotide sequence of a 5,085-base-pair DNA fragment containing these four genes. Within the DNA fragment three reading frames are present, coding for proteins of Mr 10,800, 29,700, and 43,600 and corresponding to three of the PQQ genes. In the DNA region where the fourth PQQ gene was mapped the largest possible reading frame encodes for a polypeptide of only 24 amino acids. Still, the expression of this region is essential for the biosynthesis of PQQ. A possible role for this DNA region is discussed. Sandwiched between two PQQ genes an additional reading frame is present, coding for a protein of Mr 33,600. This gene, which is probably transcribed in the same operon as three of the PQQ genes, seems not required for PQQ synthesis. Expression of the PQQ genes in Acinetobacter lwoffi and Escherichia coli K-12 led to the synthesis of the coenzyme in these organisms. Images PMID:2536663

  6. N-H⋯O versus O-H⋯O: density functional calculation and first principle molecular dynamics study on a quinoline-2-carboxamide N-oxide.

    PubMed

    Jezierska, Aneta

    2015-03-01

    N-oxide-type compounds are the object of current research interest due to the presence of resonance-assisted N-H⋯O hydrogen bonds. Here, the metric and spectroscopic parameters of N-methyl-quinoline-2-carboxamide 1-oxide were computed on the basis of density functional theory and Car-Parrinello molecular dynamics. Computations were performed in vacuo and in solid state; for both phases additional simulations with Grimme's dispersion correction were carried out. The approaches used were able to reproduce correctly the structural aspects of the studied compound and shed more light on the hydrogen bonding with special focus on bridge proton mobility. Proton transfer phenomena were found not to occur in the investigated compound, and the bridge proton was localized to the donor site. This observation is in agreement with the classical theory of the acidity of donor-acceptor sites. The presence of hydrogen bonding was confirmed using atoms-in-molecules theory. The computational results were compared with available experimental data. PMID:25690363

  7. 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains.

    PubMed

    Pissinate, Kenia; Villela, Anne Drumond; Rodrigues-Junior, Valnês; Giacobbo, Bruno Couto; Grams, Estêvão Silveira; Abbadi, Bruno Lopes; Trindade, Rogério Valim; Roesler Nery, Laura; Bonan, Carla Denise; Back, Davi Fernando; Campos, Maria Martha; Basso, Luiz Augusto; Santos, Diógenes Santiago; Machado, Pablo

    2016-03-10

    2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.

  8. Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase.

    PubMed

    Degorce, Sébastien L; Barlaam, Bernard; Cadogan, Elaine; Dishington, Allan; Ducray, Richard; Glossop, Steven C; Hassall, Lorraine A; Lach, Franck; Lau, Alan; McGuire, Thomas M; Nowak, Thorsten; Ouvry, Gilles; Pike, Kurt G; Thomason, Andrew G

    2016-07-14

    A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model. PMID:27259031

  9. Excited state intramolecular proton transfer in electron-rich and electron-poor derivatives of 10-hydroxybenzo[h]quinoline.

    PubMed

    Piechowska, Joanna; Huttunen, Kirsi; Wróbel, Zbigniew; Lemmetyinen, Helge; Tkachenko, Nikolai V; Gryko, Daniel T

    2012-10-01

    Eight previously inaccessible derivatives of 10-hydroxybenzo[h]quinoline were prepared via a straightforward strategy comprising formation of the benzo[h]quinoline skeleton followed by C-H acetoxylation at position 10. The occurrence of excited state intramolecular proton transfer (ESIPT) was detected in all cases since emission was observed only from the excited keto-tautomer. Studies on derivatives bearing both electron-donating and electron-withdrawing groups adjacent to the pyridine ring allowed us to identify some design patterns giving rise to NIR emission and large Stokes shifts. For a derivative of 10-hydroxybenzo[c]acridine, emission at 745 nm was observed, one of the lowest energy fluorescence ever reported for ESIPT system. On the basis of time-resolved measurements, proton transfer was found to be extremely fast with time constants in the range (0.08-0.45 ps). PMID:22946783

  10. Crystal structure of (pyridine-κN)bis(quinolin-2-olato-κ(2) N,O)copper(II) monohydrate.

    PubMed

    Hawks, Benjamin; Yan, Jingjing; Basa, Prem; Burdette, Shawn

    2015-02-01

    The title complex, [Cu(C9H6NO)2(C5H4N)]·H2O, adopts a slightly distorted square-pyramidal geometry in which the axial pyridine ligand exhibits a long Cu-N bond of 2.305 (3) Å. The pyridine ligand forms dihedral angles of 79.5 (5) and 88.0 (1)° with the planes of the two quinolin-2-olate ligands, while the dihedral angle between the quinoline groups of 9.0 (3)° indicates near planarity. The water mol-ecule connects adjacent copper complexes through O-H⋯O hydrogen bonds to phenolate O atoms, forming a network inter-connecting all the complexes in the crystal lattice.

  11. Synthesis and anti-cancer activity of 1,4-disubstituted imidazo[4,5-c]quinolines.

    PubMed

    Thigulla, Yadagiri; Akula, Mahesh; Trivedi, Prakruti; Ghosh, Balaram; Jha, Mukund; Bhattacharya, Anupam

    2016-01-21

    The synthesis and anti-cancer activity evaluation of fused imidazoquinoline compounds is reported in this paper. Yb(OTf)3 has been utilized as a catalyst for the synthesis of 1,4-diaryl substituted imidazo[4,5-c]quinolines via a modified Pictet-Spengler approach. The desired imidazole ring was synthesized from imines using TosMIC (toluenesulfonylmethyl isocyanide) and subsequently functionalized at the C-4 position yielding an imidazoquinoline skeleton. Importantly, the final step was carried out without the aid of any prefunctionalization to obtain the resultant compounds in good yields. The synthesized compounds, when screened for anti-cancer activity, revealed the highest activity with 4-(2-bromophenyl)-1-phenyl-1H-imidazo[4,5-c]quinoline (IC50: 103.3 μM). PMID:26592542

  12. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-10-28

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.

  13. Identification of Selective ERRγ Inverse Agonists.

    PubMed

    Kim, Jina; Im, Chun Young; Yoo, Eun Kyung; Ma, Min Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sungwoo; Kim, Nam Doo; Jeon, Jae-Han; Lee, In-Kyu; Jeon, Yong Hyun; Choi, Hueng-Sik; Kim, Seong Heon; Cho, Sung Jin

    2016-01-12

    GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  14. FXR agonist activity of conformationally constrained analogs of GW 4064

    SciTech Connect

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  15. FXR agonist activity of conformationally constrained analogs of GW 4064.

    PubMed

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Bruce Wisely, G

    2009-08-15

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  16. Inhibition of Tpl2 kinase and TNFalpha production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis.

    PubMed

    Hu, Yonghan; Green, Neal; Gavrin, Lori K; Janz, Kristin; Kaila, Neelu; Li, Huan-Qiu; Thomason, Jennifer R; Cuozzo, John W; Hall, J Perry; Hsu, Sang; Nickerson-Nutter, Cheryl; Telliez, Jean-Baptiste; Lin, Lih-Ling; Tam, Steve

    2006-12-01

    The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice. PMID:16973359

  17. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease

    PubMed Central

    Lee, Hyun Jung; Yeon, Jong Eun; Ko, Eun Jung; Yoon, Eileen L; Suh, Sang Jun; Kang, Keunhee; Kim, Hae Rim; Kang, Seoung Hee; Yoo, Yang Jae; Je, Jihye; Lee, Beom Jae; Kim, Ji Hoon; Seo, Yeon Seok; Yim, Hyung Joon; Byun, Kwan Soo

    2015-01-01

    AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models. METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW. RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α. CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD. PMID:26668503

  18. Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-selective agonist with a RXR-selective agonist.

    PubMed

    Elmazar, M M; Rühl, R; Nau, H

    2001-01-01

    To study the interaction of retinoid-induced limb defects and cleft palate on day 11 of gestation, a RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative, 20 mg/kg orally) was coadministered with a RARalpha-agonist (Am580, an arylcarboxamidobenzoic acid derivative, 5 mg/kg orally) to NMRI mice. AGN191701 was neither fetotoxic nor teratogenic at the dose used but potentiated Am580-induced limb defects and cleft palate and prevented Am580-induced fetal weight retardation. These results suggest that Am580-induced limb defects and probably cleft palate on day 11 of gestation may be mediated via RARalpha-RXR heterodimerization, particularly in the absence of toxicokinetic interactions. AGN191701 was also coadministered with a RARgamma-agonist (CD437, an adamantyl-hydroxyphenyl naphthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RARgamma-RXR heterodimerization. On day 8 of gestation, AGN191701 potentiated CD437-induced embryolethality, exencephaly, spina bifida aperta, cleft palate, and tail defects, as well as visceral and skeletal defects, but not micrognathia. On day 11 of gestation, the incidence of CD437-induced cleft palate and limb defects was also potentiated when coadministered with the RXR agonist. These results suggest that synergistic teratogenic effects can be induced by coadministration of two receptor-selective retinoids, indicating the importance of RARalpha-RXR and RARgamma-RXR heterodimers in producing structural defects during organogenesis.

  19. Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110α that reactivates latent HIV-1.

    PubMed

    Doyon, Geneviève; Sobolewski, Michele D; Huber, Kelly; McMahon, Deborah; Mellors, John W; Sluis-Cremer, Nicolas

    2014-01-01

    Combination antiretroviral therapy (cART) can effectively suppress HIV-1 replication, but the latent viral reservoir in resting memory CD4(+) T cells is impervious to cART and represents a major barrier to curing HIV-1 infection. Reactivation of latent HIV-1 represents a possible strategy for elimination of this reservoir. In this study we describe the discovery of 1,2,9,10-tetramethoxy-7H-dibenzo[de,g]quinolin-7-one (57704) which reactivates latent HIV-1 in several cell-line models of latency (J89GFP, U1 and ACH-2). 57704 also increased HIV-1 expression in 3 of 4 CD8(+)-depleted blood mononuclear cell preparations isolated from HIV-1-infected individuals on suppressive cART. In contrast, vorinostat increased HIV-1 expression in only 1 of the 4 donors tested. Importantly, 57704 does not induce global T cell activation. Mechanistic studies revealed that 57704 reactivates latent HIV-1 via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. 57704 was found to be an agonist of PI3K with specificity to the p110α isoform, but not the p110β, δ or γ isoforms. Taken together, our work suggests that 57704 could serve as a scaffold for the development of more potent activators of latent HIV-1. Furthermore, it highlights the involvement of the PI3K/Akt pathway in the maintenance of HIV-1 latency.

  20. PPARγ Agonists Promote Oligodendrocyte Differentiation of Neural Stem Cells by Modulating Stemness and Differentiation Genes

    PubMed Central

    Kanakasabai, Saravanan; Pestereva, Ecaterina; Chearwae, Wanida; Gupta, Sushil K.; Ansari, Saif; Bright, John J.

    2012-01-01

    Neural stem cells (NSCs) are a small population of resident cells that can grow, migrate and differentiate into neuro-glial cells in the central nervous system (CNS). Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor that regulates cell growth and differentiation. In this study we analyzed the influence of PPARγ agonists on neural stem cell growth and differentiation in culture. We found that in vitro culture of mouse NSCs in neurobasal medium with B27 in the presence of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) induced their growth and expansion as neurospheres. Addition of all-trans retinoic acid (ATRA) and PPARγ agonist ciglitazone or 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) resulted in a dose-dependent inhibition of cell viability and proliferation of NSCs in culture. Interestingly, NSCs cultured with PPARγ agonists, but not ATRA, showed significant increase in oligodendrocyte precursor-specific O4 and NG2 reactivity with a reduction in NSC marker nestin, in 3–7 days. In vitro treatment with PPARγ agonists and ATRA also induced modest increase in the expression of neuronal β-III tubulin and astrocyte-specific GFAP in NSCs in 3–7 days. Further analyses showed that PPARγ agonists and ATRA induced significant alterations in the expression of many stemness and differentiation genes associated with neuro-glial differentiation in NSCs. These findings highlight the influence of PPARγ agonists in promoting neuro-glial differentiation of NSCs and its significance in the treatment of neurodegenerative diseases. PMID:23185633

  1. Recent advances in the discovery of alpha1-adrenoceptor agonists.

    PubMed

    Bishop, Michael J

    2007-01-01

    The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

  2. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure

    PubMed Central

    Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.

    2013-01-01

    Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

  3. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  4. Activation of tongue-expressed GPR40 and GPR120 by non caloric agonists is not sufficient to drive preference in mice.

    PubMed

    Godinot, N; Yasumatsu, K; Barcos, M E; Pineau, N; Ledda, M; Viton, F; Ninomiya, Y; le Coutre, J; Damak, S

    2013-10-10

    There is mounting evidence that, in addition to texture and olfaction, taste plays a role in the detection of long chain fatty acids. Triglycerides, the main components of oils and dietary fat, are hydrolyzed in the mouth by a lingual lipase secreted from the von Ebner gland and the released free fatty acids are detected by the taste system. GPR40 and GPR120, two fatty acid responsive G-protein-coupled receptors (GPCRs), are expressed in taste bud cells, and knockout mice lacking either of those receptors have blunted taste nerve responses to and reduced preference for fatty acids. Here we investigated whether activation of those GPCRs is sufficient to elicit fat taste and preference. Five non-fatty acid agonists of GPR40 and two non-fatty acid agonists of GPR120 activated the glossopharyngeal nerve of wild-type mice but not of knockout mice lacking the cognate receptor. In human subjects, two-alternative forced choice (2-AFC) tests, triangle tests and sensory profiling showed that non fatty acid agonists of GPR40 dissolved in water are detected in sip and spit tests and elicit a taste similar to that of linoleic acid, whereas 2-AFC tests showed that two agonists of GPR120 in water are not perceived fattier than water alone. Wild-type mice did not show any preference for five agonists of GPR40, two agonists of GPR120 and mixtures of both agonists over water in two-bottle preference tests. Together these data indicate that GPR40 mediated taste perception is not sufficient to generate preference. PMID:23831422

  5. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  6. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits.

  7. In vitro antifungal and antibiofilm activities of halogenated quinoline analogues against Candida albicans and Cryptococcus neoformans.

