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(+)-Hydrastine, a potent competitive antagonist at mammalian GABAA receptors.  

PubMed Central

1. (+)-Hydrastine is a phthalide isoquinoline alkaloid, isolated from Corydalis stricta. It has the same 1S,9R configuration as the competitive GABAA receptor antagonist bicuculline and is the enantiomer of the commercially available (-)-hydrastine. 2. (+)-Hydrastine (CD50 0.16 mg kg-1, i.v.) was twice as potent as bicuculline (CD50 0.32 mg kg-1, i.v.) as a convulsant in mice. This action was stereoselective in that (+)-hydrastine was 180 times as potent as (-)-hydrastine. 3. (+)-Hydrastine was a selective antagonist at bicuculline-sensitive GABAA receptors in the guinea-pig isolated ileum. It did not influence phaclofen-sensitive GABAB receptors or acetylcholine receptors in this tissue. (+)-Hydrastine was a competitive antagonist of GABAA responses (pA2 6.5) more potent than bicuculline (pA2 6.1). 4. When tested against the binding of [3H]-muscimol to high affinity GABAA binding sites in rat brain membranes, (+)-hydrastine (IC50 2.37 microM) was 8 times more potent than bicuculline (IC50 19.7 microM). 5. As an antagonist of the activation of low affinity GABAA receptors as measured by the stimulation by GABA of [3H]-diazepam binding to rat brain membranes, (+)-hydrastine (IC50 0.4 microM) was more potent than bicuculline (IC50 2.3 microM). 6. (+)-Hydrastine, 10 nM to 1 mM, did not inhibit the binding of [3H]-(-)-baclofen to GABAB binding sites in rat brain membranes.

Huang, J. H.; Johnston, G. A.



Competitive NMDA receptor antagonists and spinal-cord ischemia.  


Ischemic neuronal death is associated with excitatory amino acid (EAA) release. Their action is mediated by N-methyl-D-aspartate (NMDA) receptors. Blockade of the receptors before the ischemic insult can decrease neuronal damage. Accordingly, we investigated the protective effect during spinal cord ischemia of two competitive antagonists, 4-(3-phosphonopropyl)-2-piperazine-carboxylic acid (CPP) and cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS). Male Sprague-Dawley rats underwent intrathecal administration of 10 microL saline, CGS, and CPP 10 mM solutions, in a randomized blinded fashion, and were subjected to balloon occlusion of the thoracic aorta. Proximal aortic pressure was lowered to a mean of 40 mm Hg by partial exsanguination. In the acute protocol, 21 rats divided in 3 groups of 7 (saline, CPP, and CGS) were used to calculate the aortic occlusion time (AOT) resulting in paraplegia in 50% of animals (P50). In the chronic study, 24 rats divided in 4 groups of 6 (saline, CPP, CGS, sham) underwent 12-min occlusion. The chronic animals were scored daily for 28 days and submitted to histology of the cord. In the acute study, the P50 of CGS (10 min 48 s) and CPP (11 min 11 s) was longer than saline (10 min 27 s). In the chronic groups, analysis of variance of neurologic (p = .66) and histologic (p = .66) scores did not disclose differences between CGS, CPP, and saline. In conclusion, blockade of NMDA receptors with CPP or CGS may afford some protection for durations of occlusion around the P50, but it is not beneficial when ischemic injury is more protracted. PMID:10801049

Follis, F; Blisard, K; Varvitsiotis, P S; Pett, S B; Temes, T; Wernly, J A


UDP Is a Competitive Antagonist at the Human P2Y14 Receptor  

PubMed Central

G protein-coupled P2Y receptors (P2Y-R) are activated by adenine and uracil nucleotides. The P2Y14 receptor (P2Y14-R) is activated by at least four naturally occurring UDP sugars, with UDP-glucose (UDP-Glc) being the most potent agonist. With the goal of identifying a competitive antagonist for the P2Y14-R, UDP was examined for antagonist activity in COS-7 cells transiently expressing the human P2Y14-R and a chimeric G? protein that couples Gi-coupled receptors to stimulation of phosphoinositide hydrolysis. UDP antagonized the agonist action of UDP-Glc, and Schild analysis confirmed that the antagonism was competitive (pKB = 7.28). Uridine 5?-O-thiodiphosphate also antagonized the human P2Y14-R (hP2Y14-R) with an apparent affinity similar to that of UDP. In contrast, no antagonist activity was observed with ADP, CDP, or GDP, and other uracil analogs also failed to exhibit antagonist activity. The antagonist activity of UDP was not observed at other hP2Y-R. In contrast to its antagonist action at the hP2Y14-R, UDP was a potent agonist (EC50 = 0.35 ?M) at the rat P2Y14-R. These results identify the first competitive antagonist of the P2Y14-R and demonstrate pharmacological differences between receptor orthologs.

Fricks, Ingrid P.; Maddileti, Savitri; Carter, Rhonda L.; Lazarowski, Eduardo R.; Nicholas, Robert A.; Jacobson, Kenneth A.; Harden, T. Kendall



PPADS is a reversible competitive antagonist of the NAADP receptor  

Microsoft Academic Search

NAADP has been shown to act as a second messenger in a wide range of systems from plants to mammalian cells. Although it had always been considered as a canonical second messenger, recent work has shown that it is also active when applied extracellularly. It has also been suggested that NAADP might have a direct action on P2 receptors, based

Richard A. Billington; Armando A. Genazzani



Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex  

SciTech Connect

The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative {sup 14}C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions.

Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr. (Department of Anatomy and Reproductive Biology, School of Medicine, University of Hawaii, Honolulu (USA))



The reaction site of a non-competitive antagonist in the delta-subunit of the nicotinic acetylcholine receptor.  


A site in the primary structure of the nicotinic acetylcholine receptor from Torpedo marmorata covalently labeled with the non-competitive antagonist [3H]triphenylmethylphosphonium (TPMP+) was localized. The label was found in position 262 of the delta-polypeptide chain. This site is specifically labeled in the presence of the agonist carbamoylcholine. Labeling is prevented by the non-competitive antagonist histrionicotoxin. Position 262, probably a serine, is located in the highly conserved membrane-spanning helix M2 (according to the predicted folding scheme of Finer-Moore and Stroud (1984). The relationship of this site to the receptor's ion channel and its regulation is discussed. PMID:3758027

Oberthür, W; Muhn, P; Baumann, H; Lottspeich, F; Wittmann-Liebold, B; Hucho, F



The reaction site of a non-competitive antagonist in the delta-subunit of the nicotinic acetylcholine receptor.  

PubMed Central

A site in the primary structure of the nicotinic acetylcholine receptor from Torpedo marmorata covalently labeled with the non-competitive antagonist [3H]triphenylmethylphosphonium (TPMP+) was localized. The label was found in position 262 of the delta-polypeptide chain. This site is specifically labeled in the presence of the agonist carbamoylcholine. Labeling is prevented by the non-competitive antagonist histrionicotoxin. Position 262, probably a serine, is located in the highly conserved membrane-spanning helix M2 (according to the predicted folding scheme of Finer-Moore and Stroud (1984). The relationship of this site to the receptor's ion channel and its regulation is discussed. Images Fig. 2.

Oberthur, W; Muhn, P; Baumann, H; Lottspeich, F; Wittmann-Liebold, B; Hucho, F



GABA{sub A} receptor open-state conformation determines non-competitive antagonist binding  

SciTech Connect

The {gamma}-aminobutyric acid (GABA) type A receptor (GABA{sub A}R) is one of the most important targets for insecticide action. The human recombinant {beta}3 homomer is the best available model for this binding site and 4-n-[{sup 3}H]propyl-4'-ethynylbicycloorthobenzoate ([{sup 3}H]EBOB) is the preferred non-competitive antagonist (NCA) radioligand. The uniquely high sensitivity of the {beta}3 homomer relative to the much-less-active but structurally very-similar {beta}1 homomer provides an ideal comparison to elucidate structural and functional features important for NCA binding. The {beta}1 and {beta}3 subunits were compared using chimeragenesis and mutagenesis and various combinations with the {alpha}1 subunit and modulators. Chimera {beta}3/{beta}1 with the {beta}3 subunit extracellular domain and the {beta}1 subunit transmembrane helices retained the high [{sup 3}H]EBOB binding level of the {beta}3 homomer while chimera {beta}1/{beta}3 with the {beta}1 subunit extracellular domain and the {beta}3 subunit transmembrane helices had low binding activity similar to the {beta}1 homomer. GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold by increasing the open probability of the channel. Addition of the {alpha}1 subunit rescued the inactive {beta}1/{beta}3 chimera close to wildtype {alpha}1{beta}1 activity. EBOB binding was significantly altered by mutations {beta}1S15'N and {beta}3N15'S compared with wildtype {beta}1 and {beta}3, respectively. However, the binding activity of {alpha}1{beta}1S15'N was insensitive to GABA and {alpha}1{beta}3N15'S was stimulated much less than wildtype {alpha}1{beta}3 by GABA. The inhibitory effect of etomidate on NCA binding was reduced more than 5-fold by the mutation {beta}3N15'S. Therefore, the NCA binding site is tightly regulated by the open-state conformation that largely determines GABA{sub A} receptor sensitivity. - Graphical Abstract: Display Omitted Research Highlights: > The {beta}1 and {beta}3 subunits were compared by chimeragenesis, mutagenesis and modulators. > Low {beta}1 NCA binding was rescued by replacing its transmembrane helices with those of {beta}3. > GABA at 3 {mu}M stimulated heteromers {alpha}1{beta}1 and {alpha}1{beta}3 binding levels more than 2-fold. > Mutation at 15' position in TM2 reduced GABA stimulation of NCA binding. > The open-state conformation largely determines GABAA receptor sensitivity to NCAs.

Chen Ligong [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States); Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Xue Ling [Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 (United States); Giacomini, Kathleen M. [Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158 (United States); Casida, John E., E-mail: [Environmental Chemistry and Toxicology Laboratory, Department of Environmental Science, Policy and Management, University of California, Berkeley, CA 94720 (United States)



Competitive antagonism by recognised 5HT 2 receptor antagonists at 5HT 1C receptors in pig choroid plexus  

Microsoft Academic Search

The effects of several antagonists, known to interact with 5-HT2 receptors (ritanserin, LY 53857, ICI 169,369, methysergide, mesulergine and ketanserin), were tested against 5-HT-stimulated production of inositol phosphate in pig choroid plexus, a 5-HT1C receptor model. These antagonists produced dextral shifts of the concentration response curve to 5-HT in a parallel manner, without depressing significantly the maximal response. The following

Inçi Sahin-Erdemli; Philippe Schoeffter; Daniel Hoyer



The cysteinyl-leukotriene receptor antagonist BAY u9773 is a competitive antagonist of leukotriene C 4 in the guinea-pig ileum  

Microsoft Academic Search

Two main classes of receptors exist for leukotrienes C4, D4 and E4, collectively named cysteinyl-leukotrienes (CysLTs). The CysLT1 receptor is blocked by currently available leukotriene antagonists, and the CysLT2 receptor is defined by the absence of selective antagonists. The contractile response to leukotriene C4 in guinea-pig ileum longitudinal muscle is resistant to CysLT1 receptor antagonists. However, the leukotriene E4 analogue

Magnus Bäck; Eva Wikström Jonsson; Sven-Erik Dahlén



Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists.  


Metabotropic glutamate receptors mGluR1 and mGluR5 stimulate phospholipase C, leading to an increased inositol trisphosphate level and to Ca(2+) release from intracellular stores. Cyclothiazide (CTZ), known as a blocker of AMPA receptor desensitization, produced a non-competitive inhibition of [Ca(2+)](i) increases induced by mGluR agonists in HEK 293 cells transfected with rat mGluR1a but had no effect on the [Ca(2+)](i) signals in cells expressing rat mGluR5a. In cells expressing mGluR1, CTZ also inhibited phosphoinositide hydrolysis, as well as cAMP accumulation and arachidonic acid release induced by mGluR1 agonists, indicating a direct inhibition of the receptor and not of a particular signal transduction system. However, CTZ failed to antagonize cAMP inhibition stimulated by rat mGluR2, -3, -4, -6, -7 and -8 receptors confirming its selectivity for mGluR1. The use of chimeric receptors with substituted N-terminal domains showed that CTZ did not interact with the N-terminal mGluR1a domain. Instead, mutation analysis revealed that CTZ interacts with the Thr-815 and Ala-818 residues, located at the 7th transmembrane domain, similarly as the mGluR1-selective antagonist CPCCOEt. In primary cultures of cerebellar granule neurons, expressing native metabotropic and ionotropic glutamate receptors, the final outcome of CTZ effects depended on its combined ability to potentiate AMPA receptors and inhibit mGluR1 receptors. PMID:17095021

Surin, Alexander; Pshenichkin, Sergey; Grajkowska, Ewa; Surina, Elena; Wroblewski, Jarda T



Potentiation of D2-dopamine receptor-mediated suppression of zif 268 by non-competitive NMDA receptor antagonists in reserpinized rats.  


Striatopallidal output neurons, which coexpress D2-dopamine receptors and NMDA receptors, are logically a potential site of interaction between corticostriatal glutamatergic input and dopaminergic systems. Recent hypotheses about the etiology of schizophrenia have implicated both excitatory amino acid and dopamine systems. The present study was designed to examine, in vivo, the interaction between D2-dopamine receptors and NMDA receptors in the regulation of the expression of the early immediate genes (IEGs), zif 268 and jun B, in striatopallidal neurons. We tested whether coadministration of NMDA antagonists interacted with the actions of the D2 agonist, quinpirole, on IEG expression following dopamine depletion with reserpine. When rats were pretreated with the non-competitive NMDA receptor antagonists, MK 801 (1 mg/kg) or PCP (20 mg/kg), together with quinpirole, the quinpirole reversal of reserpine induction of zif 268 mRNA was potentiated in all regions examined. MK 801 alone had no significant effect on reserpine induction of zif 268 mRNA. Pretreatment with the competitive NMDA receptor antagonist, CPP (5 mg/kg), did not significantly alter the dose response of zif 268 mRNA expression to quinpirole in any region. There was no significant effect of MK 801 on jun B mRNA expression, either on the response to quinpirole or when administered alone with reserpine. Our findings provide evidence of an interaction between the NMDA receptor channel system and the D2-dopamine system on a molecular level in striatopallidal neurons carrying output from the basal ganglia. PMID:9729266

Leslie, C A; Jung, A; Bennett, J P



Competitive and Glycine\\/NMDA Receptor Antagonists Attenuate Withdrawal-induced Behaviours and Increased Hippocampal Acetylcholine Efflux in Morphine-dependent Rats  

Microsoft Academic Search

The present study has examined the glycine\\/N-methyl-d-aspartate (NMDA) receptor antagonist, R-(+)-3-amino-l-hydroxypyrrolid-2-one (R-(+)-HA-966) and the competitive NMDA receptor antagonist, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755) on the behavioural syndrome and increased hippocampal acetylcholine efflux induced during morphine-withdrawal in the rat. Subcutaneous naltrexone (1 mg\\/kg) injection. 48 hr after implantation of a 75 mg morphine pellet, induced a robust withdrawal syndrome consisting of wet




The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation  

Microsoft Academic Search

Benzodiazepine discontinuation is characterized by a syndrome of increased activity and reduced seizure threshold that is similar to effects mediated by the glutamatergic system. To elucidate the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation, we administered lorazepam, the NMDA antagonist CPP, and the combination of these compounds either concomitantly or consecutively to mice via osmotic pumps and

Jonathan M. Koff; Gary A. Pritchard; David J. Greenblatt; Lawrence G. Miller



BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity  

Microsoft Academic Search

L-glutamate (Glu) activates at least eight different G protein-coupled receptors, the metabotropic glutamate (mGlu) receptors, which mostly act as regulators of synaptic transmission. These receptors consist of two domains: an extracellular one where agonists bind, and a transmembrane heptahelix region involved in G-protein activation. Although new mGlu receptor agonists and antagonists have been described, few are selective for a single

Stolle Andreas; Voerste Arnd; Brabet Isabelle; Mauler Frank; Joly C cile é; Antonicek Horst; Bockaert Jo; Pin Jean-Philippe


Mineralocorticoid receptor antagonists  

Microsoft Academic Search

With an increasingly aging population, the need for effective treatment of cardiovascular diseases (eg, heart failure, hypertension,\\u000a and ischemic heart disease) cannot be overemphasized. The vital importance of mineralocorticoid receptor antagonists for treating\\u000a cardiovascular conditions has only been appreciated in the last decade. The re-emergence of mineralocorticoid receptor antagonists\\u000a has provided clinicians with an important tool towards complete blockade of

Hari Krishnan Parthasarathy; Thomas M. MacDonald



Prostaglandins of the E series inhibit monoamine release via EP3 receptors: proof with the competitive EP3 receptor antagonist L-826,266.  


Prostaglandin E(2) (PGE(2)) and its analogue sulprostone inhibit noradrenaline and serotonin release in rodent tissues. We examined whether the receptor involved is blocked by the EP(3) antagonist L-826,266, whether such receptors also occur on central cholinergic neurones and retinal dopaminergic cells, whether PGE(2) is produced by the degradation of the endocannabinoid virodhamine and whether EP(3) receptor activation stimulates (35)S-GTPgammaS binding. Transmitter release was studied as electrically evoked tritium overflow in superfused tissues preincubated with (3)H-noradrenaline (which in the guinea pig retina labels dopaminergic cells), (3)H-serotonin or (3)H-choline. (35)S-GTPgammaS binding, a measure of G protein activation, was studied in mouse and guinea pig hippocampal membranes. L-826,266 antagonised the effect of sulprostone on noradrenaline release in the rat cortex, yielding a Schild plot-based pA(2) value of 7.56. Apparent pA(2) values in mouse cortex and rat vas deferens (noradrenaline release) and rat cortex (serotonin release) were 7.55, 7.87 and 7.67, respectively. PGE(2) did not affect acetylcholine release in rat brain and dopamine release in guinea pig retina. In seven mice tissues, noradrenaline release was inhibited by sulprostone but not affected by virodhamine. (35)S-GTPgammaS binding was not altered by sulprostone but stimulated by the cannabinoid agonist WIN 55,212-2. Prostaglandins of the E series inhibit monoamine release via EP(3) receptors at which L-826,266 is a competitive antagonist. EP(3) receptors that inhibit transmitter release are not present on central cholinergic neurones and retinal dopaminergic cells. Virodhamine is not converted to PGE(2). An EP(3) receptor model based on (35)S-GTPgammaS binding could not be identified. PMID:20012265

Günther, J; Schulte, K; Wenzel, D; Malinowska, B; Schlicker, E



Non-competitive metabotropic glutamate 1 receptor antagonists block activity of slowly adapting type I mechanoreceptor units in the rat sinus hair follicle.  


Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechanotransduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (YM-298198) had an IC(50) of 8.7 muM (95% CI 5.7 to 13.2 microM), representing the most potent known blocker of type I mechanoreceptors. The derivative 6-amino-N-cyclohexyl-3-methylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (desmethyl YM-298198) had a comparable potency. Another compound 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) had a similar depressant effect, although it was less potent with an approximate IC(50) of 100 microM. Between three and seven times the concentration of CPCCOEt and YM-298198 respectively was required to produce similar depressions in slowly adapting type II units. No depression, and some weak excitatory effects, were observed using the following ligands: the competitive mGlu1 receptor antagonist alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) (300 microM), the phosphoserine phosphatase inhibitor dl-2-amino-3-phosphonopropionic acid (dl-AP3) (2 mM), non-competitive mGlu5 receptor antagonists 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine (MTEP) (10 microM) and 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) (100 microM), the mGlu1 receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) (500 microM), and the mGlu5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) (1 mM). The results suggest that the non-competitive mGlu1 receptor antagonists are not acting at conventional mGlu1 receptors but at other binding sites, possibly those directly associated with mechanogated channels or on any of a number of indirect biochemical pathways. YM-298198 and related compounds may prove to be useful ligands to identify mechanosensitive channel proteins. The selective interference of type I units may provide further evidence that Merkel cells are mechanotransducers. Finally such compounds may deliver insights or treatments for Merkel cell carcinoma. PMID:19596050

Cahusac, P M B; Mavulati, S C



NSC23766, a Widely Used Inhibitor of Rac1 Activation, Additionally Acts as a Competitive Antagonist at Muscarinic Acetylcholine Receptors.  