    PubMed

    Zuo, Ran; Garrison, Aaron T; Basak, Akash; Zhang, Peilan; Huigens, Robert W; Ding, Yousong

    2016-08-01

    With the increasing prevalence of fungal infections coupled with emerging drug resistance, there is an urgent need for new and effective antifungal agents. Here we report the antifungal activities of 19 diverse halogenated quinoline (HQ) small molecules against Candida albicans and Cryptococcus neoformans. Four HQ analogues inhibited C. albicans growth with a minimum inhibitory concentration (MIC) of 100 nM, whilst 16 analogues effectively inhibited C. neoformans at MICs of 50-780 nM. Remarkably, two HQ analogues eradicated mature C. albicans and C. neoformans biofilms [minimum biofilm eradication concentration (MBEC) = 6.25-62.5 µM]. Several active HQs were found to penetrate into fungal cells, whilst one inactive analogue was unable to, suggesting that HQs elicit their antifungal activities through an intracellular mode of action. HQs are a promising class of small molecules that may be useful in future antifungal treatments. PMID:27256584

  8. Structural polymorphism in the promoter of pfmrp2 confers Plasmodium falciparum tolerance to quinoline drugs

    PubMed Central

    Mok, Sachel; Liong, Kek-Yee; Lim, Eng-How; Huang, Ximei; Zhu, Lei; Preiser, Peter Rainer; Bozdech, Zbynek

    2014-01-01

    Drug resistance in Plasmodium falciparum remains a challenge for the malaria eradication programmes around the world. With the emergence of artemisinin resistance, the efficacy of the partner drugs in the artemisinin combination therapies (ACT) that include quinoline-based drugs is becoming critical. So far only few resistance markers have been identified from which only two transmembrane transporters namely PfMDR1 (an ATP-binding cassette transporter) and PfCRT (a drug-metabolite transporter) have been experimentally verified. Another P. falciparum transporter, the ATP-binding cassette containing multidrug resistance-associated protein (PfMRP2) represents an additional possible factor of drug resistance in P. falciparum. In this study, we identified a parasite clone that is derived from the 3D7 P. falciparum strain and shows increased resistance to chloroquine, mefloquine and quinine through the trophozoite and schizont stages. We demonstrate that the resistance phenotype is caused by a 4.1 kb deletion in the 5′ upstream region of the pfmrp2 gene that leads to an alteration in the pfmrp2 transcription and thus increased level of PfMRP2 protein. These results also suggest the importance of putative promoter elements in regulation of gene expression during the P. falciparum intra-erythrocytic developmental cycle and the potential of genetic polymorphisms within these regions to underlie drug resistance. PMID:24372851

  9. A peroxisome proliferator-activated receptor-gamma agonist and other constituents from Chromolaena odorata.

    PubMed

    Dat, Nguyen Tien; Lee, Kyeong; Hong, Young-Soo; Kim, Young Ho; Minh, Chau Van; Lee, Jung Joon

    2009-06-01

    Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid and glucose metabolism and have become important therapeutic targets for various diseases. The phytochemical investigation of the chloroform-soluble extract of Chromolaena odorata led to the isolation of a PPAR-gamma agonist, (9 S,13 R)-12-oxo-phytodienoic acid (1), together with 12 other compounds. The structures of chromomoric acid G (2), a new dehydrogenated derivative of 1, and chromolanone (3) were elucidated based on spectroscopic methods. Compound 1 showed a significant effect on PPAR-gamma activation in comparison with rosiglitazone. However, compound 2 was inactive, suggesting that the dehydrogenation of the prostaglandin-like structure in 1 abrogates its PPAR-gamma agonistic activity.

  10. The Effect of Glutamate Receptor Agonists on Mouse Retinal Astrocyte [Ca2+]i

    PubMed Central

    Blandford, Stephanie N.

    2016-01-01

    Calcium-imaging techniques were used to determine if mouse retinal astrocytes in situ respond to agonists of ionotropic (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA; N-methyl-D-aspartate, NMDA) and metabotropic (S-3,5-dihydroxyphenylglycine, DHPG; trans-1-amino-1,3-cyclopentanedicarboxylic acid, ACPD) glutamate receptors. In most cases we found no evidence that retinal astrocyte intracellular calcium ion concentration ([Ca2+]i) increased in response to these glutamate agonists. The one exception was AMPA that increased [Ca2+]i in some, but not all, mouse retinal astrocytes in situ. However, AMPA did not increase [Ca2+]i in mouse retinal astrocytes in vitro, suggesting that the effect of AMPA in situ may be indirect. PMID:27413752

  11. Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.

    PubMed

    Watkins, Steven M; Reifsnyder, Peter R; Pan, Huei-ju; German, J Bruce; Leiter, Edward H

    2002-11-01

    Successful therapy for chronic diseases must normalize a targeted aspect of metabolism without disrupting the regulation of other metabolic pathways essential for maintaining health. Use of a limited number of single molecule surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may fail to predict undesirable side effects. In this study, a comprehensive metabolomic assessment of lipid metabolites was employed to determine the specific effects of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone on structural lipid metabolism in a new mouse model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg diet) suppressed Type 2 diabetes in obese (NZO x NON)F1 male mice, but chronic treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid exchange), ii) induced de novo fatty acid synthesis, iii) decreased the biosynthesis of lipids within the peroxisome, iv) substantially altered free fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual accumulation of polyunsaturated fatty acids within adipose tissue. These observations suggest that the phenotypes induced by rosiglitazone are mediated by multiple tissue-specific metabolic variables. Because many of the effects of rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome, metabolomics has excellent potential for developing clinical assessments of metabolic response to drug therapy. PMID:12401879

  12. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.

    PubMed

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M; Heiss, Elke H; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M; Atanasov, Atanas G

    2014-11-01

    Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.

  13. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review

    PubMed Central

    Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M.; Heiss, Elke H.; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M.; Atanasov, Atanas G.

    2014-01-01

    Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements. PMID:25083916

  14. Evaluation and synthesis of polar aryl- and heteroaryl spiroazetidine-piperidine acetamides as ghrelin inverse agonists.

    PubMed

    Orr, Suvi T M; Beveridge, Ramsay; Bhattacharya, Samit K; Cameron, Kimberly O; Coffey, Steven; Fernando, Dilinie; Hepworth, David; Jackson, Margaret V; Khot, Vishal; Kosa, Rachel; Lapham, Kimberly; Loria, Paula M; McClure, Kim F; Patel, Jigna; Rose, Colin; Saenz, James; Stock, Ingrid A; Storer, Gregory; von Volkenburg, Maria; Vrieze, Derek; Wang, Guoqiang; Xiao, Jun; Zhang, Yingxin

    2015-02-12

    Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series.

  15. Potential retinoid x receptor agonists for treating Alzheimer's disease from traditional chinese medicine.

    PubMed

    Chen, Kuan-Chung; Liu, Yu-Cheng; Lee, Cheng-Chun; Chen, Calvin Yu-Chian

    2014-01-01

    Alzheimer's disease is neurodegenerative disorder due to the accumulation of amyloid- β in the brain and causes dementia with ageing. Some researches indicate that the RXR agonist, Targretin, has also been used for treatment of Alzheimer's disease in mouse models. We investigate the potent candidates as RXR agonists from the vast repertoire of TCM compounds in TCM Database@Taiwan. The potential TCM compounds, β -lipoic acid and sulfanilic acid, had higher potent binding affinities than both 9-cis-retinoic acid and Targretin in docking simulation and have stable H-bonds with residues Arg316 and some equivalent hydrophobic contacts with residues Ala272, Gln275, Leu309, Phe313, Val342, Ile345, and Cys432 as Targretin. The carboxyl or sulfonyl hydroxide group can form a H-bond with key residue Arg316 in the docking pose, and the phenyl group next to the carboxyl or sulfonyl hydroxide group can form a π interaction with residue Phe313. Moreover, β -lipoic acid and sulfanilic acid have stable H-bonds with residue Gln275, Ser313, and residue Ala327, respectively, which may strengthen and stabilize TCM candidates inside the binding domain of RXR protein. Hence, we propose β -lipoic acid and sulfanilic acid as potential lead compounds for further study in drug development process with the RXR protein against Alzheimer's disease.

  16. A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists.

    PubMed

    Hale, Jeffrey J; Lynch, Christopher L; Neway, William; Mills, Sander G; Hajdu, Richard; Keohane, Carol Ann; Rosenbach, Mark J; Milligan, James A; Shei, Gan-Ju; Parent, Stephen A; Chrebet, Gary; Bergstrom, James; Card, Deborah; Ferrer, Marc; Hodder, Peter; Strulovici, Berta; Rosen, Hugh; Mandala, Suzanne

    2004-12-30

    Moderately potent, selective S1P(1) receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P(1) agonists represented by 7. Many of the new compounds are potent S1P(1) agonists that select against the S1P(2), S1P(3), and S1P(4) (although not S1P(5)) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.

  17. Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis.

    PubMed Central

    Ju, G; Labriola-Tompkins, E; Campen, C A; Benjamin, W R; Karas, J; Plocinski, J; Biondi, D; Kaffka, K L; Kilian, P L; Eisenberg, S P

    1991-01-01

    Interleukin 1 (IL-1) receptor antagonist (IL-1ra) is a naturally occurring protein that binds to the IL-1 receptor present on T cells, fibroblasts, and other cell types and acts to block IL-1-induced responses. IL-1ra is a pure antagonist and has no agonist activity in in vitro or in vivo systems. By site-specific mutagenesis, an analog of IL-1ra was created that contained a substitution of a single amino acid, Lys-145----Asp. This analog, IL-1ra K145D, exhibited partial agonist activity in the D10.G4.1 cell proliferation assay. The newly acquired agonist activity could not be neutralized by antisera to IL-1 alpha or IL-1 beta, but it could be blocked by a monoclonal antibody to the T-cell IL-1 receptor. The analog also showed agonist activity as assayed by increased prostaglandin E2 synthesis from CHO cells expressing recombinant mouse IL-1 receptor. These results with IL-1ra K145D demonstrate the importance of the region surrounding the corresponding Asp-145 residue in IL-1 beta for triggering the biological response to IL-1. Images PMID:1826365

  18. Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice

    PubMed Central

    Amos, Sally M.; Pegram, Hollie J.; Westwood, Jennifer A.; John, Liza B.; Devaud, Christel; Clarke, Chris J.; Restifo, Nicholas P.; Smyth, Mark J.; Darcy, Phillip K.; Kershaw, Michael H.

    2012-01-01

    Toll-like receptor (TLR) agonists can trigger broad inflammatory responses that elicit rapid innate immunity and promote the activities of lymphocytes, which can potentially enhance adoptive immunotherapy in the tumor-bearing setting. In the present study, we found that Polyinosinic:Polycytidylic Acid [Poly(I:C)] and CpG oligodeoxynucleotide 1826 [CpG], agonists for TLR 3 and 9, respectively, potently activated adoptively transferred T cells against a murine model of established melanoma. Intratumoral injection of Poly(I:C) and CpG, combined with systemic transfer of activated pmel-1 T cells, specific for gp10025–33, led to enhanced survival and eradication of 9-day established subcutaneous B16F10 melanomas in a proportion of mice. A series of survival studies in knockout mice supported a key mechanistic pathway, whereby TLR agonists acted via host cells to enhance IFN-γ production by adoptively transferred T cells. IFN-γ, in turn, enhanced the immunogenicity of the B16F10 melanoma line, leading to increased killing by adoptively transferred T cells. Thus, this combination approach counteracted tumor escape from immunotherapy via downregulation of immunogenicity. In conclusion, TLR agonists may represent advanced adjuvants within the setting of adoptive T-cell immunotherapy of cancer and hold promise as a safe means of enhancing this approach within the clinic. PMID:21327636

  19. Crystal structure of bis­(azido-κN)bis­(quinolin-8-amine-κ2 N,N′)iron(II)

    PubMed Central

    Setifi, Fatima; Moon, Dohyun; Koen, Robeyns; Setifi, Zouaoui; Lamsayah, Morad; Touzani, Rachid

    2016-01-01

    The search for new mol­ecular materials with inter­esting magnetic properties using the pseudohalide azide ion and quinolin-8-amine (aqin, C9H8N2) as a chelating ligand, led to the synthesis and structure determination of the title complex, [Fe(N3)2(C9H8N2)2]. The complex shows an octa­hedral geometry, with the FeII atom surrounded by six N atoms; the two N3 − anions coordinate in a cis configuration, while the remaining N atoms originate from the two quinolin-8-amine ligands with the quinoline N atoms lying on opposite sides of the Fe atom. The crystal packing is dominated by layers of hydro­philic and aromatic regions parallel to the ac plane, stabilized by a two-dimensional hydrogen-bonded network and π–π stacking. PMID:27746947

  20. Benzodiazepine Site Agonists Differentially Alter Acetylcholine Release in Rat Amygdala

    PubMed Central

    Hambrecht-Wiedbusch, Viviane S.; Mitchell, Melinda F.; Firn, Kelsie A.; Baghdoyan, Helen A.; Lydic, Ralph

    2014-01-01

    Background Agonist binding at the benzodiazepine site of γ-aminobutric acid type A receptors diminishes anxiety and insomnia by actions in the amygdala. The neurochemical effects of benzodiazepine-site agonists remain incompletely understood. Cholinergic neurotransmission modulates amygdala function, and in this study we tested the hypothesis that benzodiazepine-site agonists alter acetylcholine (ACh) release in the amygdala. Methods Microdialysis and high performance liquid chromatography quantified ACh release in the amygdala of Sprague-Dawley rats (n=33). ACh was measured before and after IV administration (3 mg/kg) of midazolam or eszopiclone, with and without anesthesia. ACh in isoflurane-anesthetized rats during dialysis with Ringer’s solution(control) was compared to ACh release during dialysis with Ringer’s solution containing (100 μM) midazolam, diazepam, eszopiclone, or zolpidem. Results In unanesthetized rats, ACh in the amygdala was decreased by IV midazolam (−51.1%; P=0.0029; 95% CI= −73.0% to −29.2%) and eszopiclone (−39.6%; P=0.0222; 95% CI= −69.8% to −9.3%). In anesthetized rats, ACh in the amygdala was decreased by IV administration of midazolam (−46.2%; P=0.0041; 95% CI= −67.9% to −24.5%) and eszopiclone (−34.0%; P=0.0009; 95% CI= −44.7% to −23.3%), and increased by amygdala delivery of diazepam (43.2%; P=0.0434; 95% CI= 2.1% to 84.3%), and eszopiclone (222.2%; P=0.0159; 95% CI= 68.5% to 375.8%). Conclusions ACh release in the amygdala was decreased by IV delivery of midazolam and eszopiclone. Dialysis delivery directly into the amygdala caused either increased (eszopiclone and diazepam) or likely no significant change (midazolam and zolpidem) in ACh release. These contrasting effects of delivery route on ACh release support the interpretation that systemically administered midazolam and eszopiclone decrease ACh release in the amygdala by acting on neuronal systems outside of the amygdala. PMID:24842176

  1. Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice

    PubMed Central

    2011-01-01

    Background The clinical use of mefloquine (MQ) has declined due to dose-related neurological events. Next generation quinoline methanols (NGQMs) that do not accumulate in the central nervous system (CNS) to the same extent may have utility. In this study, CNS levels of NGQMs relative to MQ were measured and an early lead chemotype was identified for further optimization. Experimental design The plasma and brain levels of MQ and twenty five, 4-position modified NGQMs were determined using LCMS/MS at 5 min, 1, 6 and 24 h after IV administration (5 mg/kg) to male FVB mice. Fraction unbound in brain tissue homogenate was assessed in vitro using equilibrium dialysis and this was then used to calculate brain-unbound concentration from the measured brain total concentration. A five-fold reduction CNS levels relative to mefloquine was considered acceptable. Additional pharmacological properties such as permeability and potency were determined. Results The maximum brain (whole/free) concentrations of MQ were 1807/4.9 ng/g. Maximum whole brain concentrations of NGQMs were 23 - 21546 ng/g. Maximum free brain concentrations were 0.5 to 267 ng/g. Seven (28%) and two (8%) compounds exhibited acceptable whole and free brain concentrations, respectively. Optimization of maximum free brain levels, IC90s (as a measure or potency) and residual plasma concentrations at 24 h (as a surrogate for half-life) in the same molecule may be feasible since they were not correlated. Diamine quinoline methanols were the most promising lead compounds. Conclusion Reduction of CNS levels of NGQMs relative to mefloquine may be feasible. Optimization of this property together with potency and long half-life may be feasible amongst diamine quinoline methanols. PMID:21645370

  2. SYNTHESIS AND CYTOTOXIC ACTIVITY OF NEW 5H-INDOLO[2,3-B]QUINOLINE O-AMINOGLYCOSIDES.

    PubMed

    Badowska-Rosłonek, Katarzyna; Ciesielska, Agnieszka; Switalska, Marta; Piskozub, Małgorzata; Peczyńska-Czoch, Wanda; Wietrzyk, Joanna; Kaczmarek, Łukasz

    2016-01-01

    Novel 5H-indolo[2,3-b]quinoline O-aminoglycosides were synthesized in order to check the hypothesis that the construction of hybrids composed of the active 5H-indolo[2,3-b]quinoline chromophore and daunosaminyl or acosaminyl moiety may result in the cytotoxic activity of the obtained derivatives that is much higher than the one of the parent DIMIQ (5,11-dimethyl-5H-indolo[2,3-b]quinoline) and 6H-indoloquinoline analogs. Actually, 5H-indolo[2,3-b]indoloquinoline O-aminoglycosides showed the anti-proliferative activity in vitro against human lung adenocarcinoma A549, breast cancer MCF-7, melanoma Hs294T, promyelocytic leukemia HL-60, uterine sarcoma MES-SA and colon cancer LoVo cell lines, which was 10 times higher than that of the 6H-analogs and comparable to the one of the referential DIMIQ. Unexpectedly, it appeared that except for HL-60/MX2 (P-gp-independent and topoisomerase II-dependent resistance), other MDR tumor cell lines (LoVo/DX. P-gp-dependent, MRP-, LRP-dependent multidrug resistance) and MES-SA/DX5 (P-gp-dependent resistance to doxorubicin) are also resistant to the 5H-indolo[2,3-b]indoloquinoline O-aminoglycosides tested. This is surprising because 6H-analogs, in general, 10 times less active against non-MDR tumor cell lines, as well as the DIMIQ itself, are able to overcome drug resistance in all MDR cell lines examined. The cytotoxicity of the tested compounds against tumor cell lines and against normal cells (mice fibroblasts BALB/3T3) was comparable. PMID:27476287

  3. Differences in anti-malarial activity of 4-aminoalcohol quinoline enantiomers and investigation of the presumed underlying mechanism of action

    PubMed Central

    2012-01-01

    Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The (S)-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. (R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their (S) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both (S) and (R)-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro. PMID:22401346

  4. Agonist-Directed Desensitization of the β2-Adrenergic Receptor

    PubMed Central

    Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye

    2011-01-01

    The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level. PMID:21541288

  5. Sports doping: emerging designer and therapeutic β2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  6. A Chironomus tentans bioassay for testing synthetic fuel products and effluents, with data on acridine and quinoline

    SciTech Connect

    Cushman, R.M.; McKamey, M.I.

    1981-05-01

    As part of a programme to evaluate the environmental effects of synthetic fuel products and effluents, a series of tests is being used to measure the toxicity of these products and of representative pure compounds to aquatic organisms. A method was developed using the midge, Chironomus tentans. Unlike previous C. tentans bioassays the procedure excludes effects of organic substrates, feeding, aeration and light. The midges were treated in glass beakers of filtered well water on a glass wool substrate. Calculated 48-hour LC/sub 50/ values for typical synthetic fuel products were acridine, 1.96 mg/l and quinoline, 57.2 mg/l.

  7. 3-Ethyl-4-hy-droxy-8-meth-oxy-quinolin-2(1H)-one.

    PubMed

    Kafka, Stanislav; Pevec, Andrej; Proisl, Karel; Kimmel, Roman; Košmrlj, Janez

    2012-11-01

    In the title compound, C(12)H(13)NO(3), the quinoline ring system is approximately planar with a maximum deviation from the least-squares plane of 0.058 (2) Å. In the crystal, N-H⋯O and O-H⋯O hydrogen bonds link the mol-ecules into chains running along the b-axis direction. The chains also feature π-π inter-actions between pyridine and benzene rings of inversion-related mol-ecules [centroid-centroid distance = 3.609 (2) Å].

  8. Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity.

    PubMed

    Di Pietro, Ornella; Vicente-García, Esther; Taylor, Martin C; Berenguer, Diana; Viayna, Elisabet; Lanzoni, Anna; Sola, Irene; Sayago, Helena; Riera, Cristina; Fisa, Roser; Clos, M Victòria; Pérez, Belén; Kelly, John M; Lavilla, Rodolfo; Muñoz-Torrero, Diego

    2015-11-13

    Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 μM, 6.1 μM and 29.2 μM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 μM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells. PMID

  9. Mono- and dinuclear nickel(II) complexes of resolved Schiff-base ligands with extended quinoline substituents.

    PubMed

    Prema, Dipesh; Oshin, Kayode; Desper, John; Levy, Christopher J

    2012-04-28

    The coordination chemistry of four enantiopure tetradentate bis(iminoquinoline) ligands with nickel(II) salts is reported. The previously reported ligands CBQ, CPQ, BBQ, and BPQ result from the condensation of (1R,2R)-cyclohexyldiamine or (R)-BINAM with two equivalents of 2-formylbenzo[h]quinoline or 8-isopropyl-2-quinolinecarboxaldehyde {CBQ = (1R,2R)-cyclohexanediamine-N,N'-bis(benzo[h]quinoline-2-ylmethylene), CPQ = (1R,2R)-cyclohexanediamine-N,N'-bis[[(8-isopropyl)-2-quinolinyl]methylene], BBQ = [(R)-1,1'-binaphthalene]-2,2'-diamine-N,N'-bis(benzo[h]quinoline-2-ylmethylene), BPQ = [(R)-1,1'-binaphthalene]-2,2'-diamine-N,N'-bis[[(8-isopropyl)-2-quinolinyl]methylene]}. Reaction of NiI(2) with the (1R,2R)-cyclohexyl ligands gives the mononuclear distorted trigonal-bipyramidal (TBP) complexes [Ni(N(3)-CBQ)I(2)] and [Ni(N(3)-CPQ)I(2)]. Incomplete iodide abstraction from [Ni(N(3)-CPQ)I(2)] with AgOTf leads to partial replacement of the iodide with hydroxide from adventitious water to give [Ni(N(3)-CPQ)I(1.6)(OH)(0.4)] (distorted TBP). The corresponding reaction with [Ni(N(3)-CBQ)I(2)] again fails to remove all of the iodide, resulting instead in conversion to the syn dinuclear [Ni(2)(CBQ)(μ-X)(2)I(2)] (X = Cl(0.925)I(0.075)) complex, where chloride abstraction from the solvent (CH(2)Cl(2)) has resulted in a mixed halide system and the metal centers are square-pyramidal. Reaction of Ni(OTf)(2) with CBQ leads to the isolation of the octahedral cation [Ni(CMBQ)(2)](2+), with CMBQ [(1R,2R)-cyclohexanediamine-mono-N-(benzo[h]quinoline-2-ylmethylene)] being the partial hydrolysis product of CBQ. [Ni(CMBQ)(2)][OTf](2) crystallizes as a 1:1 mixture of P and M helical diastereomers. The coordination of NiI(2) with the (R)-BINAM derived ligands yields the anti dinuclear P-helical complexes [Ni(2)(BBQ)(μ-I)(2)I(2)] and [Ni(2)(BPQ)(μ-I)(2)I(2)]: one nickel ion is coordinated in each bidentate iminoquinoline pocket and the geometry at the metal centers is distorted square

  10. 2-Oxo-4-phenyl-1,2,5,6-tetra-hydro-benzo[h]quinoline-3-carbonitrile.

    PubMed

    Asiri, Abdullah M; Faidallah, Hassan M; Al-Youbi, Abdulrahman O; Alamry, Khalid A; Ng, Seik Weng

    2011-09-01

    In the mol-ecule of the title compound, C(20)H(14)N(2)O, the tetra-hydro-benzo[h]quinoline fused-ring system is buckled owing to the ethyl-ene -CH(2)CH(2)- fragment, the benzene ring and the pyridine ring being twisted by 19.7 (1)°. The 4-substituted aromatic ring is bent away from the pyridine ring by 62.9 (1)° in order to avoid crowding the cyanide substituent. In the crystal, two mol-ecules are linked by a pair of N-H⋯O hydrogen bonds to form a centrosymmetric dimer. PMID:22065624

  11. Visible-light-promoted iminyl-radical formation from acyl oximes: a unified approach to pyridines, quinolines, and phenanthridines.

    PubMed

    Jiang, Heng; An, Xiaode; Tong, Kun; Zheng, Tianyi; Zhang, Yan; Yu, Shouyun

    2015-03-23

    A unified strategy involving visible-light-induced iminyl-radical formation has been established for the construction of pyridines, quinolines, and phenanthridines from acyl oximes. With fac-[Ir(ppy)3 ] as a photoredox catalyst, the acyl oximes were converted by 1 e(-) reduction into iminyl radical intermediates, which then underwent intramolecular homolytic aromatic substitution (HAS) to give the N-containing arenes. These reactions proceeded with a broad range of substrates at room temperature in high yield. This strategy of visible-light-induced iminyl-radical formation was successfully applied to a five-step concise synthesis of benzo[c]phenanthridine alkaloids.

  12. Crystal structure of ethyl 2,4-di­chloro­quinoline-3-carboxyl­ate

    PubMed Central

    Cabrera, Alberto; Miranda, Luis D.; Reyes, Héctor; Aguirre, Gerardo; Chávez, Daniel

    2015-01-01

    In the crystal structure of the title compound, C12H9Cl2NO2, the mean planes through the quinoline and carboxyl­ate groups have r.m.s. deviations of 0.006 and 0.021 Å, respectively, and form a dihedral angle of 87.06 (19)°. In the crystal, mol­ecules are linked via very weak C—H⋯O hydrogen bonds, forming chains, which propagate along the c-axis direction. PMID:26870538

  13. Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity

    PubMed Central

    Di Pietro, Ornella; Vicente-García, Esther; Taylor, Martin C.; Berenguer, Diana; Viayna, Elisabet; Lanzoni, Anna; Sola, Irene; Sayago, Helena; Riera, Cristina; Fisa, Roser; Clos, M. Victòria; Pérez, Belén; Kelly, John M.; Lavilla, Rodolfo; Muñoz-Torrero, Diego

    2015-01-01

    Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2–4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 μM, 6.1 μM and 29.2 μM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 μM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells

  14. 4-(2-aminooxyethoxy)-2-(ethylureido)quinoline-oligonucleotide conjugates: synthesis, binding interactions, and derivatization with peptides.

    PubMed

    Hamma, Tomoko; Miller, Paul S

    2003-01-01

    Oligo-2'-O-methylribonucleotides conjugated with 4-(2-aminooxyethoxy)-2-(ethylureido)quinoline (AOQ) and 4-ethoxy-2-(ethylureido)quinoline (EOQ) were prepared by reaction of the AOQ or EOQ phosphoramidite with the protected oligonucleotide on a controlled pore glass support. Deprotection with ethylenediamine enabled successful isolation and purification of the highly reactive AOQ-conjugated oligomer. Polyacrylamide gel electrophoresis mobility shift experiments showed that the dissociation constants of complexes formed between an AOQ- or EOQ-conjugated 8-mer and complementary RNA or 2'-O-methyl-RNA targets (9- and 10-mers) were in the low nM concentration range at 37 degrees C, whereas no binding was observed for the corresponding nonconjugated oligomer, even at a concentration of 500 nM. Fluorescence studies suggested that this enhanced affinity is most likely due to the ability of the quinoline ring of the AOQ or EOQ group to stack on the last base pair formed between the oligomer and target, thus stabilizing the duplex. The binding affinity of a 2'-O-methyl RNA 15-mer, which contained an alternating methylphosphonate/phosphodiester backbone, for a 59-nucleotide stem-loop HIV TAR RNA target, increased 2.3 times as a consequence of conjugation with EOQ. The aminooxy group of AOQ-conjugated oligomers is a highly reactive nucleophile, which reacts readily with aldehydes and ketones to form stable oxime derivatives. This feature was used to couple an AOQ-oligomer with leupeptin, a tripeptide that contains a C-terminus aldehyde group. A simple method was developed to introduce a ketone functionality into peptides that contain a cysteine residue by reacting the peptide with bromoacetone. The resulting keto-peptide was then coupled to the AOQ-oligomer. This procedure was used to prepare oligonucleotide conjugates of a tetrapeptide, RGDC, and a derivative of HIV tat peptide having a C-terminus cysteine. The combination of the unique reactivity of the aminooxy group and

  15. Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists.