Small molecules interfering with Rac1 activation are considered as potential drugs and are already studied in animal models. A widely used inhibitor without reported attenuation of RhoA activity is NSC23766 [(N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride]. We found that NSC23766 inhibits the M2 muscarinic acetylcholine receptor (M2 mAChR)-induced Rac1 activation in neonatal rat cardiac myocytes. Surprisingly, NSC27366 concomitantly suppressed the carbachol-induced RhoA activation and a M2 mAChR-induced inotropic response in isolated neonatal rat hearts requiring the activation of Rho-dependent kinases. We therefore aimed to identify the mechanisms by which NSC23766 interferes with the differentially mediated, M2 mAChR-induced responses. Interestingly, NSC23766 caused a rightward shift of the carbachol concentration response curve for the positive inotropic response without modifying carbachol efficacy. To analyze the specificity of NSC23766, we compared the carbachol and the similarly Gi??-mediated, adenosine-induced activation of Gi protein-regulated potassium channel (GIRK) channels in human atrial myocytes. Application of NSC23766 blocked the carbachol-induced K(+) current but had no effect on the adenosine-induced GIRK current. Similarly, an adenosine A1 receptor-induced positive inotropic response in neonatal rat hearts was not attenuated by NSC23766. To investigate its specificity toward the different mAChR types, we studied the carbachol-induced elevation of intracellular Ca(2+) concentrations in human embryonic kidney 293 (HEK-293) cells expressing M1, M2, or M3 mAChRs. NSC23766 caused a concentration-dependent rightward shift of the carbachol concentration response curves at all mAChRs. Thus, NSC23766 is not only an inhibitor of Rac1 activation, but it is within the same concentration range a competitive antagonist at mAChRs. Molecular docking analysis at M2 and M3 mAChR crystal structures confirmed this interpretation. PMID:23887096

Levay, Magdolna; Krobert, Kurt Allen; Wittig, Karola; Voigt, Niels; Bermudez, Marcel; Wolber, Gerhard; Dobrev, Dobromir; Levy, Finn Olav; Wieland, Thomas



Configurational Reassignment and Improved Preparation of the Competitive IL-6 Receptor Antagonist 20R,21R-Epoxyresibufogenin-3-formate  

PubMed Central

20R,21R-Epoxyresibufogenin-3-formate (1) and 20S,21S-epoxyresibufogenin-3-formate (2) were synthesized from commercial resibufogenin (3) using known procedures. The major product (1) was dextrorotatory, as was the major product from the reported synthesis of epoxyresibufogenin-3-formate; however, the literature (+)-compound was assigned the 20S,21S-configuration based on NMR data. We have now unequivocally determined, using single-crystal X-ray structure analyses of the major and minor products of the synthesis and of their derivatives, that the major product from the synthesis was (+)-20R,21R-epoxyresibufogenin-3-formate (1). Our minor synthetic product was determined to have the (-)-20S,21S-configuration (2). The (+)-20R,21R-compound 1 has been found to have high affinity for the IL-6 receptor and to act as an IL-6 antagonist. A greatly improved synthesis of 1 was achieved through oxidation of preformed resibufogenin-3-formate. This has enabled us to prepare, from the very expensive commercial resibufogenin, considerably larger quantities of 1, the only known non-peptide small molecule IL-6 antagonist.

Boos, Terrence L.; Cheng, Kejun; Greiner, Elisabeth; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.



Pharmacological analysis of calcium antagonist receptors  

SciTech Connect

This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)(/sup 3/H)desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) (/sup 3/H)desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor.

Reynolds, I.J.



The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors.  


APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve-hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC(50)=0.74 ?M), without affecting directly-elicited twitch tension up to 2.72 ?M. The compound (0.007-3.40 ?M) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 ?M, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC(50)=0.36 ?M) without significant change in the resting membrane potential of the muscle fibers up to 3.40 ?M. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (?1(2)?1??) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC(50)=0.0005 ?M), indicating a higher affinity of the compound for Torpedo (?1(2)?1??) than for the mouse (?1(2)?1??) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction. PMID:23046821

Grandi?, Marjana; Aráoz, Romulo; Molgó, Jordi; Turk, Tom; Sep?i?, Kristina; Benoit, Evelyne; Frangež, Robert



Mutation of an arginine residue in the human glycine receptor transforms ?-alanine and taurine from agonists into competitive antagonists  

Microsoft Academic Search

Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GIyR, substituting Arg271 with either Leu or Gin, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GIyR single-channel conductances to lower

Sundran Rajendra; Joseph W Lynch; Kerrie D Pierce; Chris R French; Peter H Barry; Peter R Schofield



Tachykinin NK 1 Receptor Antagonists  

Microsoft Academic Search

\\u000a This chapter is focused on the pharmacology of most relevant tachykinin NK1 receptor-selective compounds, with emphasis on the progress ofknowledge made possible by their use and on the therapeutic\\u000a perspectives of these drugs. The first peptide antagonists of SP, synthesized about 20 years ago, were hampered by poor selectivity\\u000a for NK1 receptors and other serious side effects. Since then the

R. Patacchini; C. A. Maggi


Angiotensin II receptor antagonists in arterial hypertension  

Microsoft Academic Search

Angiotensin II receptor antagonists (AT-1) represent a new group of orally active antihypertensive agents. Activation on AT-1 receptor leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone with production of thirst, and promote growth of vascular and cardiac muscle; these effects are blocked by AT-1 antagonist agents. The first chemically useful, orally active AT-1 receptor antagonist was

R Hernández-Hernández; M Velasco; MJ Armas-Hernández; MC Armas-Padilla; Rafael Hernández Hernández



The memory-facilitating effects of the competitive NMDA-receptor antagonist CGP 37849 are steroid-sensitive, whereas its memory-impairing effects are not  

Microsoft Academic Search

The retention performance of mice in a passive-avoidance task was facilitated by low doses (0.3 mg\\/kg) of the competitive NMDA-receptor blocker CGP 37849, but impaired by high doses (30 mg\\/kg). The facilitatory effect was selectively suppressed by elevation of the plasma levels of aldosterone or corticosterone, or by blockade of steroid biosynthesis or the mineralocorticoid receptors. The impairment of memory,

C. Mondadori; J. Borkowski; C. Gentsch



Proglumide analogues: potent cholecystokinin receptor antagonists.  


Proglumide [N-(benzoyl)-L-glutamic acid-1-di-n-propylamide] is a specific cholecystokinin receptor antagonist. In the present study we synthesized various analogues of proglumide and used pancreatic acini from guinea pig pancreas to examine the abilities of these analogues to function as cholecystokinin receptor antagonists. Each analogue inhibited cholecystokinin octapeptide-stimulated amylase secretion but did not stimulate amylase secretion when present alone. There was a close correlation between the ability of a particular analogue to inhibit the action of cholecystokinin on acinar cell function and its ability to inhibit binding of 125I-cholecystokinin. Structure-function studies demonstrated that neither the dipropylamide nor the benzoyl moieties are essential for inhibiting the action of cholecystokinin but that both groups are important in determining the inhibitory potency. Replacing the dipropylamide group with a hydroxyl group caused a 13-fold decrease in potency. Replacing the benzoyl moiety by an acetyl group caused a 30- to 40-fold decrease in inhibitory potency, whereas replacing the benzoyl moiety by a p-chlorophenoxyacetyl or phenoxyacetyl moiety caused a 75-fold increase in potency. Replacing both the dipropylamide moiety with a hydroxyl group and the benzoyl moiety with a phenoxyacetyl group resulted in a 5-fold decrease in inhibitory potency. Inhibition of cholecystokinin-stimulated amylase release by both the phenoxyacetyl and p-chlorophenoxyacetyl analogues was competitive in nature, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2411147

Jensen, R T; Murphy, R B; Trampota, M; Schneider, L H; Jones, S W; Howard, J M; Gardner, J D



Cocaine-taking and cocaine-seeking behaviors in rats remain stable after systemic administration of GYKI 52466, a non-competitive AMPA receptor antagonist  

PubMed Central

Given the posited role of enhanced AMPA-mediated synaptic transmission in relapse to drug seeking, we investigated whether the systemic administration of AMPA receptor antagonist GYKI 52466 inhibits cocaine-taking and cocaine-seeking behavior in rats. Rats were trained to self-administer cocaine until stable self-administration was achieved. Effects of GYKI 52466 (1, 3, or 10 mg/kg, i.v.) on cocaine self-administration were assessed. Animals were allowed to reestablish stable cocaine self-administration and were then behaviorally extinguished from drug taking. The effects of GYKI 52466 (3, 10 mg/kg, i.v.) on cocaine-induced reinstatement of drug-seeking behavior were assessed. We found that GYKI 52466 failed to inhibit cocaine-taking and cocaine-seeking in both the self-administration and reinstatement paradigms. We suggest that although AMPA receptors may be involved in cocaine reward and addiction, the AMPA receptor antagonist GYKI 52466 has low therapeutic potential for cocaine addiction treatment.

Srivastava, Ratika; Xi, Zheng-Xiong; Gardner, Eliot L.



On the simultaneous action of two competitive antagonists  

PubMed Central

1 A hypothesis is outlined predicting the conditions in which the addition of a second competitive antagonist will increase rather than reduce the response to an agonist. 2 Experiments were performed with the guinea-pig ileum as the test tissue, hexyltrimethyl ammonium as the agonist, benzilyltropine methiodide as the `slow' antagonist and pentyltriethyl ammonium as the `fast' antagonist. 3 The results are consistent with the hypothesis, if the affinity constant for hexyltrimethyl ammonium is between 2.7 and 3.7 × 104 M-1, if the dissociation time constant for the slow antagonist is greater than 10 min and if that for the fast antagonist is less than 10 seconds.

Ginsborg, B.L.; Stephenson, R.P.



V2 Receptor Antagonist; Tolvaptan  

PubMed Central

Hyponatremia is the most common electrolyte disorder in hospitalized patients. Many studies documented that it was related to increased morbidity and mortality in patients with congestive heart failure, liver cirrhosis, and neurologic diseases. Although knowledge of hyponatremia has been cumulated, the optimal management of hyponatremia remains incompletely established in clinical practice because of the diversity of underlying disease states, and its multiple causes with differing pathophysiologic mechanisms. Since vasopressin receptor antagonists have unique aquaretic effect to selectively increase electrolytes-free water excretion, clinicians could apply a more effective method to treat hyponatremia. Tolvaptan has significant evidence that it improves serum sodium levels in patients with euvolemic or hypervolemic hyponatremia related with heart failure, cirrhosis or syndrome of inappropriate anti-diuretic hormone. Tolvaptan has acceptable safety and tolerability for long-term usage in chronic hyponatremia, and the beneficial effects on serum Na+ occurred in patients with both mild and marked hyponatremia.

Yi, Joo-Hark; Shin, Hyun-Jong



Interleukin 1 receptor antagonist gene polymorphism association with lichen sclerosus  

Microsoft Academic Search

Cytokines play key roles in immune responses, inflammation and fibrosis. The balance between levels of cytokines, their receptors and specific inhibitors controls inflammatory reactions in tissues. The pathogenesis of lichen sclerosus is unknown but probably involves cytokine mediators such as interleukin 1 (IL-1) and interleukin 1 receptor antagonist (IL-1ra). The IL-1ra is a competitive inhibitor of IL-1a and IL-1ß, and

Frances E. Clay; Michael J. Cork; Joanna K. Tarlow; Alexandra I. F. Blakemore; Christine I. Harrington; Fiona Lewis; Gordon W. Duff



Synthesis of receptor antagonists of neuropeptide Y.  

PubMed Central

We report the synthesis of receptor antagonists of neuropeptide Y (NPY) by a strategy based on synthesis of mixtures of analogs and the subsequent isolation and identification of receptor antagonists from these mixtures. After screening a series of mixtures of NPY analogs by using an NPY antagonist assay, two potent receptor antagonists, designated PYX-1 and PYX-2, were isolated from an antagonist-containing mixture. Structural analysis revealed these analogs to be Ac-[3-(2,6-dichlorobenzyl)Tyr27, D-Thr32]NPY-(27-36) amide and Ac-[3-(2,6-dichlorobenzyl)Tyr27,36,D-Thr32]NPY-(27-36) amide, respectively. The receptor antagonists inhibited release of intracellular calcium elicited by NPY in human erythroleukemia cells and displaced 3H-labeled NPY from NPY receptors in rat brain membrane. The approach of screening and identifying useful analogs from synthetic mixtures may significantly reduce the time and resources previously required for development of receptor antagonists.

Tatemoto, K; Mann, M J; Shimizu, M



Tolerance to oral H 2 -receptor antagonists  

Microsoft Academic Search

The acid-inhibitory action of H2-receptor antagonists was shown to decrease after one to two weeks of dosing in healthy volunteers. This tolerance was evaluated in three randomized, placebo-controlled trials with the H2-receptor antagonists famotidine, 40 mg given after the evening meal for 28 days; ranitidine, 300 mg four times a day for seven days followed by 300 mg at night

C. H. Wilder-Smith; T. Ernst; M. Gennoni; B. Zeyen; F. Halter; H. S. Merki



Allosteric interactions between cyclothiazide and AMPA/kainate receptor antagonists.  

PubMed Central

1. Cyclothiazide blocks alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization and potentiates AMPA receptor gated currents. Interactions between cyclothiazide, and the non-competitive antagonist GYKI52466 (GYKI) and competitive antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (F) quinoxaline (NBQX) were studied at native and recombinant AMPA/kainate receptors using whole-cell recording in order to characterize the modulation by cyclothiazide of these two antagonist sites. 2. GYKI 100 microM, which is sufficient to eliminate virtually hippocampal kainate (100 microM) currents, failed to prevent access of cyclothiazide to its site of potentiation, and was unable to enhance removal of cyclothiazide potentiation. However, cyclothiazide reduced GYKI (30 microM) block from 84 +/- 8.3% to 38 +/- 12%, and slowed the onset of the block with a time course much faster than the time course for onset and offset of potentiation induced by cyclothiazide. Cyclothiazide had qualitatively similar effects upon antagonism by NBQX 1 microM. 3. Kainate activated desensitizing currents in dorsal root ganglion (DRG) neurones, which were unaffected by cyclothiazide. GYKI blocked these kainate currents with lower affinity (IC50 > 120 microM) than for hippocampal neurones (IC50 < 30 microM), and cyclothiazide did not affect GYKI antagonism. 4. Steady-state AMPA currents from homomeric GluRA-Dflip receptors in HEK 293 cells were dramatically potentiated (up to 216 fold) by cyclothiazide via reduction of desensitization. In contrast, kainate-gated currents in HEK 293 cells expressing GluR6R receptors exhibited pronounced desensitization that was unaffected by cyclothiazide. GYKI retains its inhibition at both recombinant AMPA and kainate receptors. 5. These results indicate that cyclothiazide allosterically influences two important antagonist sites on AMPA receptors. In addition, AMPA/kainate receptor subunit composition influences the affinity of GYKI for the receptor.

Yamada, K. A.; Turetsky, D. M.



The non-competitive AMPA antagonist LY 300168 (GYKI 53655) attenuates AMPA-induced hippocampal injury in neonatal rodents  

Microsoft Academic Search

In contrast with the neuroprotective efficacy of competitive and non-competitive N-methyl-d-aspartate (NMDA) antagonists versus NMDA neurotoxicity, reported neuroprotective effects of non-NMDA antagonists in limiting ?-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) toxicity have been less robust. We tested the effect of the non-competitive AMPA receptor antagonist LY 300168 (GYKI 53655; E. Lilly) (0.25 or 2.5 mg\\/kg per dose i.p. ×3 doses vs. vehicle) on

X.-H Liu; P Wang; J. D. E Barks



Therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive AMPA receptor antagonist NS1209 following status epilepticus in rats.  


Epileptogenesis, i.e., the process leading to epilepsy, is a presumed consequence of brain insults including head trauma, stroke, infections, tumors, status epilepticus (SE), and complex febrile seizures. Typically, brain insults produce morphological and functional alterations in the hippocampal formation, including neurodegeneration in CA1, CA3, and, most consistently, the dentate hilus. Most of these alterations develop gradually, over several days, after the insult, providing a therapeutic window of opportunity for neuroprotective agents in the immediate post-injury period. We have previously reported that prolonged (four weeks) treatment with the antiepileptic drug valproate (VPA) after SE prevents hippocampal damage and most of the behavioral alterations that occur after brain insult, but not the development of spontaneously occurring seizures. These data indicated that VPA, although not preventing epilepsy, might be an effective disease-modifying treatment following brain insult. The present study was designed to (1) determine the therapeutic window for the neuroprotective effect of VPA after SE; (2) compare the efficacy of different intermittent i.p. versus continuous i.v. VPA treatment protocols; and (3) compare VPA with the glutamate (AMPA) receptor antagonist NS1209. As in our previous study with VPA, SE was induced by sustained electrical stimulation of the basolateral amygdala in rats and terminated after 4 h by diazepam. In vehicle controls, >90% of the animals developed significant neurodegeneration in the dentate hilus, whereas damage in CA1 and CA3 was more variable. Hilar parvalbumin-expressing interneurons were more sensitive to the effects of seizures than somatostatin-stained hilar interneurons or hilar mossy cells. Among the various VPA treatment protocols, continuous infusion of VPA for 24 immediately following the SE was the most effective neuroprotective treatment, preventing most of the neuronal damage. Infusion with NS1209 for 24 h exhibited similar neuroprotective efficacy. These data demonstrate that short treatment after SE with either VPA or NS1209 is powerfully neuroprotective, and may be disease-modifying treatments following brain insult. PMID:21736883

Langer, Melanie; Brandt, Claudia; Zellinger, Christina; Löscher, Wolfgang



Bradykinin receptors and their antagonists  

Microsoft Academic Search

Bradykinin and related kinins act on two receptor types, named B1 and B2. Initially identified in classical bioassays, these receptors have been cloned and characterized in binding assays performed on plasma membranes of cells expressing the native or the transfected human kinin B1 or B2 receptor types. The two classification criteria recommended by Schild, namely the order of potency of

Domenico Regoli; Suzanne Nsa Allogho; Anna Rizzi; Fernand Junior Gobeil



[Endothelin receptor antagonist, phosphodiesterase inhibitor, thromboxane inhibitor].  