    PubMed

    Karaki, Samah; Becamel, Carine; Murat, Samy; Mannoury la Cour, Clotilde; Millan, Mark J; Prézeau, Laurent; Bockaert, Joël; Marin, Philippe; Vandermoere, Franck

    2014-05-01

    The serotonin 5-HT(2A) receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline, and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT(2A) receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture with enrichment in phosphorylated peptides by means of hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT(2A) receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the nonhallucinogenic 5-HT(2A) agonist lisuride. Among the 5995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI versus lisuride. These include a serine (Ser(280)) located in the third intracellular loop of the 5-HT(2A) receptor, a region important for its desensitization. The specific phosphorylation of Ser(280) by hallucinogens was further validated by quantitative mass spectrometry analysis of immunopurified receptor digests and by Western blotting using a phosphosite specific antibody. The administration of DOI, but not of lisuride, to mice, enhanced the phosphorylation of 5-HT(2A) receptors at Ser(280) in the prefrontal cortex. Moreover, hallucinogens induced a less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than did nonhallucinogenic agonists. The mutation of Ser(280) to aspartic acid (to mimic phosphorylation) reduced receptor desensitization by nonhallucinogenic agonists, whereas its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals a biased

  16. Quantitative Phosphoproteomics Unravels Biased Phosphorylation of Serotonin 2A Receptor at Ser280 by Hallucinogenic versus Nonhallucinogenic Agonists*

    PubMed Central

    Karaki, Samah; Becamel, Carine; Murat, Samy; Mannoury la Cour, Clotilde; Millan, Mark J.; Prézeau, Laurent; Bockaert, Joël; Marin, Philippe; Vandermoere, Franck

    2014-01-01

    The serotonin 5-HT2A receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline, and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT2A receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture with enrichment in phosphorylated peptides by means of hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT2A receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the nonhallucinogenic 5-HT2A agonist lisuride. Among the 5995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI versus lisuride. These include a serine (Ser280) located in the third intracellular loop of the 5-HT2A receptor, a region important for its desensitization. The specific phosphorylation of Ser280 by hallucinogens was further validated by quantitative mass spectrometry analysis of immunopurified receptor digests and by Western blotting using a phosphosite specific antibody. The administration of DOI, but not of lisuride, to mice, enhanced the phosphorylation of 5-HT2A receptors at Ser280 in the prefrontal cortex. Moreover, hallucinogens induced a less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than did nonhallucinogenic agonists. The mutation of Ser280 to aspartic acid (to mimic phosphorylation) reduced receptor desensitization by nonhallucinogenic agonists, whereas its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals a biased phosphorylation of

  17. Antitussive activity of sigma-1 receptor agonists in the guinea-pig.

    PubMed

    Brown, Claire; Fezoui, Malika; Selig, William M; Schwartz, Carl E; Ellis, James L

    2004-01-01

    1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. 2. Intraperitoneal (i.p.) administration of DEX (30 mg kg(-1)) and the sigma-1 agonists SKF-10,047 (1-5 mg kg(-1)), Pre-084 (5 mg kg(-1)), and carbetapentane (1-5 mg kg(-1)) inhibited citric-acid-induced cough in guinea-pigs. Intraperitoneal administration of a sigma-1 antagonist, BD 1047 (1-5 mg kg(-1)), reversed the inhibition of cough elicited by SKF-10,047. In addition, two structurally dissimilar sigma agonists SKF-10,047 (1 mg ml(-1)) and Pre-084 (1 mg ml(-1)) inhibited cough when administered by aerosol. 3. Aerosolized BD 1047 (1 mg ml(-1), 30 min) prevented the antitussive action of SKF-10,047 (5 mg kg(-1)) or DEX (30 mg kg(-1)) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg(-1)) prevented the antitussive action of SKF-10,047 given by aerosol (1 mg ml(-1)). 4. These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg(-1)) suggest that there may be a peripheral component to the antitussive effect.

  18. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  19. Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.

    PubMed

    Hrycyna, Christine A; Summers, Robert L; Lehane, Adele M; Pires, Marcos M; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P; Fidock, David A; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E

    2014-03-21

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H(+) ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

  20. Sequencing of the rat beta-catenin gene (Ctnnb1) and mutational analysis of liver tumors induced by 2-amino-3-methylimidazo[4,5-f]quinoline.

    PubMed

    Li, Qingjie; Dixon, Brian M; Al-Fageeh, Mohamed; Blum, Carmen A; Dashwood, Roderick H

    2002-01-23

    beta-Catenin, a protein that functions in cadherin-mediated cell-cell adhesion as well as in signal transduction, has received increasing attention in recent years due to its role as an oncogene in various human cancers. The primary sequence of the human beta-catenin gene (CTNNB1) has been known for some time, but that of the rat beta-catenin gene (Ctnnb1) has not heretofore been studied in detail. We report here the primary structure of Ctnnb1 using PCR-based methods and direct sequencing. The size of the complete Ctnnb1 gene was determined to be 9082 bp. We found the rat Ctnnb1 gene to contain 14 exons, ranging in size from 61 to 356 bp, and 13 introns ranging in size from 76 to 2524 bp. The transcription start site appears to be 157 bp upstream of the ATG codon located in exon 1. The resulting transcript is 2650 nucleotides long (encoding a protein of 781 amino acids). We found the 5' UTR to consist of 157 nucleotides and the 3' UTR to be 147 nucleotides long. The region coding for the glycogen synthase kinase-3beta domain of beta-catenin is located in exon 2 of rat Ctnnb1, in contrast to human CTNNB1 in which it is found in exon 3. Based on the newly acquired knowledge of the primary sequence, more than a dozen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced rat liver tumors were screened for the presence or absence of mutations in all 14 exons of rat Ctnnb1. Surprisingly, no mutations were found. The results are discussed in the context of the organ-specificity of IQ-induced mutations in beta-catenin, being highly prevalent in colon tumors, but much less common in liver tumors.

  1. Beta2-adrenergic agonist residues: simultaneous methyl- and butylboronic derivatization for confirmatory analysis by gas chromatography-mass spectrometry.

    PubMed

    Ramos, F; Santos, C; Silva, A; da Silveira, M I

    1998-09-25

    A derivatization procedure for confirmatory residue analysis of beta2-agonists is described. Methyl (MBA) and butyl (BBA) boronic acids are simultaneously used for the derivatization of tulobuterol, mabuterol, mapenterol, salbutamol, clenproperol, clenbuterol, clenpenterol and bromobuterol by GC-MS determination. A temperature of 55 degrees C during 60 min was selected as optimal temperature-time condition for simultaneous MBA and BBA beta2-agonists derivatization. It was also observed that stability of boronic derivatives was maintained at -20 degrees C over a period of four days. The proposed methodology was tested in urine and it could be applied for confirmatory residue analysis of clenbuterol-like compounds.

  2. Small Molecule Bax Agonists for Cancer Therapy

    PubMed Central

    Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K.; Sica, Gabriel L.; Corsino, Patrick E.; Zhou, Jia; Ding, Chunyong; White, Mark A.; Magis, Andrew T.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming

    2014-01-01

    Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here, we employed the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK program suite. Three compounds, small molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumor growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anti-cancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies. PMID:25230299

  3. [Pyridazino(3,4-c)quinolines and pyridazino(4,5-c)quinolines--synthesis and investigation of lipoxygenase inhibition].

    PubMed

    Görlitzer, K; Fabian, J; Jones, P G; Frohberg, P; Drutkowski, G

    2002-06-01

    The cyclic hemiketone acetal 6 reacts with hydrazine in tert-butanol to yield the 1-amino-2,3-dihydro-2-hydroxy-pyrrole 7, while in acetic acid a mixture of the 1-amino-pyrrole 8 and the 1,4-dihydropyridazine 9 is obtained. The X-ray crystal structure of 9 shows a boat conformation flattened about N-1 with respect to nifedipine. Removing the boc-group of 9 gives the tautomeric 2,5-dihydropyridazine 13. The lactams 15 and 17 and the cyclic hydroxamic acids 16 and 18, respectively, are synthesized from 13 or from its oxidation product 14 using reductive conditions. The cyclic hemiacetal 21 reacts with hydrazine in a different manner from 6. In acetic acid the 1-aminopyrrole 22 is formed, while ethanol yields the 1,4-dihydropyridazine 23. The pyridazine 24, obtained by dehydrogenation of 23, gives the lactam 25 and the hydroxamic acid 26, respectively, when the nitro-group is reduced. The dihydropyridazines 9, 11 and 23 are transformed photochemically to give the nitrosophenyl-pyridazines 19, 20 and 27. The chloro-substituted hydroxamic acid 28 is isolated after treatment of 27 with hydrochloric acid. The stability of the partially saturated pyridazine compounds is discussed on the basis of half wave potentials measured by anodic oxidation by means of differential pulse voltammetry. The tricyclic hydroxamic acids 18 and 28 show only a weak inhibition of 5-lipoxygenase (5-LOX). PMID:12116871

  4. Comparison of innate immune agonists for induction of tracheal antimicrobial peptide gene expression in tracheal epithelial cells of cattle.

    PubMed

    Berghuis, Lesley; Abdelaziz, Khaled Taha; Bierworth, Jodi; Wyer, Leanna; Jacob, Gabriella; Karrow, Niel A; Sharif, Shayan; Clark, Mary Ellen; Caswell, Jeff L

    2014-10-12

    Bovine respiratory disease is a complex of bacterial and viral infections of economic and welfare importance to the beef industry. Although tracheal antimicrobial peptide (TAP) has microbicidal activity against bacterial pathogens causing bovine respiratory disease, risk factors for bovine respiratory disease including BVDV and stress (glucocorticoids) have been shown to inhibit the induced expression of this gene. Lipopolysaccharide is known to stimulate TAP gene expression, but the maximum effect is only observed after 16 h of stimulation. The present study investigated other agonists of TAP gene expression in primary cultures of bovine tracheal epithelial cells. PCR analysis of unstimulated tracheal epithelial cells, tracheal tissue and lung tissue each showed mRNA expression for Toll-like receptors (TLRs) 1-10. Quantitative RT-PCR analysis showed that Pam3CSK4 (an agonist of TLR1/2) and interleukin (IL)-17A significantly induced TAP gene expression in tracheal epithelial cells after only 4-8 h of stimulation. Flagellin (a TLR5 agonist), lipopolysaccharide and interferon-α also had stimulatory effects, but little or no response was found with class B CpG ODN 2007 (TLR9 agonist) or lipoteichoic acid (TLR2 agonist). The use of combined agonists had little or no enhancing effect above that of single agonists. Thus, Pam3CSK4, IL-17A and lipopolysaccharide rapidly and significantly induce TAP gene expression, suggesting that these stimulatory pathways may be of value for enhancing innate immunity in feedlot cattle at times of susceptibility to disease.

  5. Molecular reorganization of selected quinoline derivatives in the ground and excited states—Investigations via static DFT

    SciTech Connect

    Błaziak, Kacper; Panek, Jarosław J.; Jezierska, Aneta

    2015-07-21

    Quinoline derivatives are interesting objects to study internal reorganizations due to the observed excited-state-induced intramolecular proton transfer (ESIPT). Here, we report on computations for selected 12 quinoline derivatives possessing three kinds of intramolecular hydrogen bonds. Density functional theory was employed for the current investigations. The metric and electronic structure simulations were performed for the ground state and first excited singlet and triplet states. The computed potential energy profiles do not show a spontaneous proton transfer in the ground state, whereas excited states exhibit this phenomenon. Atoms in Molecules (AIM) theory was applied to study the nature of hydrogen bonding, whereas Harmonic Oscillator Model of aromaticity index (HOMA) provided data of aromaticity evolution as a derivative of the bridge proton position. The AIM-based topological analysis confirmed the presence of the intramolecular hydrogen bonding. In addition, using the theory, we were able to provide a quantitative illustration of bonding transformation: from covalent to the hydrogen. On the basis of HOMA analysis, we showed that the aromaticity of both rings is dependent on the location of the bridge proton. Further, the computed results were compared with experimental data available. Finally, ESIPT occurrence was compared for the three investigated kinds of hydrogen bridges, and competition between two bridges in one molecule was studied.

  6. Effect of substitution group on dielectric properties of 4H-pyrano [3, 2-c] quinoline derivatives thin films

    NASA Astrophysics Data System (ADS)

    H, M. Zeyada; F, M. El-Taweel; M, M. El-Nahass; M, M. El-Shabaan

    2016-07-01

    The AC electrical conductivity and dielectrical properties of 2-amino-6-ethyl-5-oxo-4-(3-phenoxyphenyl)-5,6-dihydro-4H-pyrano[3, 2-c]quinoline-3-carbonitrile (Ph-HPQ) and 2-amino-4-(2-chlorophenyl)-6-ethyl-5-oxo-5,6-dihydro-4H-pyrano [3, 2-c] quinoline-3-carbonitrile (Ch-HPQ) thin films were determined in the frequency range of 0.5 kHz–5 MHz and the temperature range of 290–443 K. The AC electrical conduction of both compounds in thin film form is governed by the correlated barrier hopping (CBH) mechanism. Some parameters such as the barrier height, the maximum barrier height, the density of charges, and the hopping distance were determined as functions of temperature and frequency. The phenoxyphenyl group has a greater influence on those parameters than the chlorophenyl group. The AC activation energies were determined at different frequencies and temperatures. The dielectric behaviors of Ph-HPQ and Ch-HPQ were investigated using the impedance spectroscopy technique. The impedance data are presented in Nyquist diagrams for different temperatures. The Ch-HPQ films have higher impedance than the Ph-HPQ films. The real dielectric constant and dielectric loss show a remarkable dependence on the frequency and temperature. The Ph-HPQ has higher dielectric constants than the Ch-HPQ.

  7. Molecular structure and protonation trends in 6-methoxy- and 8-methoxy-2,4,5-tris(dimethylamino)quinolines

    NASA Astrophysics Data System (ADS)

    Dyablo, O. V.; Pozharskii, A. F.; Shmoilova, E. A.; Ozeryanskii, V. A.; Fedik, N. S.; Suponitsky, K. Yu.

    2016-03-01

    Molecular structure and protonation trends of 6-methoxy- 7 and 8-methoxy- 8 derivatives of 2,4,5-tris(dimethylamino)quinoline were studied using X-ray measurements, NMR spectra and theoretical calculations. It has been found that while 8 in the solid state forms protic salts of a quinolinium type, its isomer 7 behaves as a typical proton sponge giving the anilinium cation with a proton chelated by peri-NMe2 groups. In solution, both compounds are simultaneously monoprotonated at two possible centers but again a tendency of 7 to form anilinium cation is much higher if compared to 8. It has been also shown that basicity of 7 is the largest among all known derivatives of 4,5-bis(dimethylamino)quinoline and even slightly exceeds that of 1,8-bis(dimethylamino)naphthalene (parent proton sponge). This was attributed to the "buttressing effect" exhibited by the 6-MeO group. Stable double salts of 7 with picrate and perchlorate anions unprecedented for azines with conjugated aza and NMe2 groups were obtained and thoroughly studied.

  8. Effect of substitution group on dielectric properties of 4H-pyrano [3, 2-c] quinoline derivatives thin films

    NASA Astrophysics Data System (ADS)

    H, M. Zeyada; F, M. El-Taweel; M, M. El-Nahass; M, M. El-Shabaan

    2016-07-01

    The AC electrical conductivity and dielectrical properties of 2-amino-6-ethyl-5-oxo-4-(3-phenoxyphenyl)-5,6-dihydro-4H-pyrano[3, 2-c]quinoline-3-carbonitrile (Ph-HPQ) and 2-amino-4-(2-chlorophenyl)-6-ethyl-5-oxo-5,6-dihydro-4H-pyrano [3, 2-c] quinoline-3-carbonitrile (Ch-HPQ) thin films were determined in the frequency range of 0.5 kHz-5 MHz and the temperature range of 290-443 K. The AC electrical conduction of both compounds in thin film form is governed by the correlated barrier hopping (CBH) mechanism. Some parameters such as the barrier height, the maximum barrier height, the density of charges, and the hopping distance were determined as functions of temperature and frequency. The phenoxyphenyl group has a greater influence on those parameters than the chlorophenyl group. The AC activation energies were determined at different frequencies and temperatures. The dielectric behaviors of Ph-HPQ and Ch-HPQ were investigated using the impedance spectroscopy technique. The impedance data are presented in Nyquist diagrams for different temperatures. The Ch-HPQ films have higher impedance than the Ph-HPQ films. The real dielectric constant and dielectric loss show a remarkable dependence on the frequency and temperature. The Ph-HPQ has higher dielectric constants than the Ch-HPQ.

  9. A Comprehensive Study of Copper Guanidine Quinoline Complexes: Predicting the Activity of Catalysts in ATRP with DFT.

    PubMed

    Rösener, Thomas; Bienemann, Olga; Sigl, Kerstin; Schopp, Nora; Schnitter, Fabian; Flörke, Ulrich; Hoffmann, Alexander; Döring, Artjom; Kuckling, Dirk; Herres-Pawlis, Sonja

    2016-09-12

    Copper complexes of the hybrid guanidine ligands 1,3-dimethyl-N-(quinolin-8-yl)-imidazolidin-2-imine (DMEGqu) and 1,1,3,3-tetramethyl-2-(quinolin-8-yl)-guanidine (TMGqu) have been studied comprehensively with regard to their structural and electrochemical properties and their activity in atom transfer radical polymerization (ATRP). A simple analysis of the molecular structures of the complexes gives no indication about their activity in ATRP; however, with the help of DFT and NBO analysis the influence of particular coordinating donors on the electrochemical properties could be fully elucidated. With an adequate DFT methodology and newly applied theoretical isodesmic reactions it was possible to predict the relative position of the redox potentials of copper complexes containing DMEGqu and TMGqu ligands. In addition, predictions could be made as to whether the complexes of DMEGqu or TMGqu are more active in ATRP. Four new Cu(I) complexes were tested in standard ATRP reactions and kinetically investigated both in bulk and in solution. It could be proven that complexes featuring DMEGqu possess a lower redox potential and are more active in ATRP, although the tetramethylguanidine moiety represents the stronger donor.

  10. Amino substituted benzimidazo[1,2-a]quinolines: Antiproliferative potency, 3D QSAR study and DNA binding properties.

    PubMed

    Perin, Nataša; Nhili, Raja; Cindrić, Maja; Bertoša, Branimir; Vušak, Darko; Martin-Kleiner, Irena; Laine, William; Karminski-Zamola, Grace; Kralj, Marijeta; David-Cordonnier, Marie-Hélène; Hranjec, Marijana

    2016-10-21

    We describe the synthesis, 3D-derived quantitative structure-activity relationship (QSAR), antiproliferative activity and DNA binding properties of a series of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines prepared by environmentally friendly uncatalyzed microwave assisted amination. The antiproliferative activities were assessed in vitro against colon, lung and breast carcinoma cell lines; activities ranged from submicromolar to micromolar. The strongest antiproliferative activity was demonstrated by 2-amino-substituted analogues, whereas 5-amino and or 2,5-diamino substituted derivatives resulted in much less activity. Derivatives bearing 4-methyl- or 3,5-dimethyl-1-piperazinyl substituents emerged as the most active. DNA binding properties and the mode of interaction of chosen substituted benzimidazo[1,2-a]quinolines prepared herein were studied using melting temperature studies, a series of spectroscopic studies (UV/Visible, fluorescence, and circular dichroism), and biochemical experiments (topoisomerase I-mediated DNA relaxation and DNase I footprinting experiments). Both compound 36 and its bis-quaternary iodide salt 37 intercalate between adjacent base pairs of the DNA helix while compound 33 presented a very weak topoisomerase I poisoning activity. A 3D-QSAR analysis was performed to identify hydrogen bonding properties, hydrophobicity, molecular flexibility and distribution of hydrophobic regions as these molecular properties had the highest impact on the antiproliferative activity against the three cell lines. PMID:27448912

  11. Rotation-vibration interactions in the spectra of polycyclic aromatic hydrocarbons: Quinoline as a test-case species.

    PubMed

    Pirali, O; Kisiel, Z; Goubet, M; Gruet, S; Martin-Drumel, M A; Cuisset, A; Hindle, F; Mouret, G

    2015-03-14

    Polycyclic aromatic hydrocarbons (PAHs) are highly relevant for astrophysics as possible, though controversial, carriers of the unidentified infrared emission bands that are observed in a number of different astronomical objects. In support of radio-astronomical observations, high resolution laboratory spectroscopy has already provided the rotational spectra in the vibrational ground state of several molecules of this type, although the rotational study of their dense infrared (IR) bands has only recently become possible using a limited number of experimental set-ups. To date, all of the rotationally resolved data have concerned unperturbed spectra. We presently report the results of a high resolution study of the three lowest vibrational states of quinoline C9H7N, an N-bearing naphthalene derivative. While the pure rotational ground state spectrum of quinoline is unperturbed, severe complications appear in the spectra of the ν45 and ν44 vibrational modes (located at about 168 cm(-1) and 178 cm(-1), respectively). In order to study these effects in detail, we employed three different and complementary experimental techniques: Fourier-transform microwave spectroscopy, millimeter-wave spectroscopy, and Fourier-transform far-infrared spectroscopy with a synchrotron radiation source. Due to the high density of states in the IR spectra of molecules as large as PAHs, perturbations in the rotational spectra of excited states should be ubiquitous. Our study identifies for the first time this effect and provides some insights into an appropriate treatment of such perturbations. PMID:25770543

  12. 2,3-Diamino­pyridinium 4-meth­oxy­quinoline-2-carboxyl­ate

    PubMed Central

    Thanigaimani, Kaliyaperumal; Khalib, Nuridayanti Che; Arshad, Suhana; Razak, Ibrahim Abdul

    2012-01-01

    In the 4-meth­oxy­quinoline-2-carboxyl­ate anion of the title salt, C5H8N3 +·C11H8NO3 −, the dihedral angle between the quinoline ring system and the carboxyl­ate group is 16.54 (15)°. In the crystal, the cations and anions are linked via N—H⋯O and N—H⋯N hydrogen bonds, forming a centrosymmetric 2 + 2 aggregate with R 2 2(9) and R 4 2(8) ring motifs. These units are further connected via N—H⋯O hydrogen bonds into a layer parallel to the bc plane. The crystal structure is also stabilized by weak C—H⋯O hydrogen bonds and π–π inter­actions between pyridine rings [centroid–centroid distance = 3.5886 (8) Å] and between pyridine and benzene rings [centroid–centroid distance = 3.6328 (8) Å]. PMID:23476259

  13. Synthetically Tuning the 2-Position of Halogenated Quinolines: Optimizing Antibacterial and Biofilm Eradication Activities via Alkylation and Reductive Amination Pathways.

    PubMed

    Basak, Akash; Abouelhassan, Yasmeen; Norwood, Verrill M; Bai, Fang; Nguyen, Minh Thu; Jin, Shouguang; Huigens, Robert W

    2016-06-27

    Agents capable of eradicating bacterial biofilms are of great importance to human health as biofilm-associated infections are tolerant to our current antibiotic therapies. We have recently discovered that halogenated quinoline (HQ) small molecules are: 1) capable of eradicating methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin-resistant Enterococcus faecium (VRE) biofilms, and 2) synthetic tuning of the 2-position of the HQ scaffold has a significant impact on antibacterial and antibiofilm activities. Here, we report the chemical synthesis and biological evaluation of 39 HQ analogues that have a high degree of structural diversity at the 2-position. We identified diverse analogues that are alkylated and aminated at the 2-position of the HQ scaffold and demonstrate potent antibacterial (MIC≤0.39 μm) and biofilm eradication (MBEC 1.0-93.8 μm) activities against drug-resistant Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium strains while demonstrating <5 % haemolysis activity against human red blood cells (RBCs) at 200 μm. In addition, these HQs demonstrated low cytotoxicity against HeLa cells. Halogenated quinolines are a promising class of antibiofilm agents against Gram-positive pathogens that could lead to useful treatments against persistent bacterial infections. PMID:27245927

  14. Laboratory Infrared Spectra of Polycyclic Aromatic Nitrogen Heterocycles: Quinoline, and Phenanthridine in Solid Argon and H2O

    NASA Technical Reports Server (NTRS)

    Bernstein, M. P.; Mattioda, A. L.; Sandford, S. A.; Hudgins, D. M.

    2004-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are common throughout the universe. Their detection and identification are based on telescopic infrared (IR) spectra compared with laboratory data. Polycyclic Aromatic Nitrogen Heterocycles (PANHs) are heterocyclic aromatics i.e., PAHs with carbon atoms replaced by a nitrogen atom. These molecules should be present in the interstellar medium, but have received relatively little attention. We present mid-IR spectra of two PANHs, quinoline (C9H7N), and phenanthridine (C13H9N) isolated in solid argon and frozen in solid H2O at 12 K, conditions yielding data directly comparable to astronomical observations. In contrast to simple PAHs, that do not interact strongly with solid H2O, the nitrogen atoms in PANHs are potentially capable of hydrogen bonding with H2O. Whereas the IR spectrum of phenanthridine in H2O is similar to that of the same compound isolated in an argon matrix, quinoline absorptions shift up to 16 cm(sup -1) (0.072 mm) between argon and H2O. Thus, astronomers will not always be able to rely on IR band positions of matrix isolated PANHs to correctly interpret the absorptions of PANHs frozen in H2O ice grains. Furthermore, our data suggest that relative band areas also vary, so determining column densities to better than a factor of 3 will require knowledge of the matrix in which the PANH is embedded and laboratory studies of relevant samples.

  15. Amino substituted benzimidazo[1,2-a]quinolines: Antiproliferative potency, 3D QSAR study and DNA binding properties.

    PubMed

    Perin, Nataša; Nhili, Raja; Cindrić, Maja; Bertoša, Branimir; Vušak, Darko; Martin-Kleiner, Irena; Laine, William; Karminski-Zamola, Grace; Kralj, Marijeta; David-Cordonnier, Marie-Hélène; Hranjec, Marijana

    2016-10-21

    We describe the synthesis, 3D-derived quantitative structure-activity relationship (QSAR), antiproliferative activity and DNA binding properties of a series of 2-amino, 5-amino and 2,5-diamino substituted benzimidazo[1,2-a]quinolines prepared by environmentally friendly uncatalyzed microwave assisted amination. The antiproliferative activities were assessed in vitro against colon, lung and breast carcinoma cell lines; activities ranged from submicromolar to micromolar. The strongest antiproliferative activity was demonstrated by 2-amino-substituted analogues, whereas 5-amino and or 2,5-diamino substituted derivatives resulted in much less activity. Derivatives bearing 4-methyl- or 3,5-dimethyl-1-piperazinyl substituents emerged as the most active. DNA binding properties and the mode of interaction of chosen substituted benzimidazo[1,2-a]quinolines prepared herein were studied using melting temperature studies, a series of spectroscopic studies (UV/Visible, fluorescence, and circular dichroism), and biochemical experiments (topoisomerase I-mediated DNA relaxation and DNase I footprinting experiments). Both compound 36 and its bis-quaternary iodide salt 37 intercalate between adjacent base pairs of the DNA helix while compound 33 presented a very weak topoisomerase I poisoning activity. A 3D-QSAR analysis was performed to identify hydrogen bonding properties, hydrophobicity, molecular flexibility and distribution of hydrophobic regions as these molecular properties had the highest impact on the antiproliferative activity against the three cell lines.

  16. Determination of mercury(II) in aquatic plants using quinoline-thiourea conjugates as a fluorescent probe.

    PubMed

    Feng, Guodong; Ding, Yuanyuan; Gong, Zhiyong; Dai, Yanna; Fei, Qiang

    2013-01-01

    In this study, a quinoline-thiourea conjugate (1-phenyl-3-(quinoline-8-yl) thiourea, PQT) was synthesized and used as a fluorescence sensor to detect mercury ion. The observation is coincident with the well-documented phenomenon that a thiocarbonyl-containing group on a fluorochrome quenches the fluorescence due to the heavy atom effect of the S atom. The large fluorescence enhancement of PQT in the buffered MeCN-water mixture (1/1 v/v; HEPES 100 mM; pH 8.0) was caused by the Hg(2+) induced transformation of the thiourea function into a urea group. As such, protic solvents can be ascribed to hydrogen bond formation on the carbonyl oxygen to reduce the internal conversion rate. The fluorescence intensity of PQT was enhanced quantitatively with an increase in the concentration of mercury ion. The limit of detection of Hg(2+) was 7.5 nM. The coexistence of other metal ions with mercury had no obvious influence on the detection of mercury. A quinolone-thiourea conjugate was used as a fluorescent probe to detect Hg(2+) in aquatic plants and the experimental results were satisfactory. PMID:23842417

  17. A Comprehensive Study of Copper Guanidine Quinoline Complexes: Predicting the Activity of Catalysts in ATRP with DFT.