According to the advanced comprehension of pathophysiology of primary pulmonary hypertension (PPH), a therapeutical approach to PPH has changed recently. One of the breakthrough to the treatment of PPH is application of prostacyclin. It has been revealed that intravenous administration of prostacyclin has improved the prognosis and patient's quality of life. Another development of endothelin receptor antagonists and phosphodiesterase inhibitors have provided a novel pulmonary-specific effect. An endothelin receptor antagonist has a great inhibitory effect against pulmonary vasculature remodeling. In this regard, this regard, this receptor antagonist has superior effect to other medicines. Furthermore, a phosphodiesterase inhibitor shows a great decreasing effect on pulmonary hypertension with less effect on systemic blood pressure. These drugs will provide a great potential to the treatment of pulmonary hypertension. PMID:11411126

Kakinuma, Y; Miyauchi, T



Analysis of Apparent Noncompetitive Responses to Competitive H1Histamine Receptor Antagonists in Fluorescent Imaging Plate Reader-Based Calcium Assays  

Microsoft Academic Search

We have examined the utility of high throughput fluorescent imaging plate reader (FLIPR)-based calcium assays for pharmacological characterization of G-protein coupled receptors (GPCRs) using recombinant and native human H1-histamine receptors (H1-HR), expressed in HEK293 and HeLa S3 cells, respectively, as model systems. For stably transfected HEK293 cell lines, the potency of histamine for elevating intracellular calcium increased (pD2, 7.13 and

Thomas R. Miller; David G. Witte; Lynne M. Ireland; Chae Hee Kang; Jean M. Roch; Jeffrey N. Masters; Timothy A. Esbenshade; Arthur A. Hancock



OPC21268, an Orally Effective, Nonpeptide Vasopressin V1 Receptor Antagonist  

Microsoft Academic Search

An orally effective, nonpeptide, vasopressin V1 receptor antagonist, OPC-21268, has been identified. This compound selectively antagonized binding to the V1 subtype of the vasopressin receptor in a competitive manner. In vivo, the compound acted as a specific antagonist of arginine vasopressin (AVP)-induced vasoconstriction. After oral administration in conscious rats, the compound also antagonized pressor responses to AVP. OPC-21268 can be

Yoshitaka Yamamura; Hidenori Ogawa; Tomihiko Chihara; Kazumi Kondo; Toshiyuki Onogawa; Shigeki Nakamura; Toyoki Mori; Michiaki Tominaga; Youichi Yabuuchi



Excitatory Actions of NMDA Receptor Antagonists in Rat Entorhinal Cortex and Cultured Entorhinal Cortical Neurons  

Microsoft Academic Search

We have characterized excitatory effects of non-competitive NMDA receptor antagonists MK-801, PCP, and ketamine in the rat entorhinal cortex and in cultured primary entorhinal cortical neurons using expression of immediate early gene c-fos as an indicator. NMDA receptor antagonists produced a strong and dose-dependent increase in c-fos mRNA and protein expression confined to neurons in the layer III of the

Jussi Väisänen; Anni-Maija Lindén; Merja Lakso; Garry Wong; Uwe Heinemann; Eero Castrén



Non-selectivity of new bradykinin antagonists for B1 receptors.  


Two new B1 receptor antagonists, [Hyp3,Thi5,DTic7,Oic8]desArg9-BK and DArg[Hyp3,Thi5,DTic7,Oic8]desArg9-BK were tested in vitro on the rabbit jugular vein and the guinea pig ileum (preparations containing B2 receptors) and on the rabbit aorta (preparation containing B1 receptors) for pharmacological characterization. The results indicate that both compounds are antagonists on both B1 and B2 receptors, are competitive and discriminate between B2A and B2B receptor subtypes. PMID:1326066

Rhaleb, N E; Gobeil, F; Regoli, D



Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands  

Microsoft Academic Search

Interactions between pro-opiomelanocortin (POMC)- derived peptides, agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4-R) are central to energy homeostasis. In this study we have undertaken compre- hensive pharmacological analysis of these interactions using a CHOK1 cell line stably transfected with human MC4-R. Our main objectives were (1) to compare the relative affinities and potencies of POMC-derived pep- tides endogenously secreted

L E Pritchard; D Armstrong; N Davies; R L Oliver; C A Schmitz; J C Brennand; G F Wilkinson



MCH receptor peptide agonists and antagonists.  


Melanin-concentrating hormone (MCH) is an important neuropeptide hormone involved in multiple physiological processes. Peptide derivatives of MCH have been developed as tools to aid research including potent radioligands, receptor selective agonists, and potent antagonists. These tools have been used to further understand the role of MCH in physiology, primarily in rodents. However, the tools could also help elucidate the role for MCHR1 and MCHR2 in mediating MCH signaling in higher species. PMID:19397944

MacNeil, Douglas J; Bednarek, Maria A



Neuroprotective potential of ionotropic glutamate receptor antagonists  

Microsoft Academic Search

From the therapeutic point of view, the real challenge is not only to improve the symptoms, but to interfere with the pathomechanism\\u000a of the disease. That is why a considerable interest has recently been devoted to developing glutamate receptors antagonists\\u000a (mainly of the NMDA type) for acute and chronic neurodegeneration. Developing such a treatment that slows down the progression\\u000a of

Wojciech Danysz; Chris G. Parsons



NK-1 receptor antagonists: a new generation of anticancer drugs.  


After binding to the neurokinin-1 (NK-1) receptor, substance P (SP) induces tumor cell proliferation, angiogenesis, and the migration of tumor cells for invasion and metastasis. After binding to NK-1 receptors, NK-1 receptor antagonists inhibit tumor cell proliferation, angiogenesis and the migration of tumor cells. These antagonists are broad-spectrum antitumor drugs. In addition, in the host they display beneficial effects: anxiolytic, antiemetic, neuroprotector, nephroprotector, hepatoprotector, antiinflammatory and analgesic. In combination therapy with classic cytostatics, NK-1 receptor antagonists have synergic effects and minimize the side-effects of these classic drugs. Thus, NK-1 receptor antagonists could offer a new and promising generation of anticancer drugs. PMID:22512565

Munoz, M; Covenas, R



Development of selective agonists and antagonists of P2Y receptors  

PubMed Central

Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of many other members of group A G protein-coupled receptors, detailed qualitative and quantitative structure–activity relationships (SARs) were recently constructed for several of the subtypes. Agonists selective for P2Y1, P2Y2, and P2Y6 receptors and nucleotide antagonists selective for P2Y1 and P2Y12 receptors are now known. Selective nonnucleotide antagonists were reported for P2Y1, P2Y2, P2Y6, P2Y11, P2Y12, and P2Y13 receptors. At the P2Y1 and P2Y12 receptors, nucleotide agonists (5?-diphosphate derivatives) were converted into antagonists of nanomolar affinity by altering the phosphate moieties, with a focus particularly on the ribose conformation and substitution pattern. Nucleotide analogues with conformationally constrained ribose-like rings were introduced as selective receptor probes for P2Y1 and P2Y6 receptors. Screening chemically diverse compound libraries has begun to yield new lead compounds for the development of P2Y receptor antagonists, such as competitive P2Y12 receptor antagonists with antithrombotic activity. Selective agonists for the P2Y4, P2Y11, and P2Y13 receptors and selective antagonists for P2Y4 and P2Y14 receptors have not yet been identified. The P2Y14 receptor appears to be the most restrictive of the class with respect to modification of the nucleobase, ribose, and phosphate moieties. The continuing process of ligand design for the P2Y receptors will aid in the identification of new clinical targets.

Ivanov, Andrei A.; de Castro, Sonia; Harden, T. Kendall; Ko, Hyojin



Pharmacology of eprosartan, an angiotensin II receptor antagonist: Exploring hypotheses from clinical data  

Microsoft Academic Search

Selective blockade of the angiotensin II AT1 receptor represents a novel mechanism for interrupting the renin-angiotensin system without altering the potential benefits of AT2 receptor stimulation. This selective inhibition produces none of the disadvantages associated with reduced bradykinin metabolism and angiotensin II generated by non–angiotensin-converting enzyme pathways. Eprosartan is a potent (1.4 nmol\\/L) AT1 receptor antagonist that competitively blocks angiotensin

David P. Brooks; Eliot H. Ohlstein; Robert R. Ruffolo



A High-Throughput Ligand Competition Binding Assay for the Androgen Receptor and other Nuclear Receptors  

PubMed Central

Standardized, automated ligand binding assays facilitate evaluation of endocrine activities of environmental chemicals and identification of antagonists of nuclear receptor ligands. Many current assays rely on fluorescently labeled ligands which are significantly different from the native ligands. We describe a radiolabeled ligand competition scintillation proximity assay (SPA) for the androgen receptor (AR) using Ni-coated 384-well FlashPlates® and liganded AR-LBD protein. This highly reproducible, low cost assay is well-suited for automated HTS. Additionally, we show that this assay can be adapted to measure ligand affinities for other nuclear receptors (peroxisome proliferation activated receptor ?, thyroid receptors ? and ?).

Feau, Clementine; Arnold, Leggy A.; Kosinski, Aaron; Guy, R. Kiplin



Pomolic acid, triterpenoid isolated from Licania pittieri, as competitive antagonist of ADP-induced aggregation of human platelets.  


Pomolic acid (PA), triterpenoid isolated from Licania pittieri, has previously shown a potent ability to inhibit adenosine diphosphate (ADP)- and epinephrine-induced human platelet aggregation. To investigate whether PA could be an antagonist of ADP-activated receptors of human platelets (P2Y(1) and P2Y(12)), pharmacological studies were conducted to examining its ability to modulate the platelet shape change induced by a selective P2Y(1) receptor agonist MRS2365 and also the nature of its possible interaction with ADP receptors by analyzing the characteristics of log concentration-response curves of ADP constructed in the absence and in the presence of fixed concentrations of PA, using in vitro platelet aggregation assays. PA did not interfere with the activation of P2Y(1) receptor by MRS2365 to induce platelet shape change and displayed a competitive antagonism of ADP-induced platelet aggregation, which most probably involves competition for a single binding site in platelets. The estimated equilibrium dissociate constant (K(b)) of PA as ADP receptor antagonist was 15.4±0.06nM. Together, these findings give indirect evidence for the idea that PA could be a potent competitive antagonist of P2Y(12) receptor, and open the possibility to consider it as new member of the non-nucleotide generation of antiplatelet drugs. PMID:22402243

Alvarado-Castillo, Claudia; Estrada, Omar; Carvajal, Edilmo



Bicycloorthocarboxylate convulsants. Potent GABAA receptor antagonists.  


4-t-Butyl-1-(4-bromophenyl)-bicycloorthocarboxylate antagonizes gamma-aminobutyric acid (GABA)-mediated relaxation at a functional insect nerve-muscle synapse, mimicking the action of picrotoxinin, suggesting that it causes GABA antagonism through blockade of the chloride ionophore. It is also a potent GABAA receptor antagonist, inhibiting the binding of [35S]t-butyl-bicyclophosphorothionate ([35S]TBPS) to EDTA/water-dialyzed human brain P2 membranes. Structure-activity relationships of 74 1,4-bis-substituted bicycloorthocarboxylates, mostly new compounds, reveal that for high potency as a GABAA receptor antagonist the optimal 4-substituent is a C4 to C6 branched chain alkyl or cycloalkyl group (e.g., t-butyl, s-butyl, or cyclohexyl) and the optimal 1-substituent is a phenyl moiety with one or more electron-withdrawing groups (e.g., 4-cyano, 4-bromo, 4-chloro, 3,4-dichloro, or pentafluoro). Bicycloorthocarboxylate inhibitors of [35S]TBPS binding with IC50 values of 5-10 nM exceed by several-fold the potency of any GABAA receptor antagonist previously reported. The 4-t-butyl-1-(4-azidophenyl) analog, synthesized as a candidate photoaffinity label, gives an IC50 of 315 nM. The potency of bicycloorthocarboxylates for decreasing [35S]TBPS binding generally correlates with their toxicity, i.e., compounds without inhibitory activity in this brain receptor assay are of low toxicity on intraperitoneal administration to mice, and the analogs most potent as inhibitors are generally those most toxic to mice (e.g., IC50 of 5 nM and LD50 of 0.06 mg/kg for 4-t-butyl-1-(4-cyanophenyl)-bicycloorthocarboxylate). The effects of phenyl substituents on the potency of the orthobenzoates as GABAA receptor antagonists are similar to those on toxicity. In contrast to the 1-substituted phenyl compounds, 4-t-butyl-1-ethynyl-bicycloorthocarboxylate and its 4-i-propyl analog are very toxic (LD50 0.4-2 mg/kg) but have only moderate inhibitory potency (IC50 480-2900 nM), a pattern noted for many 1-alkyl-bicycloorthocarboxylates, suggesting that even within this series there may be different types of receptor-inhibitor interactions. 1-(4-Chlorophenyl)-4-cyclohexyl-bicycloorthocarboxylate is particularly sensitive to oxidative detoxification based on its 10-fold synergism of toxicity by piperonyl butoxide and marked potency loss in a coupled [35S]TBPS receptor/microsomal oxidase assay. Some benzodiazepines and phenobarbital protect against poisoning by 1-(4-bromophenyl)- and 1-ethynyl-4-t-butyl-bicycloorthocarboxylates and their 1-(4-bromophenyl)-4-cyclohexyl analog.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2993847

Casida, J E; Palmer, C J; Cole, L M



Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease.  


During a program to investigate the biochemical basis of side effects associated with the antimalarial drug mefloquine, the authors made the unexpected discovery that the (-)-(R,S)-enantiomer of the drug is a potent adenosine A2A receptor antagonist. Although the compound was ineffective in in vivo animal models of central adenosine receptor function, it provided a unique nonxanthine adenosine A2A receptor antagonist lead structure and encouraged the initiation of a medicinal chemistry program to develop novel adenosine A2A antagonists for the management of Parkinson's disease (PD). The authors have synthesized and screened more than 2,000 chemically diverse and novel adenosine A(2A antagonists. Early examples from two distinct chemical series are the thieno[3,2-dy]pyrimidine VER-6623 and the purine compounds VER-6947 and VER-7835, which have high affinity at adenosine A2A receptors (K(i) values 1.4, 1.1, and 1.7 nmol/L, respectively) and act as competitive antagonists. In particular, VER-6947 and VER-7835 demonstrate potent in vivo activity reversing the locomotor deficit caused by the D2 receptor antagonist haloperidol, with minimum effective doses comparable with that of KW6002 (0.3 to 1 mg/kg). In conclusion, the authors have discovered potent, selective, and in vivo active nonxanthine adenosine A2A antagonists that have considerable promise as a new therapy for PD. PMID:14663021

Weiss, S M; Benwell, K; Cliffe, I A; Gillespie, R J; Knight, A R; Lerpiniere, J; Misra, A; Pratt, R M; Revell, D; Upton, R; Dourish, C T



VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist.  


Vasopressin type 2 receptor (V2R) exhibits mostly important properties for hydroosmotic equilibrium and, to a lesser extent, on vasomotricity. Drugs currently acting on this receptor are analogs of the natural neuropeptide, arginine vasopressin (AVP), and hence are competitive ligands. Peptides that reproduce specific sequences of a given receptor have lately been reported to interfere with its action, and if such molecules arise from regions remote from the binding site they would be anticipated to exhibit noncompetitive antagonism, but this has yet to be shown for V2R. Six peptides reproducing juxtamembranous regions of V2R were designed and screened; the most effective peptide, cravky (labeled VRQ397), was characterized. VRQ397 was potent (IC(50) = 0.69 +/- 0.25 nM) and fully effective in inhibiting V2R-dependent physiological function, specifically desmopressin-L-desamino-8-arginine-vasopressin (DDAVP)-induced cremasteric vasorelaxation; this physiological functional assay was utilized to avoid overlooking interference of specific signaling events. A dose-response profile revealed a noncompetitive property of VRQ397; correspondingly, VRQ397 bound specifically to V2R-expressing cells could not displace its natural ligand, AVP, but modulated AVP binding kinetics (dissociation rate). Specificity of VRQ397 was further confirmed by its inability to bind to homologous V1 and oxytocin receptors and its inefficacy to alter responses to stimulation of these receptors. VRQ397 exhibited pharmacological permissiveness on V2R-induced signals, as it inhibited DDAVP-induced PGI(2) generation but not that of cAMP or recruitment of beta-arrestin2. Consistent with in vitro and ex vivo effects as a V2R antagonist, VRQ397 displayed anticipated in vivo aquaretic efficacy. We hereby describe the discovery of a first potent noncompetitive antagonist of V2R, which exhibits functional selectivity, in line with properties of a negative allosteric modulator. PMID:19641130

Rihakova, L; Quiniou, C; Hamdan, F F; Kaul, R; Brault, S; Hou, X; Lahaie, I; Sapieha, P; Hamel, D; Shao, Z; Gobeil, F; Hardy, P; Joyal, J-S; Nedev, H; Duhamel, F; Beauregard, K; Heveker, N; Saragovi, H U; Guillon, G; Bouvier, M; Lubell, W D; Chemtob, S



In silico discovery of androgen receptor antagonists with activity in castration resistant prostate cancer.  


Previously available androgen receptor (AR) antagonists (bicalutamide, flutamide, and nilutamide) have limited activity against AR in prostate cancers that relapse after castration [castration resistant prostate cancer (CRPC)]. However, recent AR competitive antagonists such as MDV3100, generated through chemical modifications to the current AR ligands, appear to have increased activity in CRPC and have novel mechanisms of action. Using pharmacophore models and a refined homology model of the antagonist-liganded AR ligand binding domain, we carried out in silico screens of small molecule libraries and report here on the identification of a series of structurally distinct nonsteroidal small molecule competitive AR antagonists. Despite their unique chemical architectures, compounds representing each of six chemotypes functioned in vitro as pure AR antagonists. Moreover, similarly to MDV3100 and in contrast to previous AR antagonists, these compounds all prevented AR binding to chromatin, consistent with each of the six chemotypes stabilizing a similar AR antagonist conformation. Additional studies with the lead chemotype (chemotype A) showed enhanced AR protein degradation, which was dependent on helix 12 in the AR ligand binding domain. Significantly, chemotype A compounds functioned as AR antagonists in vivo in normal male mice and suppressed AR activity and tumor cell proliferation in human CRPC xenografts. These data indicate that certain ligand-induced structural alterations in the AR ligand binding domain may both impair AR chromatin binding and enhance AR degradation and support continued efforts to develop AR antagonists with unique mechanisms of action and efficacy in CRPC. PMID:23023563

Shen, Howard C; Shanmugasundaram, Kumaran; Simon, Nicholas I; Cai, Changmeng; Wang, Hongyun; Chen, Sen; Balk, Steven P; Rigby, Alan C




PubMed Central

We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acutephase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.




2-Aminomethyl piperidines as novel urotensin-II receptor antagonists.  


A series of 2-aminomethyl piperidines has been discovered as novel urotensin-II receptor antagonists. The synthesis, initial structure-activity relationships, and optimization of the initial hit that resulted in the identification of potent, cross-species active, and functional urotensin-II receptor antagonists such as 1a and 11a are described. PMID:18420409

Jin, Jian; Wang, Yonghui; Wang, Feng; Shi, Dongchuan; Erhard, Karl F; Wu, Zining; Guida, Brian F; Lawrence, Sarah K; Behm, David J; Disa, Jyoti; Vaidya, Kalindi S; Evans, Christopher; McMillan, Lynette J; Rivero, Ralph A; Neeb, Michael J; Douglas, Stephen A



Aldosterone receptor antagonists: current perspectives and therapies  

PubMed Central

Aldosterone is a downstream effector of angiotensin II in the renin–angiotensin–aldosterone system and binds to the mineralocorticoid receptor. The classical view of aldosterone primarily acting at the level of the kidneys to regulate plasma potassium and intravascular volume status is being supplemented by evidence of new “off-target” effects of aldosterone in other organ systems. The genomic effects of aldosterone are well known, but there is also evidence for non-genomic effects and these recently identified effects of aldosterone have required a revision in the traditional view of aldosterone’s role in human health and disease. The aim of this article is to review the biological action of aldosterone and the mineralocorticoid receptor leading to subsequent physiologic and pathophysiologic effects involving the vasculature, central nervous system, heart, and kidneys. Furthermore, we outline current evidence evaluating the use of mineralocorticoid receptor antagonists in the treatment of primary aldosteronism, primary hypertension, resistant hypertension, obstructive sleep apnea, heart failure, and chronic kidney disease.