    PubMed

    Rösener, Thomas; Bienemann, Olga; Sigl, Kerstin; Schopp, Nora; Schnitter, Fabian; Flörke, Ulrich; Hoffmann, Alexander; Döring, Artjom; Kuckling, Dirk; Herres-Pawlis, Sonja

    2016-09-12

    Copper complexes of the hybrid guanidine ligands 1,3-dimethyl-N-(quinolin-8-yl)-imidazolidin-2-imine (DMEGqu) and 1,1,3,3-tetramethyl-2-(quinolin-8-yl)-guanidine (TMGqu) have been studied comprehensively with regard to their structural and electrochemical properties and their activity in atom transfer radical polymerization (ATRP). A simple analysis of the molecular structures of the complexes gives no indication about their activity in ATRP; however, with the help of DFT and NBO analysis the influence of particular coordinating donors on the electrochemical properties could be fully elucidated. With an adequate DFT methodology and newly applied theoretical isodesmic reactions it was possible to predict the relative position of the redox potentials of copper complexes containing DMEGqu and TMGqu ligands. In addition, predictions could be made as to whether the complexes of DMEGqu or TMGqu are more active in ATRP. Four new Cu(I) complexes were tested in standard ATRP reactions and kinetically investigated both in bulk and in solution. It could be proven that complexes featuring DMEGqu possess a lower redox potential and are more active in ATRP, although the tetramethylguanidine moiety represents the stronger donor. PMID:27505859

  18. Design, Synthesis, and Functional Activity of Labeled CD1d Glycolipid Agonists

    PubMed Central

    2013-01-01

    Invariant natural killer T cells (iNKT cells) are restricted by CD1d molecules and activated upon CD1d-mediated presentation of glycolipids to T cell receptors (TCRs) located on the surface of the cell. Because the cytokine response profile is governed by the structure of the glycolipid, we sought a method for labeling various glycolipids to study their in vivo behavior. The prototypical CD1d agonist, α-galactosyl ceramide (α-GalCer) 1, instigates a powerful immune response and the generation of a wide range of cytokines when it is presented to iNKT cell TCRs by CD1d molecules. Analysis of crystal structures of the TCR−α-GalCer–CD1d ternary complex identified the α-methylene unit in the fatty acid side chain, and more specifically the pro-S hydrogen at this position, as a site for incorporating a label. We postulated that modifying the glycolipid in this way would exert a minimal impact on the TCR–glycolipid–CD1d ternary complex, allowing the labeled molecule to function as a good mimic for the CD1d agonist under investigation. To test this hypothesis, the synthesis of a biotinylated version of the CD1d agonist threitol ceramide (ThrCer) was targeted. Both diastereoisomers, epimeric at the label tethering site, were prepared, and functional experiments confirmed the importance of substituting the pro-S, and not the pro-R, hydrogen with the label for optimal activity. Significantly, functional experiments revealed that biotinylated ThrCer (S)-10 displayed behavior comparable to that of ThrCer 5 itself and also confirmed that the biotin residue is available for streptavidin and antibiotin antibody recognition. A second CD1d agonist, namely α-GalCer C20:2 4, was modified in a similar way, this time with a fluorescent label. The labeled α-GalCer C20:2 analogue (11) again displayed functional behavior comparable to that of its unlabeled substrate, supporting the notion that the α-methylene unit in the fatty acid amide chain should be a suitable site for

  19. Development and pharmacological characterization of conformationally constrained urotensin II-related peptide agonists.

    PubMed

    Chatenet, David; Folch, Benjamin; Feytens, Debby; Létourneau, Myriam; Tourwé, Dirk; Doucet, Nicolas; Fournier, Alain

    2013-12-12

    Urotensin II (UII) and its paralog peptide, urotensin II-related peptide (URP), exert not only common but also divergent actions through the activation of UT, a specific membrane-bound receptor that belongs to the 1A G protein-coupled receptor subclass. In this study, we have designed and synthesized new URP analogues in which the intracyclic Trp residue was replaced with natural, unnatural, and constrained amino acids to determine important physicochemical features for receptor binding and activation. The biological data, highlighting the potent agonistic behavior of [Tiq(4)]URP and [Tpi(4)]URP, also suggest that the Trp residue, and more specifically the indole ring, is not critical for receptor interaction and could in fact be involved in the intramolecular stabilization of the bioactive conformation of URP. Finally, these analogues, which are intracyclic constrained URP-based agonists, could represent useful pharmacological tools for the study of the urotensinergic system. PMID:24251366

  20. DNA Aptamer Assembly as a Vascular Endothelial Growth Factor Receptor Agonist

    PubMed Central

    Ramaswamy, Vidhya; Monsalve, Adam; Sautina, Larysa; Segal, Mark S.; Dobson, Jon

    2015-01-01

    Controlling receptor-mediated processes in cells is paramount in many research areas. The activity of small molecules and growth factors is difficult to control and can lead to off-target effects through the activation of nonspecific receptors as well as binding affinity to nonspecific cell types. In this study, we report the development of a molecular trigger in the form of a divalent nucleic acid aptamer assembly toward vascular endothelial growth factor receptor-2 (VEGFR2). The assembly binds to VEGFR2 and functions as a receptor agonist with targeted receptor binding, promoting receptor phosphorylation, activation of the downstream Akt pathway, upregulation of endothelial nitric oxide synthase, and endothelial cell capillary tube formation. The agonist action we report makes this aptamer construct a promising strategy to control VEGFR2-mediated cell signaling. PMID:26125598

  1. Treating enhanced GABAergic inhibition in Down syndrome: use of GABA α5-selective inverse agonists.

    PubMed

    Martínez-Cué, Carmen; Delatour, Benoît; Potier, Marie-Claude

    2014-10-01

    Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be responsible for cognitive deficits observed throughout their lives. A change in the excitatory/inhibitory balance in adulthood would alter synaptic plasticity, potentially triggering learning and memory deficits. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system and binds to GABAA receptors, opens a chloride channel, and reduces neuronal excitability. In this review we discuss methods to alleviate neuronal inhibition in a mouse model of Down syndrome, the Ts65Dn mouse, using either an antagonist (pentylenetetrazol) or two different inverse agonists selective for the α5-subunit containing receptor. Both inverse agonists, which reduce inhibitory GABAergic transmission, could rescue learning and memory deficits in Ts65Dn mice. We also discuss safety issues since modulation of the excitatory-inhibitory balance to improve cognition without inducing seizures remains particularly difficult when using GABA antagonists.

  2. DNA Aptamer Assembly as a Vascular Endothelial Growth Factor Receptor Agonist.

    PubMed

    Ramaswamy, Vidhya; Monsalve, Adam; Sautina, Larysa; Segal, Mark S; Dobson, Jon; Allen, Josephine B

    2015-10-01

    Controlling receptor-mediated processes in cells is paramount in many research areas. The activity of small molecules and growth factors is difficult to control and can lead to off-target effects through the activation of nonspecific receptors as well as binding affinity to nonspecific cell types. In this study, we report the development of a molecular trigger in the form of a divalent nucleic acid aptamer assembly toward vascular endothelial growth factor receptor-2 (VEGFR2). The assembly binds to VEGFR2 and functions as a receptor agonist with targeted receptor binding, promoting receptor phosphorylation, activation of the downstream Akt pathway, upregulation of endothelial nitric oxide synthase, and endothelial cell capillary tube formation. The agonist action we report makes this aptamer construct a promising strategy to control VEGFR2-mediated cell signaling.

  3. Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures

    SciTech Connect

    Oyama, Takuji; Toyota, Kenji; Waku, Tsuyoshi; Hirakawa, Yuko; Nagasawa, Naoko; Kasuga, Jun-ichi; Hashimoto, Yuichi; Miyachi, Hiroyuki; Morikawa, Kosuke

    2009-08-01

    The structures of the ligand-binding domains (LBDs) of human peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ) in complexes with a pan agonist, an α/δ dual agonist and a PPARδ-specific agonist were determined. The results explain how each ligand is recognized by the PPAR LBDs at an atomic level. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPARα and PPARγ LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD–ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPARδ LBD in complex with an α/δ-selective ligand, TIPP-401, and with a related δ-specific ligand, TIPP-204, were also determined. The comparison between the two PPARδ complexes revealed how each ligand exhibits either a ‘dual selective’ or ‘single specific’ binding mode.

  4. Combined experimental and quantum chemical studies on spectroscopic (FT-IR, FT-Raman, UV-Vis, and NMR) and structural characteristics of quinoline-5-carboxaldehyde

    NASA Astrophysics Data System (ADS)

    Kumru, Mustafa; Altun, Ahmet; Kocademir, Mustafa; Küçük, Vesile; Bardakçı, Tayyibe; Şaşmaz, İbrahim

    2016-12-01

    Comparative experimental and theoretical studies have been performed on the structure and spectral (FT-IR, FT-Raman, UV-Vis and NMR) features of quinoline-5-carboxaldehyde. Quantum chemical calculations have been carried out at Hartree-Fock and density functional B3LYP levels with the triple-zeta 6-311++G** basis set. Two stable conformers of quinoline-5-carboxaldehyde arising from the orientation of the carboxaldehyde moiety have been located at the room temperature. The energetic separation of these conformers is as small as 2.5 kcal/mol with a low transition barrier (around 9 kcal/mol). Therefore, these conformers are expected to coexist at the room temperature. Several molecular characteristics of quinoline-5-carboxaldehyde obtained through B3LYP and time-dependent B3LYP calculations, such as conformational stability, key geometry parameters, vibrational frequencies, IR and Raman intensities, UV-Vis vertical excitation energies and the corresponding oscillator strengths have been analyzed. The 1H and 13C NMR chemical shifts of quinoline-5-carboxaldehyde were also investigated.

  5. Discovery of Quinoline-Derived Trifluoromethyl Alcohols, Determination of Their in vivo Toxicity and Anticancer Activity in a Zebrafish Embryo Model.

    PubMed

    Sittaramane, Vinoth; Padgett, Jihan; Salter, Philip; Williams, Ashley; Luke, Shauntelle; McCall, Rebecca; Arambula, Jonathan F; Graves, Vincent B; Blocker, Mark; Van Leuven, David; Bowe, Keturah; Heimberger, Julia; Cade, Hannah C; Immaneni, Supriya; Shaikh, Abid

    2015-11-01

    In this study the rational design, synthesis, and anticancer activity of quinoline-derived trifluoromethyl alcohols were evaluated. Members of this novel class of trifluoromethyl alcohols were identified as potent growth inhibitors in a zebrafish embryo model. Synthesis of these compounds was carried out with an sp(3) -C-H functionalization strategy of methyl quinolines with trifluoromethyl ketones. A zebrafish embryo model was also used to explore the toxicity of ethyl 4,4,4-trifluoro-3-hydroxy-3-(quinolin-2-ylmethyl)butanoate (1), 2-benzyl-1,1,1-trifluoro-3-(quinolin-2-yl)propan-2-ol (2), and trifluoro-3-(isoquinolin-1-yl)-2-(thiophen-2-yl)propan-2-ol (3). Compounds 2 and 3 were found to be more toxic than compound 1; apoptotic staining assays indicated that compound 3 causes increased cell death. In vitro cell proliferation assays showed that compound 2, with an LC50 value of 14.14 μm, has more potent anticancer activity than cisplatin. This novel class of inhibitors provides a new direction in the discovery of effective anticancer agents.

  6. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  7. GLP-1 agonist treatment: implications for diabetic retinopathy screening.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Hariman, Christian; Walker, Adrian B; Varughese, George I

    2011-12-01

    Rapid improvement in glycaemic control induced by GLP-1 agonist therapy could be yet another illustration of transient or permanent progression of diabetic retinopathy, similar to documented examples such as pregnancy and continuous subcutaneous insulin infusion. Specific guidelines would be needed to monitor this paradoxical phenomenon during treatment with GLP-1 agonists. PMID:21906831

  8. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  9. Copper(I)-Y Zeolite-Catalyzed Regio- and Stereoselective [2 + 2 + 2] Cyclotrimerization Cascade: An Atom- and Step-Economical Synthesis of Pyrimido[1,6-a]quinoline.

    PubMed

    Ramanathan, Devenderan; Pitchumani, Kasi

    2015-10-16

    An elegant copper(I)-Y zeolite-catalyzed tandem process, involving ketenimine-based termolecular [2 + 2 + 2]/[NC + CC + NC] cycloaddition, using sulfonyl azide, alkyne, and quinoline, to prepare pyrimido[1,6-a]quinolines is reported. In this straightforward, highly atom- and step-economical protocol, copper(I) promotes for azide-alkyne [3 + 2] cycloaddition which is followed by ring-rearrangement/ketenimine formation/regio- and stereoselective [2 + 2 + 2] termolecular cycloaddition and dehydrogenation cascade to yield selectively the E-isomer of pyrimido[1,6-a]quinoline. PMID:26390020

  10. Different characteristics of AMPA receptor agonists acting at AMPA receptors expressed in Xenopus oocytes.

    PubMed

    Wahl, P; Madsen, U; Banke, T; Krogsgaard-Larsen, P; Schousboe, A

    1996-07-18

    A series of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) analogues were evaluated for activity at homo-oligomeric glutamate1-flop (Glu1-flop) receptors expressed in Xenopus oocytes, using the two-electrode voltage clamp technique. (RS)-2-Amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) (EC50, 2.4 microM), a homologue of AMPA having a carboxyl group as the terminal acidic functionality, was five times more potent than AMPA (EC50, 12 microM) and 20 times more potent than kainate (EC50, 46 microM). (RS)-2-Amino-3(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (Tri-F-AMPA), in which an electronegative trifluoromethyl group is substituted for the methyl group on the isoxazole ring in the AMPA structure, was three times more potent than AMPA, whereas (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA), a bicyclic analogue of AMPA with highly restricted conformational flexibility was 10 times less potent than AMPA. The limiting slope of log-log plots of Glu1-flop receptor currents versus low agonist concentrations had a value of 1.7 for ACPA and kainate compared to 1.5 for Tri-F-AMPA and 1.3 for 5-HPCA and AMPA. The amplitude of responses evoked by near saturating concentrations of the agonists varied more than 7-fold. The sequence of efficacy was ACPA = kainate > Tri-F-AMPA > AMPA > 5-HPCA. Moreover, when saturating concentrations of Tri-F-AMPA and kainate were co-applied, the response was significantly greater than when each of the agonists was applied separately. The potency of the antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX) (estimated KB, approximately 200 nM), to block currents mediated by Glu1-flop receptors was similar for all of the agonists tested in this study. These results indicate that relatively minor changes in the molecular structure of AMPA are associated with marked effects on potency and efficacy. In particular, it is suggested that the acidity of

  11. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  12. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.

    PubMed

    Liu, Yaping; Binz, Jane; Numerick, Mary Jo; Dennis, Steve; Luo, Guizhen; Desai, Bhasha; MacKenzie, Kathleen I; Mansfield, Traci A; Kliewer, Steven A; Goodwin, Bryan; Jones, Stacey A

    2003-12-01

    Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.

  13. Differential Effects of D-Cycloserine and ACBC at NMDA Receptors in the Rat Entorhinal Cortex Are Related to Efficacy at the Co-Agonist Binding Site.

    PubMed

    Lench, Alex M; Robson, Emma; Jones, Roland S G

    2015-01-01

    Partial agonists at the NMDA receptor co-agonist binding site may have potential therapeutic efficacy in a number of cognitive and neurological conditions. The entorhinal cortex is a key brain area in spatial memory and cognitive processing. At synapses in the entorhinal cortex, NMDA receptors not only mediate postsynaptic excitation but are expressed in presynaptic terminals where they tonically facilitate glutamate release. In a previous study we showed that the co-agonist binding site of the presynaptic NMDA receptor is endogenously and tonically activated by D-serine released from astrocytes. In this study we determined the effects of two co-agonist site partial agonists on both presynaptic and postsynaptic NMDA receptors in layer II of the entorhinal cortex. The high efficacy partial agonist, D-cycloserine, decreased the decay time of postsynaptic NMDA receptor mediated currents evoked by electrical stimulation, but had no effect on amplitude or other kinetic parameters. In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses. Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid. We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

  14. Neurotensin agonist attenuates nicotine potentiation to cocaine sensitization.

    PubMed

    Fredrickson, Paul; Boules, Mona; Stennett, Bethany; Richelson, Elliott

    2014-03-01

    Tobacco usage typically precedes illicit drug use in adolescent and young adult populations. Several animal studies suggest nicotine increases the risk for subsequent cocaine abuse, and may be a negative prognostic factor for treatment of cocaine addiction; i.e., a "gateway drug". Neurotensin (NT) is a 13-amino acid neuropeptide that modulates dopamine, acetylcholine, glutamate, and GABA neurotransmission in brain reward pathways. NT69L, a NT(8-13) analog, blocks behavioral sensitization (an animal model for psychostimulant addiction) to nicotine, and nicotine self-administration in rats. The present study tested the effect of NT69L on the potentiating effects of nicotine on cocaine-induced locomotor sensitization. Male Wistar rats were injected daily for seven days with nicotine or saline (control) followed by four daily injections of cocaine. NT69L was administered 30 min prior to the last cocaine injection. Behavior was recorded with the use of activity chambers. Subchronic administration of nicotine enhanced cocaine-induced behavioral sensitization in Wistar rats, consistent with an hypothesized gateway effect. These behavioral effects of cocaine were attenuated by pretreatment with NT69L. The effect of the neurotensin agonist on cocaine sensitization in the nicotine treated group indicated a possible therapeutic effect for cocaine addiction, even in the presence of enhanced behavioral sensitization induced by nicotine. PMID:25379267

  15. Agonist Derived Molecular Probes for A2A Adenosine Receptors

    PubMed Central

    Jacobson, Kenneth A.; Pannell, Lewis K.; Ji, Xiao-duo; Jarvis, Michael F.; Williams, Michael; Hutchison, Alan J.; Barrington, William W.; Stiles, Gary L.

    2011-01-01

    The adenosine agonist 2-(4-(2-carboxyethyl)phenylethylamino)-5′-N-ethylcarboxamidoadenosine (CGS21680) was recently reported to be selective for the A2A adenosine receptor subtype, which mediates its hypotensive action. To investigate structurelactivity relationships at a distal site, CGS21680 was derivatized using a functionalized congener approach. The carboxylic group of CGS21680 has been esterified to form a methyl ester, which was then treated with ethylenediamine to produce an amine congener. The amine congener was an intermediate for acylation reactions, in which the reactive acyl species contained a reported group, or the precursor for such. For radioiodination, derivatives of p-hydroxyphenylpropionic, 2-thiophenylacetic, and p-aminophenylacetic acids were prepared. The latter derivative (PAPA-APEC) was iodinated electrophilically using [125I]iodide resulting in a radioligand which was used for studies of competition of binding to striatal A, adenosine receptors in bovine brain. A biotin conjugate and an aryl sulfonate were at least 350-fold selective for A, receptors. For spectroscopic detection, a derivative of the stable free radical tetramethyl-1-piperidinyloxy (TEMPO) was prepared. For irreversible inhibition of receptors, meta- and para-phenylenediisothiocyanate groups were incorporated in the analogs. We have demonstrated that binding at A2A receptors is relatively insensitive to distal structural changes at the 2-position, and we report high affinity molecular probes for receptor characterization by radioactive, spectroscopic and affinity labelling methodology. PMID:2561548

  16. Ratiometric emission fluorescent pH probe for imaging of living cells in extreme acidity.

    PubMed

    Niu, Weifen; Fan, Li; Nan, Ming; Li, Zengbo; Lu, Dongtao; Wong, Man Shing; Shuang, Shaomin; Dong, Chuan

    2015-03-01

    A novel ratiometric emission fluorescent probe, 1,1-dimethyl-2-[2-(quinolin-4-yl)vinyl]-1H-benzo[e]indole (QVBI), is facilely synthesized via ethylene bridging of benzoindole and quinoline. The probe exhibits ratiometric fluorescence emission (F(522nm)/F(630nm)) characteristics with pKa 3.27 and linear response to extreme-acidity range of 3.8-2.0. Also, its high fluorescence quantum yield (Φ = 0.89) and large Stokes shift (110 nm) are favorable. Moreover, QVBI possesses highly selective response to H(+) over metal ions and some bioactive molecules, good photostability, and excellent reversibility. The probe has excellent cell membrane permeability and is further applied successfully to monitor pH fluctuations in live cells and imaging extreme acidity in Escherichia coli cells without influence of autofluorescence and native cellular species in biological systems. PMID:25664606

  17. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  18. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  19. Identification of SR3335 (ML176): a Synthetic RORα Selective Inverse Agonist

    PubMed Central

    Kumar, Naresh; Kojetin, Douglas J.; Solt, Laura A.; Kumar, K. Ganesh; Nuhant, Philippe; Duckett, Derek R.; Cameron, Michael D.; Butler, Andrew A.; Roush, William R.; Griffin, Patrick R.; Burris, Thomas P.

    2010-01-01

    Several nuclear receptors (NRs) are still characterized as orphan receptors since ligands have not yet been identified for these proteins. The retinoic acid receptor-related receptors (RORs) have no well-defined physiological ligands. Here, we describe the identification of a selective RORα synthetic ligand, SR3335 (ML-176). SR3335 directly binds to RORα, but not other RORs, and functions as a selective partial inverse agonist of RORα in cell-based assays. Furthermore, SR3335 suppresses the expression of endogenous RORα target genes in HepG2 involved in hepatic gluconeogenesis including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Pharmacokinetic studies indicate that SR3335 displays reasonable exposure following an i.p. injection into mice. We assess the ability of SR3335 to suppress gluconeogenesis in vivo using a diet induced obesity (DIO) mouse model where the mice where treated with 15 mg/kg b.i.d., i.p. for 6-days followed by a pyruvate tolerance test. SR3335 treated mice displayed lower plasma glucose levels following the pyruvate challenge consistent with suppression of gluconeogenesis. Thus, we have identified the first selective synthetic RORα inverse agonist and this compound can be utilized as a chemical tool to probe the function of this receptor both in vitro and in vivo. Additionally, our data suggests that RORα inverse agonists may hold utility for suppression of elevated hepatic glucose production in type 2 diabetics. PMID:21090593

  20. Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors.

    PubMed

    DiRaddo, John O; Miller, Eric J; Bowman-Dalley, Carrie; Wroblewska, Barbara; Javidnia, Monica; Grajkowska, Ewa; Wolfe, Barry B; Liotta, Dennis C; Wroblewski, Jarda T

    2015-09-01

    The elemental anion chloride is generally considered a passive participant in neuronal excitability, and has never been shown to function as an agonist in its own right. We show that the antagonist-mediated, glutamate-independent inverse agonism of group II and III metabotropic glutamate (mGlu) receptors results from inhibition of chloride-mediated activation. In silico molecular modeling, site-directed mutagenesis, and functional assays demonstrate (1) that chloride is an agonist of mGlu3, mGlu4, mGlu6, and mGlu8 receptors with its own orthosteric site, and (2) that chloride is not an agonist of mGlu2 receptors. Molecular modeling-predicted and site-directed mutagenesis supported that this unique property of mGlu2 receptors results from a single divergent amino acid, highlighting a molecular switch for chloride insensitivity that is transduced through an arginine flip. Ultimately, these results suggest that activation of group II and III mGlu receptors is mediated not only by glutamate, but also by physiologically relevant concentrations of chloride. PMID:26089372

  1. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

    SciTech Connect

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao; Han, Xiang Hua; Lee, Dong-Ho; Lee, Hak-Ju; Hwang, Bang Yeon; Lee, Sung-Joon

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  2. Antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists.

    PubMed

    Labrie, F; Bélanger, A; Kelly, P A; Séguin, C; Cusan, L; Lefebvre, F A; Reeves, J J; Lemay, A; Faure, N; Gourdeau, Y; Raynaud, J P

    1981-01-01

    This paper reviews the mechanisms responsible for the antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists. Large doses of the LHRH agonist LHRH-EA lead to a marked reduction of testicular and secondary sex organ weight, LH receptor levels, and plasma testosterone concentration. A marked inhibition of basal testicular and testosterone concentrations is obtained after daily administration of the LHRH agonists at doses greater than 10 ng. Treatment with low doses of the LHRH agonist can lead to an increased steroidogenic response to LH. Treatment with low doses of LHRH agonists could stimulate Leydig cell function while high doses are history. A study of the effects of longterm treatment with an LHRH agonsist on spermatogenesis revelaed that testis, prostate, and seminal vesicle weight decreased and plasma LH and FSH levels increased over 12 weeks. Comparison of the effects of increasing doses of LHRH agonist on testicular and ovarian gonadotropin receptors and steroidogenesis in male rats indicates that single or repeated administration of LHRH agonists can lead to loss of testicular LH receptors in the absence of the pituitary gland. The loss of ovarian gonadotropin receptors in female rats is also investigated. Antifertility effects of LHRH ethylamide are accompanied by a marked loss of LH/hCG and FSH receptors in ovarian tissue. The injection of 1,3, or 10 ng LHRH-EA in intact rats has no significant effect on ovarian LH receptor levels. A study of the direct action of LHRH agonists at the ovarian level demonstrates a close relationship between the binding activity of a large series of LHRH agonists and antagonists in the anterior pituitary gland and the ovary. Inhibition of testicular steroidogenesis in man by treatment with a potent LHRH agonist is also demonstrated. Intranasal administration of LHRH ethylamide has luteolytic effects in normal women. Daily administration of LHRH-EA inhibited ovulation in all but 2 of 89 treatment

  3. pH-Dependent Surface-Enhanced Raman Scattering of 8-Hydroxy Quinoline Adsorbed on Silver Hydrosol.

    PubMed

    Chowdhury; Ghosh; Misra

    2000-08-15

    Surface-enhanced Raman scattering (SERS) of 8-hydroxy quinoline (HQ) adsorbed on silver hydrosols are compared with the FTIR and normal Raman spectrum in the bulk and in solution. Definite evidence of the charge transfer interaction to the overall contribution in the SER enhancement has been reported. The excitation profile study also supports the evidence of a charge transfer interaction. The effect of pH variation on the SER band intensity is explained in terms of chemisorption of the molecule on bare and chlorinated silver surfaces. The apparent enhancement factor calculations of the principal Raman bands indicate that in the surface-adsorbed state, an HQ molecule is oriented neither flat nor vertical to the silver surface but is tilted. Copyright 2000 Academic Press.

  4. Fluorescence reaction of 5-(p-methoxyphenylazo)-8-(p-tolylsulfonamido)quinoline with cobalt(II) and its analytical application

    SciTech Connect

    Zeng Zuotao ) Xu Qiheng )

    1992-08-01

    5-(p-Methoxyphenylazo)-8-(p-tolylsulfonamido)quinoline(MTAQ) has been synthesized. The product was checked by IR, thermogravimetry, NMR and elemental analysis. A highly sensitive spectrofluorimetric method has been developed for the determination of cobalt(II) based on the formation of a complex with MTAQ in slightly basic medium aqueous solution and in the presence of nonionic surfactant, tween-80. The complex shows two excitation maxima at 304 nm and 338 nm, its emission maximum is centered at 402nm. The fluorescence intensity is proportional to cobalt(II) concentration in the range of 0-85 ppb. The method has good selectivity and has been applied to the direct fluorimetric determination of trace cobalt(II) in pig's liver, Dianchi shrimp and celery.

  5. Synthesis and characterization of a new photoluminescent material tris (2-methyl-8-hydroxy quinoline) lanthanum La(mq)3

    NASA Astrophysics Data System (ADS)

    Kumar, Rahul; Bhargava, Parag

    2016-05-01

    A new photoluminescence material, tris (2-methyl-8-hydroxy quinoline) lanthanum has been synthesized and characterized by different techniques. The prepared material La(mq)3 was characterized for structural, thermal and photoluminescence analysis. Structural analysis of this material was done by fourier transformed infrared spectroscopy (FTIR) and mass spectroscopy. Thermal analysis of this material was done by thermal gravimetric analysis (TGA) shows the thermal stability up to 400°C. Absorption and emission spectra of the material was measured by UV-visible spectroscopy and photoluminescence spectroscopy. Solution of this material La(mq)3 in ethanol showed absorption peak at 385nm respectively which may be attributed due to (π - π*) transitions. The photoluminescence spectra of La(mq)3 in ethanol solution showed intense peak at 430 nm.

  6. Novel aromatic N-oxyl radical based on the benzo[ g]quinoline skeleton: synthesis and intermolecular ferromagnetic interaction

    NASA Astrophysics Data System (ADS)

    Yao, Masaru; Inoue, Hidenari; Yoshioka, Naoki

    2005-01-01

    A novel stable organic radical, 2,2-diphenyl-1,2-dihydrobenzo[ g]quinoline- N-oxyl ( 2), has been synthesized and structurally characterized in order to examine the ring extension effect on the known derivative, 2,2-diphenyl-1,2-dihydroquinoline- N-oxyl ( 1). Based on SQUID measurement, 2 exhibited a ferromagnetic interaction obeying the Bleaney-Bowers equation with 2 J = +4.6 cm -1. The X-ray analysis revealed an intermolecular edge-edge association of the aryl ring and N-oxyl moiety in the crystal of 2. The bifurcated edge-edge contacts between the α-spin site (nitroxyl O atom) and the β-spin site (aryl-H atoms) are responsible for the ferromagnetic interaction of 2.

  7. Photoelectric and electrical properties of soluble polyphenylquinolines containing an oxygen or phenylamine bridge group between quinoline moieties

    SciTech Connect

    Aleksandrova, E. L.; Svetlychnyi, V. M. Miagkova, L. A.; Nekrasova, T. N.; Tameev, A. R.; Vannikov, A. V.; Kudryavtsev, V. V.

    2009-03-15

    Photoelectric and electrical properties of polyphenylquinolines differing in the structure of donor bridge groups between quinoline moieties have been studied. It is demonstrated that films of the polymers synthesized exhibit a photosensitivity at the level of 10{sup 5} cm{sup 2} J{sup -1} (integrated sensitivity 5 x 10{sup -4} lx{sup -1} . s{sup -1}), with a quantum yield of carrier photogeneration of 0.07 and a carrier drift mobility on the order of 10{sup -6} cm{sup 2} V{sup -1} s{sup -1}. The fact that the electron and hole drift mobilities in polyphenylquinoline with a phenylamine bridge group are balanced makes the polymer promising for development of film-type devices based on the bipolar conductivity of a material (e.g., single-layer light-emitting diode)

  8. Anticancer drug design using scaffolds of β-lactams, sulfonamides, quinoline, quinoxaline and natural products. Drugs advances in clinical trials.