Guichard, Jason L; Clark, Donald; Calhoun, David A; Ahmed, Mustafa I



LPA receptor agonists and antagonists (WO2010051053)  

PubMed Central

Summary Lysophosphatidic acid (LPA) is a bioactive lipid involved in signaling pathways that result in cell survival, proliferation, migration, and invasion. These cellular responses are a critical element of both normal development as well as pathophysiology. In particular, disregulated LPA production and function have been linked with cancer and cardiovascular disease. RxBio, Inc., have generated several series of LPA analogs with varied agonist/antagonist function at the LPA1–3 G protein-coupled receptor targets of LPA signaling. These analogs are simplified relative to LPA, through deletion of the glycerol moiety linking the LPA phosphate and fatty acid groups. One of the example compounds was shown to protect intestinal crypt cells from radiation-induced apoptosis in mice when whole-body irradiation occurred two hours after oral dosing.

Parrill, Abby L.



Antagonists show GTP-sensitive high-affinity binding to the sigma-1 receptor  

PubMed Central

BACKGROUND AND PURPOSE Sigma-1 receptors are atypical receptors with potentially two transmembrane domains. Antagonists require doses significantly higher than their published affinities to have biological effects. We have reassessed the binding characteristics of these ligands and found antagonists bind to high- and low-affinity states not distinguished by agonists. EXPERIMENTAL APPROACH The affinities of sigma-1 receptor ligands was assessed using radioligand saturation and competition binding of [3H]-(+)-pentazocine to permeabilized MDA-MB-468 cells. This was compared with the effect of ligands on metabolic activity using an MTS-based assay and calcium signalling using cells loaded with the calcium dye, Fura-2. KEY RESULTS Sigma-1 receptor antagonists, but not agonists, show GTP- and suramin-sensitive high-affinity binding. Functional responses (calcium signalling and metabolic activity), while associated with sigma-1 receptor binding, required binding to an unidentified, low-affinity target. CONCLUSIONS AND IMPLICATIONS Sigma-1 receptors are coupled to G proteins. This interaction is only observed when analysing antagonist binding. The identity of the G protein remains to be resolved. The concept of agonist and antagonist at the sigma-1 receptor needs to be revisited.

Brimson, JM; Brown, CA; Safrany, ST



Evidence for low brain penetration by the H1-receptor antagonist temelastine (SK&F 93944).  


Competition by the potent selective H1-receptor antagonist temelastine (SK & F 93944) with [3H]mepyramine binding to mouse cortex H1-receptors has been measured in vitro and vivo. The data were compared with that obtained using the classical H1-receptor antagonists mepyramine and promethazine and indicated that temelastine has relatively low ability to penetrate the blood-brain barrier compared with the latter two compounds. These studies also revealed that temelastine has relatively low affinity for mouse cortex H1-receptors compared with its affinity for H1-receptors in guinea-pig ileum and cortex, suggesting that it may be a useful compound with which to investigate potential H1-receptor tissue and species-related differences. PMID:2881790

Calcutt, C R; Ganellin, C R; Jackson, B; Leigh, B K; Owen, D A; Smith, I R



Adenosine receptor subtype-selective antagonists in inflammation and hyperalgesia  

Microsoft Academic Search

In this study, we examined the effects of systemic and local administration of the subtype-selective adenosine receptor antagonists\\u000a PSB-36, PSB-1115, MSX-3, and PSB-10 on inflammation and inflammatory hyperalgesia. Pharmacological blockade of adenosine receptor\\u000a subtypes after systemic application of antagonists generally led to a decreased edema formation after formalin injection and,\\u000a with the exception of A3 receptor antagonism, also after the

Andras Bilkei-Gorzo; Osama M. Abo-Salem; Alaa M. Hayallah; Kerstin Michel; Christa E. Müller; Andreas Zimmer



Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists.  


Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS. PMID:23098108

Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Seltzman, Herbert; Mathews, James; Snyder, Rodney; Fennell, Tim; Maitra, Rangan



Adenosine A1 receptor antagonists in clinical research and development  

Microsoft Academic Search

Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and\\/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase

Berthold Hocher



Bronchodilator effects of the H1 receptor antagonist--clemastine  

Microsoft Academic Search

We investigated the specific H1 receptor antagonist, clemastine, in 15 children with asthma. In the respiratory unit, clemastine was an effective bronchodilator but in a clinical trial we could not show any significant benefit compared with placebo.

R L Henry; I G Hodges; A D Milner; G M Stokes



Does H 2 receptor antagonist-resistant ulcer exist?  

Microsoft Academic Search

Summary  Recently the term H2 receptor antagonist-resistant (H2RA-resistant) ulcer has been used increasingly commonly, instead of the conventional term of intractable ulcer, to designate\\u000a an ulcer which does not respond to treatment with an H2 receptor antagonist (H2RA). However, many authors report that an H2RA resistant ulcer can be cured by increasing the dosage of H2RA, or using another H2RA. In

Keiichi Kawai



Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents — preclinical studies  

Microsoft Academic Search

Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-d-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatogolical antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum\\/brain levels, and their potency as NMDA receptor antagonists. In the

W. Danysz; C. G. Parsons; J. Kornhuber; W. J. Schmidt; G. Quack



[Angiotensin1-receptor antagonist losartan. Part I. Basic clinical pharmacology].  


This is the initial part in a series of papers dealing with various aspects of clinical pharmacology of the first AT(1)-receptor antagonist losartan and its therapeutic use in hypertension, diabetic nephropathy, chronic heart failure, and acute phase of myocardial infarction. Mechanisms of action, pharmacological effects of losartan and other AT(1)-receptor antagonists, as well as data on pharmacokinetics of losartan, its long term tolerability and safety are reviewed in this communication. PMID:12891291

Sidorenko, B A; Preobrazhenski?, D V; Stetsenko, T M; Malysheva, N V; Tsurko, V V; Tarykina, E V



Deficiency of Interleukin-1 Receptor Antagonist Responsive to Anakinra.  


? We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy. PMID:22471702

Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael



Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine  

PubMed Central

ELIC, the pentameric ligand-gated ion channel from Erwinia chrysanthemi, is a prototype for Cys-loop receptors. Here we show that acetylcholine is a competitive antagonist for ELIC. We determine the acetylcholine–ELIC cocrystal structure to a 2.9-Å resolution and find that acetylcholine binding to an aromatic cage at the subunit interface induces a significant contraction of loop C and other structural rearrangements in the extracellular domain. The side chain of the pore-lining residue F247 reorients and the pore size consequently enlarges, but the channel remains closed. We attribute the inability of acetylcholine to activate ELIC primarily to weak cation-? and electrostatic interactions in the pocket, because an acetylcholine derivative with a simple quaternary-to-tertiary ammonium substitution activates the channel. This study presents a compelling case for understanding the structural underpinning of the functional relationship between agonism and competitive antagonism in the Cys-loop receptors, providing a new framework for developing novel therapeutic drugs.

Pan, Jianjun; Chen, Qiang; Willenbring, Dan; Yoshida, Ken; Tillman, Tommy; Kashlan, Ossama B.; Cohen, Aina; Kong, Xiang-Peng; Xu, Yan; Tang, Pei



Effects of competitive N-methyl-D-aspartate antagonists on midbrain dopamine neurons: an electrophysiological and behavioral comparison to phencyclidine.  


Electrophysiological and behavioral methods were used to evaluate and compare the effects of the competitive N-methyl-D-aspartate (NMDA) receptor blocker, NPC 12626, with the non-competitive NMDA antagonist, phencyclidine (PCP), on the activity of mesolimbic dopamine neurons. NPC 12626 (50 mg/kg, i.p.) produced a degree of locomotor hyperactivity comparable to that seen with PCP (5 mg/kg). However, 6-hydroxydopamine lesions of the nucleus accumbens blocked the PCP-induced hyperactivity but not the behavioral activation evoked by NPC 12626. Single-unit extracellular recordings from ventral tegmental A10 dopamine neurons also found marked differences between the competitive and non-competitive NMDA antagonists. Intravenous injections of NPC 12626 and CGS 19755 in doses up to 60 mg/kg failed to change A10 activity. This was in contrast to the striking bimodal dose-dependent increase-decrease in firing rate elicited by PCP. The absence of an effect of NPC 12626 on A10 neurons was not evidently related to a lack of access to central sites since NPC pretreatment (40 mg/kg, i.v.) completely antagonized the neurotoxicity caused by intrastriatal injection of quinolinic acid, an NMDA agonist, but not that caused by the non-NMDA compound, kainic acid. Thus, competitive NMDA antagonists do not share PCP's properties of activating mesolimbic dopaminergic systems, and as such they may be devoid of the potent psychotomimetic effects or the abuse liability associated with non-competitive NMDA receptor blockers such as PCP. PMID:1836840

French, E D; Ferkany, J; Abreu, M; Levenson, S



Structural features of various proglumide-related cholecystokinin receptor antagonists.  


Thirteen proglumide derivatives that varied in the length of the di-n-alkyl group and in the substitutions on the benzoyl moiety were tested for their ability to interact with guinea pig pancreatic cholecystokinin (CCK) receptors. Each derivative was more potent than proglumide. There was a close correlation between their abilities to inhibit CCK-stimulated amylase release and to inhibit binding of 125I-CCK. For the di-n-alkyl derivatives the relative potency was n-pentyl greater than n-hexyl greater than n-butyl greater than n-propyl. For the benzoyl moiety, adding two electron-withdrawing groups increased potency more than adding a single electron-withdrawing group or adding electron-donating groups. The 3,4-dichloro-di-n-pentyl derivative of proglumide was 1,300 times more potent than proglumide, and its action was specific, competitive, and it functioned as a CCK receptor antagonist in rat, mouse, and guinea pig pancreas. For all proglumide derivatives there was a good correlation (r = 0.84, P less than 0.001) between their abilities to inhibit CCK-stimulated amylase release and that previously reported for their abilities to inhibit CCK-induced gallbladder contraction. However, certain proglumide derivatives had a much higher affinity for the pancreatic CCK receptor than for the CCK receptor mediating gallbladder contraction. For other proglumide derivatives the pattern was reversed. These results demonstrate that both the di-n-alkyl group and the substitution on the benzoyl moiety of proglumide are equally important determinants of affinity and that derivatives such as the di-n-pentyl 3,4-dichloro analogue can be produced that are 1,300 times more potent than proglumide.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2431626

Jensen, R T; Zhou, Z C; Murphy, R B; Jones, S W; Setnikar, I; Rovati, L A; Gardner, J D



The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats  

Microsoft Academic Search

It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar

Eliza Koros; Holger Rosenbrock; Gerald Birk; Carmen Weiss; Frank Sams-Dodd



Biochemical and Pharmacological Profile of a Potent and Selective Endothelin B-Receptor Antagonist, BQ-788  

Microsoft Academic Search

We describe the characteristics of a potent and selective endothelin (ET) B-receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1 -methoxycarbonyltryptophanyl-D-norleucine]. In vitro, this compound potently and competitively inhibits 125I-labeled endothelin 1 (ET-1) binding to ET_B receptors on human Girardi heart cells (IC50, 1.2 nM) but only poorly inhibits the binding to ET_A receptors on human neuroblastoma cell line SK-N-MC cells (IC50, 1300 nM). In

Kiyofumi Ishikawa; Masaki Ihara; Kazuhito Noguchi; Toshiaki Mase; Nobuyuki Mino; Toshihiko Saeki; Takahiro Fukuroda; Takehiro Fukami; Satoshi Ozaki; Toshio Nagase; Masaru Nishikibe; Mitsuo Yano



NK-1 receptor antagonists: a new paradigm in pharmacological therapy.  


The neuropeptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems and it is known that after binding to the neurokinin-1 (NK-1) receptors, SP regulates many biological functions in the central nervous system such as emotional behaviour, stress, depression, anxiety, emesis, migraine, alcohol addiction and neurodegeneration. SP has been also implicated in pain, inflammation, hepatotoxicity and in virus proliferation, and it plays an important role in cancer (e.g., tumour cell proliferation, angiogenesis, and the migration of tumour cells for invasion and metastasis). By contrast, it is known that after binding to NK-1 receptors, NK-1 receptor antagonists specifically inhibit the above-mentioned biological functions mediated by SP. Thus, these antagonists exert an anxyolitic, antidepressant, antiemetic, antimigraine, antialcohol addiction or neuroprotector effect in the central nervous system, and they play a role in analgesic, antiinflammatory, hepatoprotector processes and in antivirus proliferation. Regarding cancer, NK-1 receptor antagonists exert an antitumour action (inducing tumour cell death by apoptosis), and induce antiangiogenesis and inhibit the migration of tumour cells. It is also known that NK-1 receptors have a widespread distribution and that they are overexpressed in tumour cells. Thus, NK-1 receptor antagonists are molecularly targeted agents. In general, current drugs have a single therapeutic effect, although less commonly they may exert several. However, the data reported above indicate that NK-1 receptor antagonists are promising drugs, exerting many therapeutic effects (the action of such antagonists is dose-dependent and, depending on the concentration, has more positive effects). In this review, we update the multiple therapeutic effects exerted by NK-1 receptor antagonists. PMID:21466470

Muñoz, M; Coveñas, R



Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein  

Microsoft Academic Search

A human myelomonocytic cell line, U937, produced an interleukin-1 (IL-1) receptor antagonist protein (IRAP) which was purified and partially sequenced. A complementary DNA coding for IRAP was cloned and sequenced. The mature translation product of the cDNA has been expressed in Escherichia coli and was an active competitive inhibitor of the binding of IL-1 to the T-cell\\/fibroblast form of the

D. B. Carter; M. R. Deibel; C. J. Dunn; C.-S. C. Tomich; A. L. Laborde; J. L. Slightom; A. E. Berger; M. J. Bienkowski; F. F. Sun; R. N. McEwan; P. K. W. Harris; A. W. Yem; G. A. Waszak; J. G. Chosay; L. C. Sieu; M. M. Hardee; H. A. Zurcher-Neely; I. M. Reardon; R. L. Heinrikson; S. E. Truesdell; J. A. Shelly; T. E. Eessalu; B. M. Taylor; D. E. Tracey



Aminotriarylmethane Dyes Are High-Affinity Noncompetitive Antagonists of the Nicotinic Acetylcholine Receptor  

Microsoft Academic Search

A series of aminotriarylmethane dyes were examined for bind- ing to the nicotinic acetylcholine receptor (AChR) from Torpedo californica. Several compounds were found to bind to the non- competitive antagonist site of the AChR as demonstrated by inhibition of (3H)phencyclidine binding; apparent KD values ranged from 50 nM to .100 mM. One dye with high affinity, crystal violet, revealed a



Tamoxifen resistant breast cancer: coregulators determine the direction of transcription by antagonist-occupied steroid receptors  

Microsoft Academic Search

Pharmacological antagonists of steroid receptor action had been thought to exert their effects by a passive mechanism driven principally by the ability of the antagonist to compete with agonist for the ligand binding site. However, recent analyses of antagonist-occupied receptor function suggest a more complex picture. Antagonists can be subdivided into two groups, type I, or pure antagonists, and type

Glenn S Takimoto; J. Dinny Graham; Twila A Jackson; Lin Tung; Roger L Powell; Lawrence D Horwitz; Kathryn B Horwitz



Discovery of aminobenzyloxyarylamides as ? opioid receptor selective antagonists: application to preclinical development of a ? opioid receptor antagonist receptor occupancy tracer.  


Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for ? opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K(i) = 0.565 nM for ? opioid receptor binding while having a K(i) = 35.8 nM for ? opioid receptors and a K(i) = 211 nM for ? opioid receptor binding. Compound 25 was also a potent antagonist of ? opioid receptors when tested in vitro using a [(35)S]-guanosine 5'O-[3-thiotriphosphate] ([(35)S]GTP-?-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake. PMID:21958337

Mitch, Charles H; Quimby, Steven J; Diaz, Nuria; Pedregal, Concepcion; de la Torre, Marta G; Jimenez, Alma; Shi, Qing; Canada, Emily J; Kahl, Steven D; Statnick, Michael A; McKinzie, David L; Benesh, Dana R; Rash, Karen S; Barth, Vanessa N



Antidiuretic Effects of the Endothelin Receptor Antagonist Avosentan  

PubMed Central

Several clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypothesized that avosentan which was described as a predominant ETA receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ETB receptors may occur. Incremental doses of the predominant ETA receptor antagonist SPP301 (0.003; 0.03; 3?mg/kg) were administered intravenously to anesthetized Sprague-Dawley rats undergoing saline diuresis. Diuresis, glomerular filtration rate, and blood pressure (BP) were monitored. SPP301 decreased urine output (5.6; 34.8; 58.8% decrease from vehicle) and fractional excretion of water (5.7; 31.7; 56.4% decrease from vehicle) in a concentration-dependent manner. Glomerular filtration rate was unchanged while BP was reduced by 10?mmHg only by the highest dose of SPP301. Administration of the ETB selective receptor antagonist BQ-788 (3?mg/kg) following SPP301 3?mg/kg did not further decrease urine output or water excretion and was without effect on glomerular filtration rate. These data indicate that increasing concentrations of SPP301 may also block ETB receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with predominant ETA receptor blockers.

Baltatu, Ovidiu Constantin; Iliescu, Radu; Zaugg, Christian E.; Reckelhoff, Jane F.; Louie, Pat; Schumacher, Christoph; Campos, Luciana Aparecida



Effect of histamine-2 receptor antagonists on blood alcohol levels  

Microsoft Academic Search

OBJECTIVE: To determine the effect, if any, of histamine type 2 receptor antagonists (H2RAs) on serum alcohol levels under various conditions including type of H2RA receptor antagonist, alcohol dose, and fed status of the subject.\\u000a \\u000a \\u000a STUDY DESIGN: Meta-analysis of the published literature.\\u000a \\u000a \\u000a \\u000a \\u000a DATA SOURCES: Studies were identified by MEDLINE (January 1982 through December 1997) using the key words H2 receptor

David S. Weinberg; Daniel Burnham; Jesse A. Berlin



Identification of three muscarinic receptor subtypes in rat lung using binding studies with selective antagonists  

SciTech Connect

Heterogeneity of the muscarinic receptor population in the rat central and peripheral lung was found in competition binding experiments against ({sup 3}H)quinuclidinyl benzilate (({sup 3}H)QNB) using the selective antagonists pirenzepine, AF-DX 116 and hexahydrosiladifenidol (HHSiD). Pirenzepine displaced ({sup 3}H)QNB with low affinity from preparations of central airways indicating the absence of M{sub 1} receptors in the trachea and bronchi. Muscarinic receptors in the central airways are comprised of both M{sub 2} and M{sub 3} receptors since AF-DX 116, an M{sub 2}-selective antagonist, bound with high affinity to 70% of the available sites while HHSiD, an M{sub 3}-selective antagonist bound with high affinity to the remaining binding sites. In the peripheral lung, pirenzepine bound with high affinity to 14% of the receptor population, AF-DX 116 bound with high affinity 79% of the binding sites while HHSiD bound with high affinity to 18% of the binding sites. The presence of M{sub 1} receptors in the peripheral airways but not in the central airways was confirmed using ({sup 3}H)telenzepine, an M{sub 1} receptor ligand. ({sup 3}H)Telenzepine showed specific saturable binding to 8% of ({sup 3}H)QNB labeled binding sites in homogenates of rat peripheral lung, while there was no detectable specific binding in homogenates of rat trachea or heart.

Fryer, A.D.; El-Fakahany, E.E. (Univ. of Maryland, Baltimore (USA))



Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells.  


Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. Since the association and dissociation rates of G protein-coupled receptor antagonists can influence their pharmacological activity in vivo, we used human PASMC to characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium release and inositol-1-phosphate (IP(1)) assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with K(b) values of 0.14 nM, 0.12 nM and 1.1 nM, respectively. Macitentan, but not ambrisentan and bosentan, displayed slow apparent receptor association kinetics as evidenced by increased antagonistic potency upon prolongation of antagonist pre-incubation times. In compound washout experiments, macitentan displayed a significantly lower receptor dissociation rate and longer receptor occupancy half-life (ROt(1/2)) compared to bosentan and ambrisentan (ROt(1/2):17 minutes versus 70 seconds and 40 seconds, respectively). Because of its lower dissociation rate macitentan behaved as an insurmountable antagonist in calcium release and IP(1) assays, and unlike bosentan and ambrisentan it blocked endothelin receptor activation across a wide range of endothelin-1 (ET-1) concentrations. However, prolongation of the ET-1 stimulation time beyond ROt(1/2) rendered macitentan a surmountable antagonist, revealing its competitive binding mode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and they lacked inhibitory activity at high ET-1 concentrations. Thus, macitentan is a competitive ERA with significantly slower receptor dissociation kinetics than the currently approved ERAs. Slow dissociation caused insurmountable antagonism in functional PASMC-based assays and this could contribute to an enhanced pharmacological activity of macitentan in ET-1-dependent pathologies. PMID:23077657

Gatfield, John; Mueller Grandjean, Celia; Sasse, Thomas; Clozel, Martine; Nayler, Oliver



2-Aminopyridine derivatives as potential ?(2) receptor antagonists.  


?(2) Receptor research is receiving increasing interest with regard to the potential of ?(2) proteins as targets for tumor therapy and diagnosis. Nevertheless, knowledge about the ?(2) receptor is far from conclusive. The paucity and modest affinity of known ?(2) antagonists represent one of the limitations to ?(2) receptor research. Previous studies of the high-affinity ?(2) agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine 4 (PB28) suggested that a decrease in lipophilicity might lead to ?(2) ligands devoid of antiproliferative activity (potential ?(2) antagonists). With the aim of producing ?(2) receptor antagonists, we replaced the tetralin nucleus of compound 4 with a 2-aminopyridine moiety. A series of compounds with high affinity for both ? subtypes and with no antiproliferative activity in various cells (mouse HT-22, human SK-N-SH, MCF-7wt, and MCF-7?(1)) were obtained. The effect on Ca(2+) mobilization was investigated for high-affinity compounds 18 and 4, which showed opposite effects. All of the data support the new 2-aminopyridines as high-affinity ? ligands with ?(2) antagonist and ?(1) agonist activity, and, despite the lack of significant ?(2) versus ?(1) selectivity, these novel compounds may be better tools for ? receptor research than the known low-affinity ?(2) antagonists. PMID:22890883

Abate, Carmen; Ferorelli, Savina; Niso, Mauro; Lovicario, Cesarea; Infantino, Vittoria; Convertini, Paolo; Perrone, Roberto; Berardi, Francesco



NMDA Receptor antagonists prevent acute ammonia toxicity in mice  

Microsoft Academic Search

We proposed that acute ammonia toxicity is mediated by activation of NMDA receptors. To confirm this hypothesis we have tested\\u000a whether different NMDA receptor antagonists, acting on different sites of NMDA receptors, prevent death of mice induced by\\u000a injection of 14 mmol\\/Kg of ammonium acetate, a dose that induces death of 95% of mice. MK-801, phencyclidine and ketamine,\\u000a which block

Carlos Hermenegildo; Goizane Marcaida; Carmina Montoliu; Santiago Grisolía; María-Dolores Miñana; Vicente Felipo



The novel small molecule ?9?10 nicotinic acetylcholine receptor antagonist ZZ-204G is analgesic  

PubMed Central

Chronic pain is inadequately managed with currently available classes of analgesic drugs. Recently, peptide antagonists of the ?9?10 nicotinic acetylcholine receptor were shown to be analgesic. The present study was conducted to characterize a novel small molecule, non-peptide antagonist at nicotinic receptors. The tetrakis-quaternary ammonium compound ZZ-204G was evaluated for functional activity on cloned nicotinic receptors expressed in Xenopus oocytes. In-vivo efficacy was assessed in rat models of tonic inflammatory pain (formalin test), neuropathic pain (chronic constriction nerve injury), and thermal nociception (tail flick test). ZZ-204G was an antagonist at nicotinic receptors inhibiting the ?9?10 subtype with an IC50 of 0.51 (0.35–0.72) nM. Antagonist activity at other nicotinic subtypes (?1?1??, ?2?2, ?2?4, ?3?2, ?3?4, ?4?2, ?4?4, ?6/?3?2?3, ?6/?3?4 and ?7) was 10–1000-fold lower than at the ?9?10 subtype. In competition binding assays, the ki of ZZ-204G at ?-aminobutyric acid(A), serotonin(3), ?-aminobutyric acid(B), ?- and ?-opioid receptors was 1000- to >10,000- fold lower than at ?9?10 nicotinic receptors. Parenteral administration of ZZ-204G dose-dependently decreased nociceptive behaviors (paw flinches) in the formalin test and mechanical hyperalgesia in the chronic constriction nerve injury model of neuropathic pain. ZZ-204G was not antinociceptive in the tail flick assay. Results from the rotarod assay indicated that lower doses of ZZ-204G that were analgesic did not alter motor function. In summary, ZZ-204G represents a prototype small molecule antagonist for ?9?10 nicotinic receptors and provides a novel molecular scaffold for analgesic agents with the potential to treat chronic inflammatory or neuropathic pain.

Holtman, Joseph R.; Dwoskin, Linda P.; Dowell, Cheryl; Wala, Elzbieta P.; Zhang, Zhenfa; Crooks, Peter A.; McIntosh, J. Michael



Characterization of a novel non-steroidal glucocorticoid receptor antagonist  

Microsoft Academic Search

Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing’s syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (Ki=13.2nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes

Qun-Yi Li; Meng Zhang; Tina M. Hallis; Therese A. DeRosier; Jian-Min Yue; Yang Ye; Dale E. Mais; Ming-Wei Wang



Tyrosine urea muscarinic acetylcholine receptor antagonists: achiral quaternary ammonium groups.  


Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction. PMID:23099092

Jin, Qi; Davis, Roderick S; Bullion, Ann M; Jin, Jian; Wang, Yonghui; Widdowson, Katherine L; Palovich, Michael R; Foley, James J; Schmidt, Dulcie B; Buckley, Peter T; Webb, Edward F; Salmon, Michael; Belmonte, Kristen E; Sarau, Henry M; Busch-Petersen, Jakob



Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5HT 3A receptors  

Microsoft Academic Search

We developed a structure–property–activity relationship (SPAR)-model for psychopharmacological drugs acting as non-competitive 5-HT3A receptor antagonists by using a decision-tree learner provided by the RapidMiner machine learning tool. A single molecular descriptor, namely the molecular dipole moment per molecular weight (?\\/MW), predicts whether or not a substance non-competitively antagonizes 5-HT-induced Na+ currents. A low ?\\/MW is compatible with drug-cumulation in apolar

Johannes Kornhuber; Lothar Terfloth; Stefan Bleich; Jens Wiltfang; Rainer Rupprecht



Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold.  


The orphan G-protein-coupled receptor GPR55, which is activated by 1-lysophosphatidylinositol and interacts with cannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson's disease, neuropathic pain, and cancer. We applied ?-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure-activity relationship study for GPR55. Selectivity versus the related receptors CB1, CB2, and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2H-chromen-2-one (12, PSB-SB-489, IC50 = 1.77 ?M, pA2 = 0.547 ?M). Derivatives with long alkyl chains in position 7 were potent, possibly allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (69, PSB-SB-487, IC50 = 0.113 ?M, KB = 0.561 ?M) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC50 = 0.261 ?M) were the most potent GPR55 antagonists of the present series. PMID:23679955

Rempel, Viktor; Volz, Nicole; Gläser, Franziska; Nieger, Martin; Bräse, Stefan; Müller, Christa E



Are CB1 Receptor Antagonists Nootropic or Cognitive Impairing Agents?  

PubMed Central

For more than a decade, a considerable amount of research has examined the effects of rimonabant (SR 141716) and other CB1 receptor antagonists in both in vivo and in vitro models of learning and memory. In addition to its utility in determining whether the effects of drugs are mediated though a CB1 receptor mechanism of action, these antagonists are useful in providing insight into the physiological function of the endogenous cannabinoid system. Several groups have reported that CB1 receptor antagonists enhance memory duration in a variety of spatial and operant paradigms, but not in all paradigms. Conversely, disruption of CB1 receptor signaling also impairs extinction learning in which the animal actively suppresses a learned response when reinforcement has been withheld. These extinction deficits occur in aversively motivated tasks, such as in fear conditioning or escape behavior in the Morris water maze task, but not in appetitively motivated tasks. Similarly, in electrophysiological models, CB1 receptor antagonists elicit a variety of effects, including enhancement of long-term potentiation (LTP), while disrupting long-term depression (LTD) and interfering with transient forms of plasticity, including depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). The collective results of the in vivo and in vitro studies employing CB1 receptor antagonists, demonstrate that these receptors play integral roles in different components of cognitive processing. Functionally, pharmacological blockade of CB1 receptors may strengthen memory duration, but interferes with extinction of learned behaviors that are associated with traumatic or aversive memories.

Varvel, Stephen A.; Wise, Laura E.; Lichtman, Aron H.



The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice  

Microsoft Academic Search

The neurosteroid pregnenolone sulfate (PREG-S) has been shown to modulate positively NMDA receptor activity and to have memory enhancing properties in mice. The present study was designed to evaluate the effects of post-training administration of PREG-S, alone or in combination with D-2-amino-5-phosphonovalerate (D-AP5), a competitive NMDA receptor antagonist, in Y-maze avoidance and appetitively motivated lever-press learning tasks and in a

C. Mathis; E. Vogel; B. Cagniard; F. Criscuolo; A. Ungerer



PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats  

PubMed Central

Background and purpose: Rimonabant (AcompliaTM, SR141716A), a cannabinoid CB1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB1 antagonist with a different pharmacological mechanism may lead to a safer alternative. To this end we have screened a proprietary small molecule library and have discovered a novel class of allosteric antagonist at CB1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo. Experimental approach: A CB1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [35S]-GTP?S, cAMP and radioligand binding assays. An acute rat feeding model was used to evaluate its effects on food intake and body weight in vivo. Key results: In CB1 receptor yeast reporter assays, PSNCBAM-1 blocked the effects induced by agonists such as CP55,940, WIN55212-2, anandamide (AEA) or 2-arachidonoyl glycerol (2-AG). The antagonist characteristics of PSNCBAM-1 were confirmed in [35S]-GTP?S binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB2 receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [3H]CP55,940 despite its antagonist effects. In an acute rat feeding model, PSNCBAM-1 decreased food intake and body weight. Conclusions and implications: PSNCBAM-1 exerted its effects through selective allosteric modulation of the CB1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB1 receptor antagonist.

Horswill, J G; Bali, U; Shaaban, S; Keily, J F; Jeevaratnam, P; Babbs, A J; Reynet, C; Wong Kai In, P



Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists  

SciTech Connect

Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

Zuercher, William J.; Buckholz† , Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen M.; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M. (GSKNC)



P2Y1 receptor antagonists as novel antithrombotic agents.  


The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable. PMID:18445527

Pfefferkorn, Jeffrey A; Choi, Chulho; Winters, Thomas; Kennedy, Robert; Chi, Liguo; Perrin, Lisa A; Lu, Gina; Ping, Yun-Wen; McClanahan, Tom; Schroeder, Richard; Leininger, Michael T; Geyer, Andrew; Schefzick, Sabine; Atherton, James



In vitro pharmacological profile of the A2A receptor antagonist istradefylline.  


Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson's disease (PD). Istradefylline is an adenosine A2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of istradefylline as an A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration-response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A2A receptor antagonist. The in vitro pharmacological profile of istradefylline helps to explain the in vivo profile of istradefylline and may be useful for clinical pharmacokinetic-pharmacodynamic considerations of efficacy and safety. PMID:23812646

Saki, Mayumi; Yamada, Koji; Koshimura, Etsuko; Sasaki, Katsutoshi; Kanda, Tomoyuki



Endothelin receptor antagonists as disease modifiers in systemic sclerosis.  


Systemic sclerosis (SSc) is a multisystem connective tissue disease of unknown etiology that is characterized by inflammation, vascular dysfunction and fibrosis of the skin and visceral organs. SSc is clinically diverse both in terms of the burden of skin and organ involvement and the rate of progression of the disease. Recent studies indicate that the endothelin system, especially ET-1 and the ETA and ETB receptors may play a key role in the pathogenesis of SSc. A new class of drugs, endothelin receptor antagonists has been introduced for treatment of patients with pulmonary arterial hypertension (PAH). Bosentan, a dual endothelin receptor antagonist as well as Sitaxsentan and Ambrisentan, selective blockers of the ETA receptor have proven effective in SSc-PAH. This effect may be mediated through both a vasodilatory and antifibrotic effect, thus making these agents attractive as potential disease modifying agents for SSc. PMID:21184655

Shetty, Nagalakshmi; Derk, Chris T



The effects on Schild regressions of antagonist removal from the receptor compartment by a saturable process  

Microsoft Academic Search

1.A theoretical model of the effects of a saturable removal mechanism for an antagonist diffusing into the receptor compartment of a tissue is used to calculate expected deviations in Schild regressions.2.At concentrations of antagonist which do not saturate the removal mechanism, there can be a deficit of antagonist in the receptor compartment as compared to the concentration of antagonist bathing

Terry P. Kenakin; Deborah Beek



Prostaglandins and progesterone receptor antagonists in human fertility regulation.  


Anti-progesterone medicines have now been extensively studied for human fertility regulation. The combination of the anti-progesterone Mifepristone with prostaglandin analogues such as Gemeprost and Misoprostol have been used in several European centres for medical abortion. Used before nine weeks gestation, these medicines have similar efficacy to surgical abortion. In addition, administration of progesterone antagonists within five days of unprotected intercourse appear effective in pregnancy prevention. Anti-progesterone medicines are not currently available in Australia. The introduction of progesterone receptor antagonists and modern prostaglandins would save approximately $10,000,000 per year to the Australian Health Budget. Furthermore, the introduction of progesterone receptor antagonists for emergency contraception would have even greater financial and emotional savings for Australian women. In Australia, when known carcinogens can be purchased over the counter, it is surely time for Australians to consider effective emergency contraception bought over the counter. PMID:7848216

Healy, D L



Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists.  


A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure-activity relationships (SAR), installation of various groups at the 3-6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction. PMID:22617492

Jiang, Rong; Song, Xinyi; Bali, Purva; Smith, Anthony; Bayona, Claudia Ruiz; Lin, Li; Cameron, Michael D; McDonald, Patricia H; Kenny, Paul J; Kamenecka, Theodore M



A case of an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage  

PubMed Central

Background: The competitive GH receptor antagonist pegvisomant is reported to normalise IGF-1 levels in up to 97 % of acromegalic patients at a maximum dosage of 40 mg/d. Description of Case: We present an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage. The 60-year-old male patient presenting with typical clinical signs of acromegaly has underwent multiple transsphenoidal surgeries and pituitary irradiation, while currently available pharmacological therapies for acromegaly have been exhausted. Results: Biochemical control of the disease could only be achieved until uptitration of pegvisomant to 60 mg/d which was tolerated well. Conclusions: The current treatment algorithm for acromegaly should be modified to treat cases of persistent and uncontrolled disease.

Dimopoulou, C; Sievers, C; Bidlingmaier, M; Stalla, GK



Different affinity states of alpha-1 adrenergic receptors defined by agonists and antagonists in bovine aorta plasma membranes  

Microsoft Academic Search

Evidence for a nonlinear relationship between alpha-1 adrenergic receptor occupancy and tissue responses, together with the finding of different affinity states for agonist binding, has raised the possibility of functional heterogeneity of alpha-1 adrenergic receptors. We have conducted studies to examine: 1) binding characteristics of (³H)prazosin, 2) competition of antagonists at these sites and 3) different affinity states of the

G. Jagadeesh; R. C. Deth



New high affinity peptide antagonists to the spinal galanin receptor.  

PubMed Central

1. The role of endogenous galanin in somatosensory processing has been studied with galanin receptor antagonists. The new galanin receptor ligands C7, M32, M38 and M40 bind with high affinity (Kd in nanomolar range) to spinal cord galanin receptors and possess oxidative stability as compared to earlier generations of peptide ligands. These peptides have been examined in the spinal flexor reflex model where exogenous galanin exhibited biphasic excitatory and inhibitory effects. 2. Intrathecal administration of C7 [galanin(1-13)-spantide] and M32 [galanin (1-13)-neuropeptide Y(25-36) amide] blocked facilitation of the nociceptive flexor reflex induced by 30 pmol intrathecal galanin in decerebrate, spinalized rats in a dose-dependent manner, thus behaving as antagonists of the galanin receptor. In contrast, M38[galanin(1-13)-(Ala-Leu)3-Ala amide] and M40 [galanin(1-13)-Pro-Pro-(Ala-Leu)2-Ala amide], exhibited only weak antagonism at high doses in this model. Moreover, lower doses of M40 potentiated galanin-induced reflex facilitation. C7 was neurotoxic at high doses in the rat spinal cord. 3. M32 and C7 were potent antagonists of galanin receptors in rat spinal cord, in correlation with their in vitro binding characteristics. In contrast, M38 and M40, despite their high in vitro affinity, exhibited only very weak antagonism. Moreover, M40 may also behave as a partial agonist. 4. Previous studies have shown that the galanin receptor may be heterogeneous. The discrepancy between in vitro binding and in vivo antagonistic potency of M38 and M40 may also suggest the presence of different galanin receptor subtypes within the rat spinal cord. However, other explanations for the discrepancy, such as differences in metabolic stability, diffusion rates and penetration to the site of action are also possible.

Xu, X. J.; Wiesenfeld-Hallin, Z.; Langel, U.; Bedecs, K.; Bartfai, T.



New high affinity peptide antagonists to the spinal galanin receptor.  


1. The role of endogenous galanin in somatosensory processing has been studied with galanin receptor antagonists. The new galanin receptor ligands C7, M32, M38 and M40 bind with high affinity (Kd in nanomolar range) to spinal cord galanin receptors and possess oxidative stability as compared to earlier generations of peptide ligands. These peptides have been examined in the spinal flexor reflex model where exogenous galanin exhibited biphasic excitatory and inhibitory effects. 2. Intrathecal administration of C7 [galanin(1-13)-spantide] and M32 [galanin (1-13)-neuropeptide Y(25-36) amide] blocked facilitation of the nociceptive flexor reflex induced by 30 pmol intrathecal galanin in decerebrate, spinalized rats in a dose-dependent manner, thus behaving as antagonists of the galanin receptor. In contrast, M38[galanin(1-13)-(Ala-Leu)3-Ala amide] and M40 [galanin(1-13)-Pro-Pro-(Ala-Leu)2-Ala amide], exhibited only weak antagonism at high doses in this model. Moreover, lower doses of M40 potentiated galanin-induced reflex facilitation. C7 was neurotoxic at high doses in the rat spinal cord. 3. M32 and C7 were potent antagonists of galanin receptors in rat spinal cord, in correlation with their in vitro binding characteristics. In contrast, M38 and M40, despite their high in vitro affinity, exhibited only very weak antagonism. Moreover, M40 may also behave as a partial agonist. 4. Previous studies have shown that the galanin receptor may be heterogeneous. The discrepancy between in vitro binding and in vivo antagonistic potency of M38 and M40 may also suggest the presence of different galanin receptor subtypes within the rat spinal cord. However, other explanations for the discrepancy, such as differences in metabolic stability, diffusion rates and penetration to the site of action are also possible. PMID:8640348

Xu, X J; Wiesenfeld-Hallin, Z; Langel, U; Bedecs, K; Bartfai, T



Antagonists of B2 bradykinin receptors  

Microsoft Academic Search

Bradykinin and its active metabolites, produced by kal- likreins at their sites of action, potently elicit a variety of biological effects: hypotension, bronchoconstriction, gut and uterine contraction, epithelial secretion in airway, gut, and exocrine glands, vascular permeability, pain, connective tissue proliferation, cytokine release, and eicosanoid formation. These effects are mediated by at least two broad classes of receptors. The most



Migrastatin acts as a muscarinic acetylcholine receptor antagonist.  