    PubMed

    Balderas-Renteria, I; Gonzalez-Barranco, P; Garcia, A; Banik, B K; Rivera, G

    2012-01-01

    Eleven years after the start of a new millennium characterized by amazing scientific development, the cure for cancer remains a major challenge for humanity. In this regard, scientific efforts have focused on the search for new therapeutic targets that involve specific recognition and stop the spread of cancer cells, as well as the development of new therapeutic options that show greater specificity and better therapeutic efficacy. This review includes recent published literature about new anticancer drug design using scaffolds of β-lactams, sulfonamides, quinoline, quinoxaline and natural products, and focuses on the structure-activity relationships of scaffolds that have been reported to potently inhibit cell growth of human tumor cell lines. It describes not only those synthetic or natural compounds aimed at specific molecular targets of cancer cells in vitro, but also compounds currently in clinical trials.

  9. Spectral properties of 1H-pyrazolo[3,4-b]quinoline substituted with N,N-diethylamine moiety

    NASA Astrophysics Data System (ADS)

    Kolbus, Anna; Grabka, Danuta; Danel, Andrzej; Szary, Karol

    2016-07-01

    Photophysical properties of 6-N,N-diethyl-3-methyl-1-phenyl-1H-pyrazol[3,4-b]quinoline (DEPQ), a potential material for electroluminescent applications, were investigated. The absorption and fluorescence spectra and fluorescence lifetimes were recorded in a great number of solvents with different polarity. The red shifts in absorption and fluorescence maxima with the solvent's polarity were observed. Different trends in values of quantum yield for non-polar and polar solvents suggest two different deactivation ways of the excited state, depending on solvent polarity. DEPQ in non-polar solvents emits from locally excited states while deactivation DEPQ in polar solvents indicates charge transfer (CT) fluorescence. Several electro-optical parameters were also calculated.

  10. Sensitive determination of quinoline yellow using poly (diallyldimethylammonium chloride) functionalized reduced graphene oxide modified grassy carbon electrode.

    PubMed

    Fu, Li; Zheng, Yuhong; Wang, Aiwu; Cai, Wen; Lin, Haitao

    2015-08-15

    A novel poly (diallyldimethylammonium chloride) functionalized reduced graphene oxide (PDDA-RGO) nanocomposite modified electrode was fabricated, and applied for the electrochemical determination of quinoline yellow (QY). The formation of PDDA-RGO nanocomposite was confirmed by SEM, FTIR and Raman spectroscopy. The electrocatalytic activity of PDDA-RGO nanocomposite to the oxidation of QY was evaluated using cyclic voltammetry and differential pulse voltammetry. Under the optimal conditions, the proposed sensor exhibited excellent electrochemical performance towards detection of QY. The linear range is from 0.01 to 10 μM, and the detection limit is down to 0.002 μM (S/N=3). The proposed sensor also exhibited excellent anti-interference property, repeatability and stability. In addition, the proposed electrochemical sensor was successfully applied to determination of QY in soft drink. PMID:25794730

  11. Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats.

    PubMed

    Sárvári, Miklós; Deli, Levente; Kocsis, Pál; Márk, László; Maász, Gábor; Hrabovszky, Erik; Kalló, Imre; Gajári, Dávid; Vastagh, Csaba; Sümegi, Balázs; Tihanyi, Károly; Liposits, Zsolt

    2014-10-01

    The mesocortical dopaminergic pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) contributes to the processing of reward signals. This pathway is regulated by gonadal steroids including estradiol. To address the putative role of estradiol and isotype-selective estrogen receptor (ER) agonists in the regulation of the rodent mesocortical system, we combined fMRI, HPLC-MS and qRT-PCR techniques. In fMRI experiments adult, chronically ovariectomized rats, treated with either vehicle, estradiol, ERα agonist 16α-lactone-estradiol (LE2) or ERβ agonist diarylpropionitrile (DPN), received a single dose of d-amphetamine-sulphate (10mg/kg, i.p.) and BOLD responses were monitored in the VTA and the PFC. Ovariectomized rats showed no significant response to amphetamine. In contrast, the VTA of ER agonist-substituted ovariectomized rats showed robust amphetamine-evoked BOLD increases. The PFC of estradiol-replaced animals was also responsive to amphetamine. Mass spectroscopic analysis of dopamine and its metabolites revealed a two-fold increase in both dopamine and 3,4-dihydroxyphenylacetic acid content of the PFC in estradiol-replaced animals compared to ovariectomized controls. qRT-PCR studies revealed upregulation of dopamine transporter and dopamine receptor in the VTA and PFC, respectively, of ER agonist-treated ovariectomized animals. Collectively, the results indicate that E2 and isotype-selective ER agonists can powerfully modulate the responsiveness of the mesocortical dopaminergic system, increase the expression of key genes related to dopaminergic neurotransmission and augment the dopamine content of the PFC. In a broader sense, the findings support the concept that the manifestation of reward signals in the PFC is dependent on the actual estrogen milieu of the brain. PMID:24976584

  12. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    SciTech Connect

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  13. Rotation-vibration interactions in the spectra of polycyclic aromatic hydrocarbons: Quinoline as a test-case species

    SciTech Connect

    Pirali, O.; Gruet, S.; Kisiel, Z.; Martin-Drumel, M. A.; Cuisset, A.; Hindle, F.; Mouret, G.

    2015-03-14

    Polycyclic aromatic hydrocarbons (PAHs) are highly relevant for astrophysics as possible, though controversial, carriers of the unidentified infrared emission bands that are observed in a number of different astronomical objects. In support of radio-astronomical observations, high resolution laboratory spectroscopy has already provided the rotational spectra in the vibrational ground state of several molecules of this type, although the rotational study of their dense infrared (IR) bands has only recently become possible using a limited number of experimental set-ups. To date, all of the rotationally resolved data have concerned unperturbed spectra. We presently report the results of a high resolution study of the three lowest vibrational states of quinoline C{sub 9}H{sub 7}N, an N-bearing naphthalene derivative. While the pure rotational ground state spectrum of quinoline is unperturbed, severe complications appear in the spectra of the ν{sub 45} and ν{sub 44} vibrational modes (located at about 168 cm{sup −1} and 178 cm{sup −1}, respectively). In order to study these effects in detail, we employed three different and complementary experimental techniques: Fourier-transform microwave spectroscopy, millimeter-wave spectroscopy, and Fourier-transform far-infrared spectroscopy with a synchrotron radiation source. Due to the high density of states in the IR spectra of molecules as large as PAHs, perturbations in the rotational spectra of excited states should be ubiquitous. Our study identifies for the first time this effect and provides some insights into an appropriate treatment of such perturbations.

  14. Design, synthesis, in-vitro antiproliferative activity and kinase profile of new picolinamide based 2-amido and ureido quinoline derivatives.

    PubMed

    El-Damasy, Ashraf Kareem; Seo, Seon Hee; Cho, Nam-Chul; Kang, Soon Bang; Pae, Ae Nim; Kim, Key-Sun; Keum, Gyochang

    2015-08-28

    New 2-amido and ureido quinoline derivatives substituted with 2-N-methylamido-pyridin-4-yloxy group at the 5-position of quinoline (18 final compounds) have been designed and synthesized as anticancer sorafenib congeners. Among the synthesized derivatives, fourteen compounds were selected for evaluation of their antiproliferative activity over a panel of 60 cancer cell lines at a single dose concentration of 10 μM at National Cancer Institute (NCI, USA). Four compounds, 9b-d and 9f showed promising mean growth inhibitions and thus were further tested at five-dose testing mode to determine their IC50 values. The data revealed that 2,4-difluorophenyl (9b) and 4-chloro-3-trifluoromethylphenyl (9d) urea compounds are the most active derivatives with significant efficacies and superior potencies than sorafenib in 36 and 12 cancer cell lines, respectively, belonging particularly to renal carcinoma cell (RCC), ovarian, and non small cell lung cancer (NSCL). Compound 9b and 9d were found to be six and two times more potent than sorafenib against A498 RCC line, with IC50 values of 0.42 μM and 1.36 μM, respectively. Accordingly, compound 9d was screened over a panel of 41 oncogenic kinases at a single dose concentration of 10 μM to profile its kinase inhibitory activity. Interestingly, the compound showed highly selective inhibitory activities ( 81.8% and 96.3%) against BRAF(V600E) and C-RAF kinases with IC50 values of 316 nM and 61 nM, respectively. In addition, molecular docking, cell cycle analysis, compliance to Lipinski's rule of five, and in silico toxicity assessment have been reported. PMID:26218653

  15. Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator.

    PubMed

    Vajda, Eric G; López, Francisco J; Rix, Peter; Hill, Robert; Chen, Yanling; Lee, Kyoung-Jin; O'Brien, Z; Chang, William Y; Meglasson, Martin D; Lee, Yong-Hee

    2009-02-01

    Selective androgen receptor modulators (SARMs) are a new class of molecules in development to treat a variety of diseases. SARMs maintain the beneficial effects of androgens, including increased muscle mass and bone density, while having reduced activity on unwanted side effects. The mechanisms responsible for the tissue-selective activity of SARMs are not fully understood, and the pharmacokinetic (PK)/pharmacodynamic (PD) relationships are poorly described. Tissue-specific compound distribution potentially could be a mechanism responsible for apparent tissue selectivity. We examined the PK/PD relationship of a novel SARM, LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one], in a castrated rat model of androgen deficiency. LGD-3303 has potent activity on levator ani muscle but is a partial agonist on the preputial gland and ventral prostate. LGD-3303 never stimulated ventral prostate above intact levels despite increasing plasma concentrations of compound. Tissue-selective activity was maintained when LGD-3303 was dosed orally or by continuous infusion, two routes of administration with markedly different time versus exposure profiles. Despite the greater muscle activity relative to prostate activity, local tissue concentrations of LGD-3303 were higher in the prostate than in the levator ani muscle. LGD-3303 has SARM properties that are independent of its pharmacokinetic profile, suggesting that the principle mechanism for tissue-selective activity is the result of altered molecular interactions at the level of the androgen receptor.

  16. Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists.

    PubMed

    Gong, Hua; Yang, Michael; Xiao, Zili; Doweyko, Arthur M; Cunningham, Mark; Wang, Jinhong; Habte, Sium; Holloway, Deborah; Burke, Christine; Shuster, David; Gao, Ling; Carman, Julie; Somerville, John E; Nadler, Steven G; Salter-Cid, Luisa; Barrish, Joel C; Weinstein, David S

    2014-08-01

    Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described. PMID:24980053

  17. Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides.

    PubMed

    Asami, Taiji; Nishizawa, Naoki; Ishibashi, Yoshihiro; Nishibori, Kimiko; Nakayama, Masaharu; Horikoshi, Yasuko; Matsumoto, Shin-ichi; Yamaguchi, Masashi; Matsumoto, Hirokazu; Tarui, Naoki; Ohtaki, Tetsuya; Kitada, Chieko

    2012-10-15

    Metastin/kisspeptin, a 54-amino acid peptide, is the ligand of the G-protein-coupled receptor KISS1R which plays a key role in pathways that regulate reproduction and cell migration in many endocrine and gonadal tissues. The N-terminally truncated decapeptide, metastin(45-54), has 3-10 times higher receptor affinity and intracellular calcium ion-mobilizing activity but is rapidly inactivated in serum. In this study we designed and synthesized stable KISS1R agonistic decapeptide analogs with selected substitutions at positions 47, 50, and 51. Replacement of glycine with azaglycine (azaGly) in which the α-carbon is replaced with a nitrogen atom at position 51 improved the stability of amide bonds between Phe(50)-Gly(51) and Gly(51)-Leu(52) as determined by in vitro mouse serum stability studies. Substitution for tryptophan at position 47 with other amino acids such as serine, threonine, β-(3-pyridyl)alanine, and D-tryptophan (D-Trp), produced analogs that were highly stable in mouse serum. D-Trp(47) analog 13 showed not only high metabolic stability but also excellent KISS1R agonistic activity. Other labile peptides may have increased serum stability using amino acid substitution. PMID:22975302

  18. The RARgamma selective agonist CD437 inhibits gastric cell growth through the mechanism of apoptosis.

    PubMed

    Jiang, S Y; Lin, D Y; Shyu, R Y; Reichert, U; Yeh, M Y

    1999-04-01

    Retinoids are differentiation-inducing agents that exhibit multiple functions. Their activities are mediated through interaction with nuclear retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the activities of synthetic retinoids on the growth of five gastric cancer cell lines. The effects of agonists selective for RARalpha, RARbeta and RARgamma (AM580, CD2019 and CD437, respectively) on cell growth were determined, in comparison to all-trans retinoic acid, by measuring total cellular DNA. AM580 and CD2019 had little or no effect on the growth of all five cell lines. In contrast, the RARgamma agonist CD437 inhibited cell growth up to 90-99% in both retinoic acid sensitive and resistant gastric cancer cells at a concentration of 1 microM. The growth suppression caused by CD437 was accompanied by the induction of apoptosis as judged by morphological criteria and DNA ladder formation. However, the extent of CD437-induced growth suppression was not correlated with RARgamma mRNA levels, which indicates that CD437 induces apoptosis in gastric cancer cells via an RARgamma independent pathway.

  19. In vitro susceptibility of Campylobacter jejuni to 27 antimicrobial agents and various combinations of beta-lactams with clavulanic acid or sulbactam.

    PubMed Central

    Van der Auwera, P; Scorneaux, B

    1985-01-01

    The in vitro susceptibility of human isolates of Campylobacter jejuni was investigated with 27 antibiotics and 8 combinations of beta-lactams with clavulanic acid or sulbactam. Ansamycin, the new quinolines, erythromycin, and cefpirome were the most active drugs against C. jejuni; amoxicillin, ampicillin, cefotaxime, and ceftazidime 90% of the isolates, greater than or equal to 50 mg/liter). The activity of various beta-lactams was unchanged by the addition of clavulanic acid or sulbactam. PMID:2994557

  20. Neuroprotective action of group I metabotropic glutamate receptor agonists against oxygen-glucose deprivation-induced neuronal death.

    PubMed

    Kalda, A; Kaasik, A; Vassiljev, V; Pokk, P; Zharkovsky, A

    2000-01-24

    The metabotropic glutamate receptor (mGluR) non-selective agonist (1S,3R)-1-aminocycloheptane-trans-1,3-dicarboxylic acid [(1S, 3R)ACPD] and group I selective receptor agonist 3, 5-dihydrophenylglycine (DHPG) effectively attenuated oxygen-glucose deprivation (OGD)-induced death of the cultured cerebellar granule cells. Furthermore, (1S,3R)ACPD (100 microM) reduced the number of apoptotic cells. Antiapoptotic action of (1S,3R)ACPD was prevented by the group I selective antagonist (RS)-1-aminoindan-1, 5-dicarboxylic acid (AIDA, 100 microM) and protein kinase C (PKC) inhibitor bisindolylmaleimide (BMI, 1 microM).