Migrastatin and its analogs have various biological activities such as inhibition of cell migration and anchorage-independent growth of cancer cells. Although its biosynthesis and chemical synthesis have been under investigation, little is known about the biological target of migrastatin. Here, we found that migrastatin inhibited intracellular calcium mobilization induced by carbachol in neuroblastoma SK-N-SH cells without affecting Ca2+ mobilization and cAMP accumulation induced by ligands of other receptors. The binding of [3H] N-methylscopolamine, an antagonist for muscarinic receptor was also inhibited by migrastain. Functionally, migrastatin inhibited Ca2+ mobilization induced by carbachol in primary cultures of smooth muscle cells of rat bladder. This study reveals that migrastatin acts as a muscarinic acetylcholine receptor antagonist. PMID:17256466

Nakae, Koichi; Nishimura, Yoshio; Ohba, Syunichi; Akamatsu, Yuzuru



Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists  

PubMed Central

The C-5 halogenation of the vanillyl moiety of resiniferatoxin, an ultrapotent agonist of vanilloid TRPV1 receptors, results in a potent antagonist for these receptors. Here, we have synthesized a series of halogenated derivatives of ‘synthetic capsaicin' (nonanoyl vanillamide=nordihydrocapsaicin) differing for the nature (iodine, bromine–chlorine) and the regiochemistry (C-5, C-6) of the halogenation.The activity of these compounds was investigated on recombinant human TRPV1 receptors overexpressed in HEK-293 cells. None of the six compounds exerted any significant agonist activity, as assessed by measuring their effect on TRPV1-mediated calcium mobilization. Instead, all compounds antagonized, to various extents, the effect of capsaicin in this assay.All 6-halo-nordihydrocapsaicins behaved as competitive antagonists against human TRPV1 according to the corresponding Schild's plots, and were more potent than the corresponding 5-halogenated analogues. The iodo-derivatives were more potent than the bromo- and chloro-derivatives.Using human recombinant TRPV1, 6-iodo-nordihydrocapsaicin (IC50=10 nM against 100 nM capsaicin) was about four times more potent than the prototypical TRPV1 antagonist, capsazepine, and was tested against capsaicin also on native TRPV1 in: (i) rat dorsal root ganglion neurons in culture; (ii) guinea-pig urinary bladder; and (iii) guinea-pig bronchi. In all cases, except for the guinea-pig bronchi, the compound was significantly more potent than capsazepine as a TRPV1 antagonist.In conclusion, 6-iodo-nordihydrocapsaicin, a stable and easily prepared compound, is a potent TRPV1 antagonist and a convenient replacement for capsazepine in most of the in vitro preparations currently used to assess the activity of putative vanilloid receptor agonists.

Appendino, Giovanni; Harrison, Selena; De Petrocellis, Luciano; Daddario, Nives; Bianchi, Federica; Schiano Moriello, Aniello; Trevisani, Marcello; Benvenuti, Francesca; Geppetti, Pierangelo; Di Marzo, Vincenzo



Response properties of antral mechanosensitive afferent fibers and effects of ionotropic glutamate receptor antagonists.  


The ionotropic glutamate receptors N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are present peripherally in the primary sensory afferent neurons innervating the viscera. Multiple studies have reported roles of glutamate receptors in gastric functions. However, no study has previously shown the direct influence of ionotropic glutamate receptor antagonist on vagal sensory neurons. The objective of this study was to investigate the effects of NMDA and AMPA receptor antagonists on mechanotransduction properties of vagal afferent fibers innervating the rat stomach. Action potentials were recorded from the hyponodal vagus nerve innervating the antrum of the Long-Evans rats. For antral distension (AD), a small latex balloon was inserted into the stomach and positioned in the antrum. The antral contractions were recorded with solid-state probe inserted into the water-filled balloon. Antral units were identified to isovolumic (0.2-1 ml) or isobaric AD (5-60 mm Hg). NMDA and AMPA receptor antagonists were injected in a cumulative fashion (1-100 micromol/kg, i.v.). After the conclusion of experiment, the abdomen was opened and receptive field was mapped by probing the serosa of the stomach. Thirty-two fibers were identified to AD. The receptive fields of 26 fibers were located in the posterior part of the antrum. All fibers exhibited spontaneous firing (mean: 7.00+/-0.97 impulses/s). Twenty fibers exhibited a rhythmic firing that was in phase with antral contractions, whereas 12 fibers exhibited non-rhythmic spontaneous firing unrelated to spontaneous antral contraction. Both groups of fibers exhibited a linear increase in responses to graded isovolumic or isobaric distensions. NMDA (memantine HCl and dizocilpine (MK-801)) and AMPA/kainate (6-cyano-7-nitroquinoxaline 2,3-dione; CNQX) receptor antagonists dose-dependently attenuated the mechanotransduction properties of these fibers to AD. However, competitive NMDA antagonist dl-2-amino-5 phosphopentanoic acid (AP-5) had no effect. The study documents that glutamate receptor antagonists can attenuate responses of gastric vagal sensory afferent fibers innervating the distal stomach, offering insight to potential pharmacological agents in the treatment of gastric disorders. PMID:15099685

Sengupta, J N; Petersen, J; Peles, S; Shaker, R



Novel potent selective phenylglycine antagonists of metabotropic glutamate receptors  

Microsoft Academic Search

The metabotropic glutamate (mGlu) receptor antagonist properties of novel phenylglycine analogues were investigated in adult rat cortical slices (mGlu receptors negatively coupled to adenylyl cyclase), neonatal rat cortical slices and in cultured rat cerebellar granule cells (mGlu receptors coupled to phosphoinositide hydrolysis). (RS)-?-methyl-4-phosphonophenylglycine (MPPG), (RS)-?-methyl-4-sulphonophenylglycine (MSPG), (RS)-?-methyl-4-tetrazolylphenylglycine (MTPG), (RS)-?-methyl-3-carboxymethyl-4-hydroxyphenylglycine (M3CM4HPG) and (RS)-?-methyl-4-hydroxy-3-phosphonomethylphenylglycine (M4H3PMPG) were demonstrated to have potent and selective

Jennifer S. Bedingfield; David E. Jane; Martyn C. Kemp; Nicholas J. Toms; Peter J. Roberts



Novel thioamide derivatives as neutral CB1 receptor antagonists.  


A novel class of cannabinoid-1 (CB1) receptor antagonists for the treatment of obesity is presented. The carboxamide linker in a set of 5,6-diaryl-pyrazine-2-amide derivatives was transformed into the corresponding thioamide, by using a one-pot synthesis. The structural series of thioamides not only showed retained CB1 potency (below 10nM), but also showed improved solubility. In addition, the neutral antagonist 2c significantly reduced body weight in cafeteria diet obese mice. PMID:20005704

Boström, Jonas; Olsson, Roine I; Tholander, Joakim; Greasley, Peter J; Ryberg, Erik; Nordberg, Henrik; Hjorth, Stephan; Cheng, Leifeng



N-methyl-D-aspartate receptor antagonists enhance histamine neuron activity in rodent brain.  


The modulation of histamine neuron activity by various non-competitive NMDA-receptor antagonists was evaluated by changes in tele-methylhistamine (t-MeHA) levels and histidine decarboxylase (hdc) mRNA expression induced in rodent brain. The NMDA open-channel blockers phencyclidine (PCP) and MK-801 enhanced t-MeHA levels in mouse brain by 50-60%. Ifenprodil, which interacts with polyamine sites of NR2B-containing NMDA receptors, had no effect. PCP also increased hdc mRNA expression in the rat tuberomammillary nucleus. The enhancement of t-MeHA levels elicited by MK-801 (ED50 of approximately 0.1 mg/kg) was observed in the hypothalamus, cerebral cortex, striatum and hippocampus. Control t-MeHA levels and the t-MeHA response to MK-801 were not different in male and female mice. Double immunostaining for HDC and NMDA receptor subunits showed that histamine neurons of the rat tuberomammillary nucleus express NMDA receptor subunit 1 (NR1) with NMDA receptor subunit 2A (NR2A) and NMDA receptor 2B subunit (NR2B). In addition, immunoreactivity for the neuronal glutamate transporter EAAC1 was observed near most histaminergic perikarya. Hence, these findings support the existence of histamine/glutamate functional interactions in the brain. The increase in histamine neuron activity induced by NMDA receptor antagonists further suggests a role of histamine neurons in psychotic disorders. In addition, the decrease in MK-801-induced hyperlocomotion observed in mice after administration of ciproxifan further strengthens the potential interest of H3-receptor antagonist/inverse agonists for the symptomatic treatment of schizophrenia. PMID:16923161

Faucard, Raphaël; Armand, Vincent; Héron, Anne; Cochois, Véronique; Schwartz, Jean-Charles; Arrang, Jean-Michel



Pharmacology of A-216546: a highly selective antagonist for endothelin ET(A) receptor.  


Endothelins, 21-amino acid peptides involved in the pathogenesis of various diseases, bind to endothelin ET(A) and ET(B) receptors to initiate their effects. Here, we characterize the pharmacology of A-216546 ([2S-(2,2-dimethylpentyl)-4S-(7-methoxy-1,3-benzodioxol-5-yl )-1-(N,N-di(n-butyl) aminocarbonylmethyl)-pyrrolidine-3R-carboxylic acid), a potent antagonist with > 25,000-fold selectivity for the endothelin ET(A) receptor. A-216546 inhibited [125I]endothelin-1 binding to cloned human endothelin ET(A) and ET(B) receptors competitively with Ki of 0.46 and 13,000 nM, and blocked endothelin-1-induced arachidonic acid release and phosphatidylinositol hydrolysis with IC50 of 0.59 and 3 nM, respectively. In isolated vessels, A-216546 inhibited endothelin ET(A) receptor-mediated endothelin-1-induced vasoconstriction, and endothelin ET(B) receptor-mediated sarafotoxin 6c-induced vasoconstriction with pA2 of 8.29 and 4.57, respectively. A-216546 was orally available in rat, dog and monkey. In vivo, A-216546 dose-dependently blocked endothelin-1-induced pressor response in conscious rats. Maximal inhibition remained constant for at least 8 h after dosing. In conclusion, A-216546 is a potent, highly endothelin ET(A) receptor-selective and orally available antagonist, and will be useful for treating endothelin-1-mediated diseases. PMID:10082200

Wu-Wong, J R; Dixon, D B; Chiou, W J; Dayton, B D; Novosad, E I; Adler, A L; Wessale, J L; Calzadilla, S V; Hernandez, L; Marsh, K C; Liu, G; Szczepankiewicz, B; von Geldern, T W; Opgenorth, T J



High-affinity urokinase receptor antagonists identified with bacteriophage peptide display.  

PubMed Central

Affinity selection of a 15-mer random peptide library displayed on bacteriophage M13 has been used to identify potent ligands for the human urokinase receptor, a key mediator of tumor cell invasion. A family of receptor binding bacteriophage ligands was obtained by sequentially and alternately selecting the peptide library on COS-7 monkey kidney cells and baculovirus-infected Sf9 insect cells overexpressing the human urokinase receptor. Nineteen peptides encoded by the random DNA regions of the selected bacteriophage were synthesized and tested in a urokinase receptor binding assay, where they competed with the labeled N-terminal fragment of urokinase with IC50 values ranging from 10 nM to 10 microM. All of the isolated peptides were linear and showed two relatively short conserved subsequences: LWXXAr (Ar = Y, W, F, or H) and XFXXYLW, neither of which is found in urokinase or its receptor. Competition experiments demonstrated that the most potent peptide, clone 20, prevented binding of bacteriophage displaying the urokinase receptor binding sequence (urokinase residues 13-32). In addition, this peptide blocked other apparently unrelated receptor binding bacteriophage, suggesting overlapping receptor interaction sites for all of these sequences. These results provide a demonstration of bacteriophage display identifying peptide ligands for a receptor expressed on cells and yield leads for the development of urokinase receptor antagonists. Images

Goodson, R J; Doyle, M V; Kaufman, S E; Rosenberg, S



Adenosine A(2A) Receptor Antagonists and Parkinson's Disease.  


This Review summarizes and updates the work on adenosine A(2A) receptor antagonists for Parkinson's disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chemistry approaches to this attractive and promising target to treat Parkinson's disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on preparing selective A(2A) antagonists, but a few approaches to dual A(2A)/A(1) antagonists will also be highlighted. The in vivo profiles of compounds will be highlighted and discussed to compare activities across different chemical series. A clinical report and update will be given on compounds that have entered clinical trials. PMID:22860156

Shook, Brian C; Jackson, Paul F



Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine  

PubMed Central

Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR) antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as was eplerenone in subsequent heart failure trials. Neither acts as an aldosterone antagonist in the heart as the cardiac MR are occupied by cortisol, which becomes an aldosterone mimic in conditions of tissue damage. The accepted term “MR antagonist”, (as opposed to “aldosterone antagonist” or, worse, “aldosterone blocker”), should be retained, despite the demonstration that they act not to deny agonist access but as inverse agonists. The prevalence of primary aldosteronism is now recognized as accounting for about 10% of hypertension, with recent evidence suggesting that this figure may be considerably higher: in over two thirds of cases of primary aldosteronism therapy including MR antagonists is standard of care. MR antagonists are safe and vasoprotective in uncomplicated essential hypertension, even in diabetics, and at low doses they also specifically lower blood pressure in patients with so-called resistant hypertension. Nowhere are more than 1% of patients with primary aldosteronism ever diagnosed and specifically treated. Given the higher risk profile in patients with primary aldosteronism than that of age, sex, and blood pressure matched essential hypertension, on public health grounds alone the guidelines for first-line treatment of all hypertension should mandate inclusion of a low-dose MR antagonist.

Funder, John W



[Thromboxane A2 synthase inhibitor and receptor antagonist].  


Thromboxane A2 (TxA2) plays an important role in asthma. TxA2 are newly generated after cellular activation and are produced by not only platelets but also eosinophils, basophils, alveolar macrophages, and neutrophils. Pharmacological actions of TxA2 include potent bronchoconstriction, increased microvascular leakage, impairment of mucociliary clearance, and induction of airway hyperresponsiveness. Recent study demonstrated that TxA2 receptor antagonist decreased the number of eosinophils in bronchial biopsy specimens, suggesting that this type of agent possesses anti-inflammatory actions in asthma. Furthermore, addition of TxA2 synthase inhibitor significantly increased the PEF values in the persistent asthmatic patients despite the treatment with moderate-dose of inhaled corticosteroids. Therefore, these results suggest that TxA2 synthase inhibitor and receptor antagonist are useful for the treatment with symptomatic patients who had already been treated with inhaled corticosteroids. PMID:11676143

Minoguchi, K; Adachi, M



Photoaffinity labeling adenosine A1 receptors with an antagonist /sup 125/I-labeled aryl azide derivative of 8-phenylxanthine  

SciTech Connect

We have derivatized a series of /sup 125/I-labeled 8-phenylxanthines with photoactive aryl azide groups on the 1- or 3-position of the xanthine ring. A 3-azidophenethyl derivative was found to be optimal for use as an antagonist photoaffinity label for adenosine A1 receptors. Following photoactivation, radioactivity was covalently and specifically incorporated into a 34,000-dalton and, to a lesser extent, into a 24,000-dalton polypeptide of rat brain membranes. Photoincorporation into both polypeptides was competitively inhibited by adenosine analogues with a potency order typical of adenosine A1 receptors, but the 24,000-dalton polypeptide bound both agonists and antagonists with lower affinity than the 34,000-dalton polypeptide. Specific photolabeling of receptors in brain membranes of rat, guinea pig, dog, and cow did not show any variation in the 34,000-dalton adenosine receptor binding subunit. The adenosine agonist photoaffinity label (/sup 125/I)N6-(4-azido-3-iodobenzyl)adenosine also specifically photolabeled the 34,000-dalton polypeptide, but photoincorporation of the agonist was less efficient than the antagonist and, unlike the antagonist, was greatly reduced by guanosine 5'-(beta,gamma-imidotriphosphate). The results indicate that the antagonist photoaffinity label may be more useful than agonists particularly for labeling uncoupled receptors.

Earl, C.Q.; Patel, A.; Craig, R.H.; Daluge, S.M.; Linden, J.



Palonosetron: a second-generation 5-hydroxytryptamine receptor antagonist.  


Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine (5-HT)3 receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a clinical problem. A new agent, palonosetron, has recently been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. In a single dosing study, palonosetron was highly effective in controlling CINV compared with a single dose of dolasetron or ondansetron in patients receiving moderately emetogenic chemotherapy. Palonosetron in combination with dexamethasone demonstrated control of CINV in patients receiving highly emetogenic chemotherapy. Palonosetron appeared to be as effective in subsequent courses of chemotherapy compared with the initial course of chemotherapy. There were no clinically relevant differences seen among palonosetron, ondansetron or dolasetron in laboratory, electrocardiographic or vital-sign changes, and adverse reactions reported in the clinical trials were the most common reactions reported for the 5-HT3 receptor antagonist class. Recent studies using palonosetron-based anti-emetic combinations in moderately and highly emetogenic chemotherapy, as well as in the clinical setting of multiple-day chemotherapy, have been reported. Future studies may consider the use of palonosetron with current and other new agents and in other clinical settings, such as bone marrow transplantation and radiation therapy. PMID:17026451

Navari, Rudolph M



Bronchoprotection with a Leukotriene Receptor Antagonist in Asthmatic Preschool Children  

Microsoft Academic Search

We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double- blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5 mg\\/d for 2 d on the bron- choconstriction induced by hyperventilation of cold, dry air in 13 asthmatic children 3




Interleukin1 receptor antagonist gene polymorphism and gingivitis in children  

Microsoft Academic Search

AIM: To investigate the role of the polymorphism of a variable numbers of tandem repeats of interleukin-1 receptor antagonist gene (IL-1RN) on gingivitis in children. MATERIALS AND METHODS: A total of 146 Caucasian subjects (98 subjects with gingivitis and 48 controls) aged 8-12 years, were enrolled. Plaque and Calculus Indices were recorded to assess the oral hygiene. Gingival and Bleeding

M Dashash; DB Drucker; IV Hutchinson; AS Blinkhorn



Iontophoresis of Endothelin Receptor Antagonists in Rats and Men  

Microsoft Academic Search

IntroductionThe treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.MethodsCathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1

Matthieu Roustit; Sophie Blaise; Claire Arnaud; Marcin Hellmann; Claire Millet; Diane Godin-Ribuot; Boris Dufournet; Jean Boutonnat; Christophe Ribuot; Jean-Luc Cracowski



Equilibrium interactions of corepressors and coactivators with agonist and antagonist complexes of glucocorticoid receptors.  


Corepressors and coactivators can modulate the dose-response curve and partial agonist activity of glucocorticoid receptors (GRs) complexed with agonist and antagonist steroids, respectively, in intact cells. We recently reported that GR-antagonist complexes bind to the coactivator TIF2, (transcriptional intermediary factor 2), which is consistent with the whole-cell effects of coactivators being mediated by direct interactions with GR complexes. We now ask whether the whole-cell modulatory activity of corepressors also entails binding to both GR-agonist and -antagonist complexes and whether the association of corepressors and coactivators with GR complexes involves competitive equilibrium reactions. In mammalian two-hybrid assays with two different cell lines and in cell-free pull-down and whole-cell immunoprecipitation assays, the corepressors NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor) associate with agonist and antagonist complexes of GRs. Both N- and C-terminal regions of GR are needed for corepressor binding, which requires the CoRNR box motifs that mediate corepressor binding to other nuclear/steroid receptors. Importantly, whole-cell GR interactions with corepressors are competitively inhibited by excess coactivator and vice versa. However, the regions of the coactivator TIF2 that compete for GR binding to corepressor and coactivator are not the same, implying a molecular difference in GR association with coactivators and corepressors. Finally, when the whole-cell ratio of coactivators to corepressors is altered by selective cofactor binding to exogenous thyroid receptor beta +/- thyroid hormone, the GR dose-response-curve and partial agonist activity are appropriately modified. Such modifications are independent of histone acetylation. We conclude that mutually antagonistic equilibrium interactions of corepressors and coactivators modulate the dose-response curve and partial agonist activity of GR complexes in a manner that is responsive to the intracellular ratio of these two classes of cofactors. This modulation provides an attractive mechanism for differential control of gene expression during development, differentiation, homeostasis, and endocrine therapies. PMID:15016838

Wang, Qi; Blackford, John A; Song, Liang-Nian; Huang, Ying; Cho, Sehyung; Simons, S Stoney



Leukotriene-receptor antagonists. Role in asthma management.  

PubMed Central

OBJECTIVE: To examine the role of leukotriene-receptor antagonists (LTRAs) in management of asthma. QUALITY OF EVIDENCE: Most data were derived from randomized, double-blind, controlled trials. MAIN MESSAGE: Leukotrienes appear to have an important role in the pathophysiology of asthma, including airway inflammation. Leukotriene-receptor antagonists are effective in improving asthma control end points, such as allergen, ASA, and exercise challenge, in clinical models of asthma. In chronic asthma, LTRA administration reduces asthma symptoms and rescue beta 2-agonist use, changes that are paralleled by improvements in lung function. Both zafirlukast and montelukast decrease circulating levels of eosinophils and could have other useful anti-inflammatory properties. Administration of LTRAs allows doses of inhaled corticosteroids to be reduced. Currently available LTRAs are free of serious side effects and are available as oral formulations. CONCLUSIONS: Leukotriene-receptor antagonists belong to a new class of asthma medication. While inhaled corticosteroids remain first-line therapy for managing chronic asthma, LTRAs should be considered for patients with ASA-sensitive asthma; as adjunct therapy when low to moderate doses of inhaled steroid alone provide incomplete control; or as adjunct therapy to allow reduction in doses of inhaled corticosteroids.

D'Urzo, A. D.; Chapman, K. R.



Pharmacological properties of JDTic: a novel ?-opioid receptor antagonist  

Microsoft Academic Search

Biological studies were conducted on (3R)-7-Hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), the first potent ?-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (?)-opioid receptor agonist, enadoline, AD50s of 4.1

Ivy Carroll; James B. Thomas; Linda A. Dykstra; Arthur L. Granger; Richard M. Allen; James L. Howard; Gerald T. Pollard; Mario D. Aceto; Louis S. Harris



Characterization of protoberberine analogs employed as novel human P2X{sub 7} receptor antagonists  

SciTech Connect

The P2X{sub 7} receptor (P2X{sub 7}R), a member of the ATP-gated ion channel family, is regarded as a promising target for therapy of immune-related diseases including rheumatoid arthritis and chronic pain. A group of novel protoberberine analogs (compounds 3-5), discovered by screening of chemical libraries, was here investigated with respect to their function as P2X{sub 7}R antagonists. Compounds 3-5 non-competitively inhibited BzATP-induced ethidium ion influx into hP2X{sub 7}-expressing HEK293 cells, with IC{sub 50} values of 100-300 nM. This antagonistic action on the channel further confirmed that both BzATP-induced inward currents and Ca{sup 2+} influx were strongly inhibited by compounds 3-5 in patch-clamp and Ca{sup 2+} influx assays. The antagonists also effectively suppressed downstream signaling of P2X{sub 7} receptors including IL-1{beta} release and phosphorylation of ERK1/2 and p38 proteins in hP2X{sub 7}-expressing HEK293 cells or in differentiated human monocytes (THP-1 cells). Moreover, IL-2 secretion from CD3/CD28-stimulated Jurkat T cell was also dramatically inhibited by the antagonist. These results imply that novel protoberberine analogs may modulate P2X{sub 7} receptor-mediated immune responses by allosteric inhibition of the receptor. - Graphical abstract: Display Omitted

Lee, Ga Eun; Lee, Won-Gil; Lee, Song-Yi; Lee, Cho-Rong; Park, Chul-Seung [School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712 (Korea, Republic of); Chang, Sunghoe [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Park, Sung-Gyoo; Song, Mi-Ryoung [School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712 (Korea, Republic of); Kim, Yong-Chul, E-mail: [School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712 (Korea, Republic of)



Systemic administration of MK-801, a non-competitive NMDA-receptor antagonist, elicits a behavioural deficit of rats in the Active Allothetic Place Avoidance (AAPA) task irrespectively of their intact spatial pretraining  

Microsoft Academic Search

Spatial orientation is considered to be an animal model of human cognitive functions. Efficient navigation is believed to require a brain representation of the environment. The role of NMDA-receptor-dependent neurotransmission in encoding spatial representations has been intensively studied; however, its involvement in organizing spatial information into neural representations is poorly understood. We tested the effect of NMDA-receptor blockade on the

Ales Stuchlík; Karel Vales



The Q43L mutant of neuregulin 2? is a pan-ErbB receptor antagonist.  


The ErbB4 receptor tyrosine kinase possesses both tumour suppressor and oncogenic activities. Thus pharmacological agents are needed to help elucidate ErbB4 functions. However, limitations of existing ErbB4 agonists and antagonists have led us to seek novel ErbB4 antagonists. The Q43L mutant of the ErbB4 agonist NRG2? (neuregulin 2?) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2?/Q43L may be an ErbB4 antagonist. NRG2?/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2?/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2?. In addition, NRG2? stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2? stimulates greater Akt phosphorylation than does NRG2?/Q43L. Moreover, EGFR [EGF (epidermal growth factor) receptor] kinase activity (but not that of ErbB4) is critical for coupling ErbB4 to proliferation. Experiments utilizing ErbB4 splicing isoforms and mutants suggest that NRG2? and NRG2?/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2?/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2?/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2?/Q43L and other antagonistic ligands stimulate ErbB tyrosine phosphorylation on a set of residues distinct from that stimulated by agonists, thus suggesting a novel mechanism of ErbB receptor regulation. Moreover, NRG2?/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics. PMID:22216880

Wilson, Kristy J; Mill, Christopher P; Gallo, Richard M; Cameron, Elizabeth M; VanBrocklin, Henry; Settleman, Jeffrey; Riese, David J



The agonist paradox: agonists and antagonists of acetylcholine receptors and opioid receptors.  


In contrast to antagonists, agonists tend to induce considerable conformational changes in their receptors, resulting in opening of ion channels, either directly or via secondary messengers. These conformational transformations require great energy expenses. However, the experimentally determined free energies of complexation between agonists and receptors are often relatively smaller than those for the corresponding antagonists. To rationalize this so-called 'agonist paradox', which has not been clarified in the literature, we have developed an alternative model. Our model may help to discriminate between agonists and antagonists of the acetylcholine (ACh) and mu-opioid receptors. For this purpose, a series of ligands (1-18) have been analyzed both in structural terms and with respect to complexation geometry within the anionic binding sites of these two receptor types. PMID:17191984

Dukhovich, Felix S; Darkhovskii, Michael B; Gorbatova, Elena N; Polyakov, Victor S



Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist.  


Endothelins (ET) are potent vasoactive peptides implicated in the pathogenesis of a number of vascular diseases. The effects of ET on mammalian organs and cells are initiated by binding to ETA or ETB receptors. In this report, we document the pharmacology of A-127722, a novel ETA-selective receptor antagonist. A-127722 inhibits [125I]ET-1 binding to cloned human ETA and ETB receptors competitively with Ki values of 69 pM and 139 nM, respectively. A-127722 exhibits a dose-dependent inhibition of ET-1-induced arachidonic acid release in human pericardium smooth muscle cells with a pA2 value of 10.5 and inhibits ET-1-induced vasoconstriction in isolated rat aorta with a pA2 value of 9.2. In vivo, A-127722 dose-dependently blocks the pressor response to ET-1 (0.3 nmol/kg i.v.) in conscious rats. Statistically significant (P < .05) antagonism is seen at doses greater than 0.1 mg/kg p.o. Maximal inhibition, at 10 mg/kg, remains constant for at least 8 hr after dosing. No effect is seen on the ETB-mediated transient vasodepressor effect of exogenous ET-1. In conclusion, A-127722 is ETA-selective, orally bioavailable and efficacious for inhibiting the effects of ET in the rat, and A-127722 is the most potent ET receptor antagonist yet reported. PMID:8632312

Opgenorth, T J; Adler, A L; Calzadilla, S V; Chiou, W J; Dayton, B D; Dixon, D B; Gehrke, L J; Hernandez, L; Magnuson, S R; Marsh, K C; Novosad, E I; Von Geldern, T W; Wessale, J L; Winn, M; Wu-Wong, J R



Cardioprotective effects of mineralocorticoid receptor antagonists at reperfusion  

PubMed Central

Aim Pretreatment with mineralocorticoid receptor (MR) antagonists is reported to reduce myocardial infarct size from ischemia/reperfusion. Here, we tested whether the MR antagonists potassium canrenoate and eplerenone could protect in the more clinically relevant schedule of administration at the end of ischemia. Methods and results In all models, hearts were subjected to 30 min regional ischemia followed by 120 min (rabbits 4 h) reperfusion. A bolus of canrenoate 5 min prior to reperfusion in open-chest mice decreased infarct size in a dose-dependent manner. Maximum protection was seen at 1 mg/kg where infarction was 18% of that in the control (p<0.001). Ecto-5?-nucleotidase (CD73), as well as adenosine A2b receptor knock-out mice could no longer be protected, suggesting a role for adenosine and the A2b receptor in the mechanism. A 1 mg/kg bolus of canrenoate prior reperfusion also reduced infarct size in open-chest rabbits. To explore the underlying mechanisms we studied isolated rat hearts. Eplerenone (10 ?M) at the end of ischemia was similarly protective in the rat heart and the protection was abolished by co-treatment with inhibitors of the adenosine receptor, protein kinase C, PI3-kinase, and ERK. In addition eplerenone or canrenoate treatment increased phosphorylation of the pro-survival kinases Akt and ERK1/2 at reperfusion in the rat hearts. Conclusion Taken together, MR antagonists when given at the end of ischemia are highly effective and potent cardioprotective drugs with a signaling similar to that of ischemic preconditioning and, hence, could be a very promising candidate for the treatment of acute myocardial infarction in man.

Schmidt, Katharina; Tissier, Renaud; Ghaleh, Bijan; Drogies, Tim; Felix, Stephan B.; Krieg, Thomas



Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine.  

PubMed Central

The selectivity profiles of the muscarinic receptor antagonists dicyclomine and trihexyphenidyl have been examined in binding and functional studies and compared with those of pirenzepine and atropine. Dicyclomine, trihexyphenidyl and pirenzepine demonstrated the highest affinity for the M1 muscarinic receptor subtype as revealed in competition experiments against [3H]-pirenzepine labelling of cortical membranes. Their affinity values lay in a narrow range (3.7-14 nM) approaching that of atropine (1.6 nM). Competition experiments against [3H]-N-methylscopolamine in cardiac and glandular (salivary) membranes revealed differences between the drugs examined. Dicyclomine, trihexyphenidyl and pirenzepine displayed low affinity for the cardiac and intermediate affinity for the glandular receptors. Thus, the drugs appeared to discriminate between the M1 (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC50s varying only slightly (1.6-4.6 nM). The rank order of selectivity was: pirenzepine greater than dicyclomine greater than trihexyphenidyl greater than atropine. Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M1-receptor mediated ganglionic responses (McN A-343 pressor effect in pithed rats and nictitating membrane contraction in cats) than at inhibiting peripheral muscarinic responses in the heart and cardiovascular smooth muscle (vagal bradycardia in rats and cats and vagally-induced vasodilatation in cats). The muscarinic antagonists so far examined can be categorized into two groups. Trihexyphenidyl, dicyclomine and pirenzepine, included in one group, are characterized by a higher affinity for the neuronal (M1) muscarinic receptor, hence they antagonize functional responses mediated by the M1 subtype. Atropine, a member of the other group, shows essentially no selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Giachetti, A.; Giraldo, E.; Ladinsky, H.; Montagna, E.



Potential Clinical Implications of the Urotensin II Receptor Antagonists  

PubMed Central

Urotensin II (UII) binds to its receptor, UT, playing an important role in the heart, kidneys, pancreas, adrenal gland, and central nervous system. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, however, this constriction–dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome, and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) activity leading to smooth muscle cell proliferation and foam cell infiltration, insulin resistance (DMII), as well as inflammation, high blood pressure, and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

Tsoukas, Philip; Kane, Emilie; Giaid, Adel



Molecular properties of psychopharmacological drugs determining non-competitive inhibition of 5-HT3A receptors.  


We developed a structure-property-activity relationship (SPAR)-model for psychopharmacological drugs acting as non-competitive 5-HT(3A) receptor antagonists by using a decision-tree learner provided by the RapidMiner machine learning tool. A single molecular descriptor, namely the molecular dipole moment per molecular weight (mu/MW), predicts whether or not a substance non-competitively antagonizes 5-HT-induced Na(+) currents. A low mu/MW is compatible with drug-cumulation in apolar lipid rafts. This study confirms that size-intensive descriptors allow the development of compact SPAR models. PMID:19144451

Kornhuber, Johannes; Terfloth, Lothar; Bleich, Stefan; Wiltfang, Jens; Rupprecht, Rainer



Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists  

Microsoft Academic Search

In the present study, QSAR calculations were performed on the receptor-based alignment of 58 non-peptide human oxytocin receptor antagonists. With the aid of different scoring functions (AutoDock 3.05 built-in and X-Score 1.2) the evolved receptor–ligand complexes were characterized. By means of various datasets it was confirmed that the scoring functions were not capable to predict the biological activity correctly in

Balázs Jójárt; Árpád Márki



Bosentan, a dual endothelin receptor antagonist, activates the pregnane X nuclear receptor  

Microsoft Academic Search

Recent clinical studies have shown that bosentan, a dual endothelin receptor antagonist, decreases the exposure to various substrates of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. The aim of the study was to investigate the effect of bosentan, its metabolites and glibenclamide on the activity of the pregnane X receptor, a nuclear receptor that regulates the transcription of CYP3A4. CV-1

Paul L. M van Giersbergen; Carmela Gnerre; Alexander Treiber; Jasper Dingemanse; Urs A Meyer



Binding optimization through coordination chemistry: CXCR4 chemokine receptor antagonists from ultra rigid metal complexes  

PubMed Central

A new copper(II) containing bis-macrocyclic CXCR4 chemokine receptor antagonist is shown to have improved binding properties to the receptor protein in comparison to the drug AMD3100 (Plerixafor, Mozobil™). The interaction of the metallodrug has been optimized by using ultra rigid chelator units that offer an equatorial site for coordination to the amino acid side chains of the protein. Binding competition assays with anti-CXCR4 antibodies show that the new compound stays bound longer and it has improved anti-HIV potency in vitro (EC50 = 4.3 nM). X-ray structural studies using acetate as a model for carboxylate amino acid side chains indicate the nature of the coordination interaction.

Khan, Abid; Nicholson, Gary; Greenman, John; Madden, Leigh; McRobbie, Graeme; Pannecouque, Christophe; De Clercq, Erik; Ullom, Robert; Maples, Danny L.; Maples, Randall L.; Silversides, Jon D.; Hubin, Timothy J.; Archibald, Stephen J.



Pharmacological characterization of the muscarinic receptor antagonist, glycopyrrolate, in human and guinea-pig airways  

PubMed Central

In this study we have evaluated the pharmacological profile of the muscarinic antagonist glycopyrrolate in guinea-pig and human airways in comparison with the commonly used antagonist ipratropium bromide.Glycopyrrolate and ipratropium bromide inhibited EFS-induced contraction of guinea-pig trachea and human airways in a concentration-dependent manner. Glycopyrrolate was more potent than ipratropium bromide.The onset of action (time to attainment of 50% of maximum response) of glycopyrrolate was similar to that obtained with ipratropium bromide in both preparations. In guinea-pig trachea, the offset of action (time taken for response to return to 50% recovery after wash out of the test antagonist) for glycopyrrolate (t1/2 [offset]=26.4±0.5?min) was less than that obtained with ipratropium bromide (81.2±3.7?min). In human airways, however, the duration of action of glycopyrrolate (t1/2 [offset]>96?min) was significantly more prolonged compared to ipratropium bromide (t1/2 [offset]=59.2±17.8?min).In competition studies, glycopyrrolate and ipratropium bromide bind human peripheral lung and human airway smooth muscle (HASM) muscarinic receptors with affinities in the nanomolar range (Ki values 0.5–3.6?nM). Similar to ipratropium bromide, glycopyrrolate showed no selectivity in its binding to the M1–M3 receptors. Kinetics studies, however, showed that glycopyrrolate dissociates slowly from HASM muscarinic receptors (60% protection against [3H]-NMS binding at 30?nM) compared to ipratropium bromide.These results suggest that glycopyrrolate bind human and guinea-pig airway muscarinic receptors with high affinity. Furthermore, we suggest that the slow dissociation profile of glycopyrrolate might be the underlying mechanism by which this drug accomplishes its long duration of action.

Haddad, El-Bdaoui; Patel, Hema; Keeling, Joelle E; Yacoub, Magdi H; Barnes, Peter J; Belvisi, Maria G



Lack of IL1 receptor antagonistic activity of the capsular F1 antigen of Yersinia pestis  

Microsoft Academic Search

Because capsular F1 antigen of Yersinia pestis is reported to share sequence homology with interleukin-1 receptor antagonist (IL-1ra), we investigated the potential IL-1 receptor antagonistic activity of F1 on human endothelial cells (EC). The biological activities of IL-1 receptor antagonist (IL-1ra) or IL-1ra-like molecule were measured by its ability to suppress the IL-1?-mediated induction of adhesion molecules (ICAM and ELAM)

Teresa Krakauer; David Heath



Pharmacological profile of a high affinity dipeptide NK1 receptor antagonist, FK888.  

PubMed Central

1. In our search for compounds that inhibit the binding of [3H]-substance P (SP) to guinea-pig lung membranes, the dipeptide SP antagonist, FK888, was developed by chemical modification of the parent compound, (D-Pro4, D-Trp7,9,10, Phe11)SP4-11. 2. In a [3H]-SP binding assay using guinea-pig lung membranes and rat brain cortical synaptic membranes, FK888 displaced [3H]-SP binding with a Ki value of 0.69 +/- 0.13 nM and 0.45 +/- 0.17 microM, respectively, in a competitive manner. 3. FK888 inhibited the contraction of guinea-pig isolated ileum induced by SP in the presence of atropine and indomethacin (a NK1 receptor bioassay) with a pA2 value of 9.29 (8.60-9.98). 4. FK888 inhibited contractions of rat vas deferens by NKA (a NK2 receptor bioassay) and of rat portal vein by NKB (a NK3 receptor bioassay) at concentrations at least 10,000 times greater than that required to inhibit contractions of guinea-pig ileum. 5. FK888 also inhibited SP-induced airway oedema in guinea-pig after both intravenous and oral administration. 6. These data demonstrate that FK888 is a potent and selective NK1 antagonist which is active both in vitro and in vivo.

Fujii, T.; Murai, M.; Morimoto, H.; Maeda, Y.; Yamaoka, M.; Hagiwara, D.; Miyake, H.; Ikari, N.; Matsuo, M.



Transcriptional Regulation by Competition between ELP Isoforms and Nuclear Receptors  

Microsoft Academic Search

ELP is a transcription factor belonging to the nuclear receptor superfamily. The consensus binding sequence for ELP contains a half site of the nuclear receptor recognition element. We demonstrated previously that ELP1, the repressor type isoform of ELP, competes for binding with the retinoic acid receptor and represses retinoic acid-induced transactivation. In this study, competitive repression by ELP1 was investigated

Naoe Kotomura; Yasuharu Ninomiya; Kazuhiko Umesono; Ohtsura Niwa



Pharmacological characterization of the ghrelin receptor antagonist, GSK1614343 in rat RC-4B/C cells natively expressing GHS type 1a receptors.  


A novel growth hormone secretagogues type 1a (GHS1a) receptors antagonist (2R)-N'-[3,5- bis(trifluoromethyl)phenyl]-2-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(3- pyridinyl)ethanohydrazide (GSK1614343) was functionally characterised in rat pituitary adenoma cell line, RC-4B/C endogenously expressing GHS1a receptors. The antagonism profile of GSK1614343 was compared with that of 6-[(4-fluorophenyl)oxy]-2-methyl-3-{[(3S)-1-(1-methylethyl)-3- piperidinyl]methyl}-4(3H)-quinazolinone (YIL-781) another ghrelin receptor antagonist recently published. The activity of both compounds was also evaluated at rat recombinant GHS1a receptors. The characterization of the two antagonists was performed by intracellular calcium mobilization measurements by using fluorometric imaging plate reader (FLIPR) technology and inositol phosphate (IP) turnover measurements by [3H]-IP accumulation assay. RC-4B/C and U2-OS cells transiently transduced with rat GHS1a receptors virus were used. In RC-4B/C cells, GSK1614343 and YIL-781, depressed the ghrelin maximal response in FLIPR assay as result of hemi-equilibria phenomenon. When using the [3H]-IP accumulation assay both compounds behaved as competitive antagonist with pKB values of 8.03 for GSK1614343 and 7.54 for YIL-781. In rat recombinant receptor, GSK1614343 and YIL-781 inhibited the calcium response induced by ghrelin with pIC50 values of 7.90 and 8.27, respectively. GSK1614343 and YIL-781 did not show intrinsic activity in both endogenously expressed and recombinant rat GHS1a receptors. The new ghrelin receptor antagonist GSK1614343 is a potent competitive antagonist in rat pituitary RC-4B/C cells endogenously expressing GHS1a receptors when equilibrium conditions between ligand and receptor are reached in the test assay. GSK1614343 represents a useful tool to investigate the physiological relevance of the ghrelin system in rat models. PMID:21034740

Perdonà, Elisabetta; Faggioni, Federico; Buson, Alberto; Sabbatini, Fabio Maria; Corti, Corrado; Corsi, Mauro



Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity  

Microsoft Academic Search

Studies were conducted to assess progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) with respect to PR agonistic and antagonistic activities in vivo. These properties are not always adequately reflected in transactivation in vitro models. Studies were performed in pregnant rats, estrogen-primed rabbits (McPhail -Test), and cycling and pregnant guinea pigs. Tested compounds included mifepristone (RU486), onapristone, J867, J956, J1042,

Walter Elger; Julia Bartley; Birgitt Schneider; Günther Kaufmann; Gerd Schubert; Kristof Chwalisz



Difference in solute excretion during correction of hyponatremic patients with cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone by oral vasopressin V 2 receptor antagonist VPA985  

Microsoft Academic Search

VPA-985 is an orally active, competitive vasopressin V2 receptor antagonist that in normal human beings increases water excretion without affecting solute excretion. Whether solute excretion is affected in patients with hyponatremia resulting from inappropriate secretion of antidiuretic hormone (SIADH) or from cirrhosis treated with VPA-985 is unknown. Six hyponatremic patients with SIADH and 5 hyponatremic patients with cirrhosis with ascitis

G Decaux



Purification and reconstitution of the calcium antagonist receptor of the voltage-sensitive calcium channel  

SciTech Connect

Treatment with digitonin solubilized the calcium antagonist receptor as a stable complex with (/sup 3/H)nitrendipine from rat brain membranes. The solubilized complex retains allosteric coupling to binding sites for diltiazem, verapamil, and inorganic calcium antagonist sites. The calcium antagonist receptor from cardiac sarcolemma and the transverse-tubule membrane of skeletal muscle is also efficiently solubilized with digitonin and the receptor in all three tissues is a large glycoprotein with a sedimentation coefficient of 20 S. The T-tubule calcium antagonist receptor complex was extensively purified by a combination of chromatography on WGA-Sepharose, ion exchange chromatography, and sedimentation on sucrose gradients to yield preparations estimated to be 41% homogeneous by specific activity and 63% homogeneous by SDS gel electrophoresis. Analysis of SDS gels detect three polypeptides termed ..cap alpha..(Mr 135,000), ..beta..(Mr 50,000), and ..gamma..(Mr 32,000) as noncovalently associated subunits of the calcium antagonist receptor. The ..cap alpha.. and ..gamma.. subunits are glycosylated polypeptides, and the molecular weight of the core polypeptides are 108,000 and 24,000 respectively. The calcium antagonist receptor was reconstituted into a phospholipid bilayer by adding CHAPS and exogeneous lipid to the purified receptor followed by rapid detergent removal. This procedure resulted in the incorporation of 45% of the calcium antagonist receptor into closed phospholipid vesicles. Data suggests that the ..cap alpha.., ..beta.., and ..gamma.. subunits of the T-tubule calcium antagonist receptor are sufficient to form a functional calcium channel.

Curtis, B.M.



Recent advances on A? adenosine receptor antagonists by QSAR tools.  


Adenosine receptors (ARs) are widespread on virtually every human organ/tissue, and have long been considered promising therapeutic targets in a wide range of conditions, ranging from cerebral diseases to cancer, including inflammatory disorders. The knowledge acquired up to date in relation to ARs, in particular regarding the molecular biology of the A3 AR has provided a solid basis that led to the proposal of this receptor as a novel therapeutic target enabling the rational design and development of potent and selective A3 AR ligands. This review attempts to summarize the most recent developments in the A3 research field, focusing in particular on Quantitative Structure-Activity Relationships (QSAR) based studies that supported so far the design of new, potent and selective human A3 AR antagonists. In addition, a classical QSAR modeling study carried out on two series of pyrazolo-triazolopyrimidine derivatives is presented as a case study. Specifically, a systematic evaluation of linear and non-linear models along with a variety of structure representations and feature selection tools is reported. The combination of these techniques (neural networks to capture non-linear relationships in the data and feature selection to prevent over-fitting) was found to produce QSAR models with good overall accuracy and robustness, as well as predictivity on external data. Moreover, the study indicated that the antagonist activity of these derivatives is largely explained by electrostatic, steric and hydrogen-bonding factors, highlighting the role of the size, shape and type of inhibitor in forming effective blocking of the A3 AR subtype. The developed QSAR models could then be usefully employed to design new compounds selectively active towards the A3 adenosine receptor. PMID:22352915

Luan, Feng; Borges, Fernanda; Cordeiro, M Natália D S



Regional effects of MK-801 on dopamine release: effects of competitive NMDA or 5-HT2A receptor blockade.  


The open channel N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine (MK-801) and phencyclidine (PCP) increase the firing rate of both A9 and A10 dopaminergic neurons in the rat. In the A10 nucleus, this effect of MK-801 is reportedly prevented by either competitive NMDA antagonists or serotonin2 (5-HT2) antagonists. The present study examined the neurochemical correlates of these effects using the technique of in vivo microdialysis in conscious rats. In contrast to its reported electrophysiological effects at the cell body level, MK-801 (2 mg/kg, i.p.) has divergent effects on dopamine release in the terminal fields of the A9 and A10 systems. MK-801 stimulated dopamine release in both the medial prefrontal cortex and the nucleus accumbens but tended to decrease release in the striatum. Stimulated dopamine release in the nucleus accumbens was selectively blocked by either the competitive NMDA receptor antagonist, MDL 100,453 or the 5-HT2A receptor antagonist, MDL 100,907. Neither MDL 100,453 nor MDL 100,907 affected MK-801-induced release in the medial prefrontal cortex. The results illustrate the complex regulation of the forebrain dopaminergic systems by glutamate and indicate that the serotonergic system, via the 5-HT2A receptor, may play an important role in this regulation. PMID:8667221

Schmidt, C J; Fadayel, G M



Luteinizing hormone-releasing hormone (LHRH) receptor agonists vs antagonists: a matter of the receptors?  


Luteinizing hormone-releasing hormone (LHRH) agonists and antagonists are commonly used androgen deprivation therapies prescribed for patients with advanced prostate cancer (PCa). Both types of agent target the receptor for LHRH but differ in their mode of action: agonists, via pituitary LRHR receptors (LHRH-Rs), cause an initial surge in luteinizing hormone (LH), follicle-stimulating hormone (FSH) and, subsequently, testosterone. Continued overstimulation of LHRH-R down-regulates the production of LH and leads to castrate levels of testosterone. LHRH antagonists, however, block LHRH-R signalling causing a rapid and sustained inhibition of testosterone, LH and FSH. The discovery and validation of the presence of functional LHRH-R in the prostate has led to much work investigating the role of LHRH signalling in the normal prostate as well as in the treatment of PCa with LHRH agonists and antagonists. In this review we discuss the expression and function of LHRH-R, as well as LH/human chorionic gonadotropin receptors and FSH receptors and relate this to the differential clinical responses to agonists and antagonists used in the hormonal manipulation of PCa. PMID:23418666

Tolkach, Yuri; Joniau, Steven; Van Poppel, Hendrik



Opioid agonist and antagonist treatment differentially regulates immunoreactive ?-opioid receptors and dynamin-2 in vivo  

Microsoft Academic Search

Opioid agonists and antagonists can regulate the density of ?-opioid receptors in whole animal and in cell culture. High intrinsic efficacy agonists (e.g., etorphine), but not lower intrinsic efficacy agonists (e.g., morphine), produce ?-opioid receptor down-regulation and can alter the abundance of ?-opioid receptor mRNA. Conversely, opioid antagonists substantially increase the density of ?-opioid receptors without changing its mRNA. ?-Opioid

Byron C. Yoburn; Vishal Purohit; Kaushal Patel; Qiuyu Zhang



5HT 3 receptor antagonists and anxiety; a preclinical and clinical review  

Microsoft Academic Search

The present paper reviews the evidence for anxiolytic activity of 5-HT3 receptor antagonists in animal models of anxiety and in clinical trials in humans. Compared to the established anxiolytics (benzodiazepine receptor agonists and, to a lesser extent, 5-HT1A receptor agonists) 5-HT3 receptor antagonists display a different anxiolytic profile. They are anxiolytic in a limited number of animal anxiety models. If

Berend Olivier; Ineke van Wijngaarden; Willem Soudijn



Endogenous Alzheimer's brain factor and oxidized glutathione inhibit antagonist binding to the muscarinic receptor  

Microsoft Academic Search

An endogenous inhibitor (< 3,500 Da) of antagonist binding to the muscarinic acetylcholine receptor has been extracted from Alzheimer's disease (AD) brain with trifluoracetic acid. Oxidized glutathione, (GSSG) has also been found to inhibit antagonist binding to the receptor. However, in its reduced form, glutathione (GSH) like other reducing agents, markedly enhances the inhibitory effect of both GSSG and the

William H. Frey; Melissa M. Najarian; Kavita S. Kumar; Carolyn R. Emory; Patrick M. Menning; John C. Frank; Melissa N. Johnson; Thomas A. Ala



Inhibition of tolerance to spinal morphine antinociception by low doses of opioid receptor antagonists  

Microsoft Academic Search

Ultra-low doses of opioid receptor antagonists inhibit development of chronic spinal morphine tolerance. As this phenomenon mechanistically resembles acute tolerance, the present study examined actions of opioid receptor antagonists on acute spinal morphine tolerance. In adult rats, administration of three intrathecal injections of morphine (15 ?g) at 90 min intervals produced a significant decline of the antinociceptive effect and loss of agonist

Benjamin McNaull; Tuan Trang; Maaja Sutak; Khem Jhamandas



Prazosin, an alpha 1-adrenergic Receptor Antagonist, Suppresses Experimental Autoimmune Encephalomyelitis in the Lewis Rat  

Microsoft Academic Search

Prazosin, an antagonist of alpha 1-adrenergic receptors, has been found to suppress the clinical and histological expression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Suppression was more significant in females than in males and was a dose-dependent phenomenon. Analysis of the effect of other adrenergic receptor antagonists supports the conclusion that the suppressive effect of prazosin is a

Celia F. Brosnan; Ellen A. Goldmuntz; Wendy Cammer; Stephen M. Factor; Barry R. Bloom; William T. Norton



Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist  

Microsoft Academic Search

Human monocytes induced with adherent IgG secrete an interleukin-1 receptor antagonist which could be important for the in vivo regulation of IL-1 activity. A complementary DNA for this molecule has been isolated from a human monocyte library. Analysis of monocyte RNA indicates that the gene is transcriptionally regulated. The sequence of the receptor antagonist indicates that it is structurally similar

Stephen P. Eisenberg; Ron J. Evans; William P. Arend; Evie Verderber; Michael T. Brewer; Charles H. Hannum; Robert C. Thompson



Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for “NMDA antagonist modelling” of schizophrenia  

Microsoft Academic Search

Rationale  Little attention has been paid to the relative equivalence of behavioural effects of NMDA receptor antagonists in rodents,\\u000a with different compounds often used interchangeably to “model” aspects of schizophrenia in preclinical studies.\\u000a \\u000a \\u000a \\u000a Objectives  To further resolve such conjecture, the present study systematically compared eight different NMDA receptor antagonists: MK-801,\\u000a PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in

Gary Gilmour; Elsa Y. Pioli; Sophie L. Dix; Janice W. Smith; Michael W. Conway; Wendy T. Jones; Sally Loomis; Rebecca Mason; Shahram Shahabi; Mark D. Tricklebank



IL-1? Receptor Antagonist Reduces Inflammation in Hemodialysis Patients  

PubMed Central

Chronic inflammation is highly prevalent in maintenance hemodialysis (MHD) patients and associates with increased mortality. IL-1?, a pro-inflammatory cytokine, is elevated in MHD patients. A balance between IL-1? and its naturally occurring antagonist may determine the inflammatory response and its consequences in this population. We performed a pilot randomized placebo-controlled trial to evaluate the efficacy of the administration of recombinant human IL-1 receptor antagonist (IL-1ra) on biomarkers of inflammation and nutrition in MHD patients with three consecutive high sensitivity C-reactive protein (hsCRP) measurements >5 mg/L. We randomly assigned 22 patients to placebo or IL-1ra (1:1) for 4 weeks; 14 completed the trial. Patients in the IL-1ra arm had a 53% reduction in mean hsCRP compared with 1% in the placebo arm (P = 0.008), a 40% reduction in mean IL-6 levels compared with a 20% increase in the placebo arm (P = 0.03), and a 23% increase in mean prealbumin compared with 6% in the placebo arm (P = NS). In conclusion, the administration of IL-1ra in MHD patients can lower biomarkers of inflammation. Whether IL-1ra administration improves survival in this population requires additional long-term studies.

Hung, Adriana M.; Ellis, Charles D.; Shintani, Ayumi; Booker, Cindy



Asymmetric synthesis of a selective endothelin A receptor antagonist.  


An asymmetric synthesis of a selective endothelin A receptor antagonist 1b is described. Asymmetric conjugate addition of aryllithium derived from 18 to the chiral oxazoline 17 followed by hydrolysis afforded 15 in 96% ee via purification as (S)-(-)-1-phenylethylamine salt. Pd(OAc)(2)/dppf (1,1'-bis(diphenylphosphino)ferrocene) catalyzed carbonylation followed by chemoselective addition of aryllithium derived from 23 which gave ketone 24. Diastereoselective reduction of the ketone with catecholborane followed by concomitant activation of the resulting alcohol and cyclization gave the late intermediate 26. Introduction of amino moiety on the pyridine ring by imidoyl rearrangement followed by deprotection and purification by crystallization furnished the enantiomerically pure target molecule 1b in 8% overall yield from 16. PMID:12192138

Kato, Yoshiaki; Niiyama, Kenji; Jona, Hideki; Okada, Shigemitsu; Akao, Atsushi; Hiraga, Shouichi; Tsuchiya, Yoshimi; Tomimoto, Koji; Mase, Toshiaki



Two Cases of H2-Receptor Antagonist Hypersensitivity and Cross-Reactivity  

PubMed Central

H2-receptor antagonists, such as cimetidine, ranitidine and famotidine, are some of the most commonly prescribed medications for gastric acid-related disorders. These compounds are generally well-tolerated and anaphylactic reactions to them are rare. Here, we report two cases of H2-receptor antagonist-induced anaphylactic reactions: the first presented with sudden dyspnea, sneezing, urticaria, and swelling of the eyelids after ranitidine intake. The second presented with sudden severe urticaria, facial swelling, chest discomfort, dizziness, and hypotension. Possible cross-reactivity with other H2-receptor antagonists was assessed by oral challenge and skin tests. To date, only a few reports addressing cross-reactivity among H2-receptor antagonists have been published. We review the literature and summarize the data available on drug cross-reactivity in H2-receptor antagonist hypersensitivity.

Song, Woo-Jung; Kim, Min-Hye; Lee, Sang-Min; Kwon, Yong-Eun; Kim, Sae-Hoon; Cho, Sang-Heon; Min, Kyung-Up; Kim, You-Young



Straub tail reaction in mice treated with ?(1) receptor antagonist in combination with methamphetamine.  


Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific ? receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative ?(1) receptor agonist) and partially by PB 28 (a putative ?(2) receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative ?(1) receptor antagonist), but not SM-21, a putative ?(2) receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective ?-agonist), suggesting that the STR may be mediated by activation of opioid receptor system. PMID:22981417

Kitanaka, Junichi; Kitanaka, Nobue; Hall, F Scott; Uhl, George R; Tanaka, Koh-Ichi; Nishiyama, Nobuyoshi; Takemura, Motohiko



Rates and equilibria for a photoisomerizable antagonist at the acetylcholine receptor of Electrophorus electroplaques  

PubMed Central

Voltage-jump and light-flash experiments have been performed on isolated Electrophorus electroplaques exposed simultaneously to nicotinic agonists and to the photoisomerizable compound 2,2'-bis- [alpha-(trimethylammonium)methyl]-azobenzene (2BQ). Dose-response curves are shifted to the right in a nearly parallel fashion by 2BQ, which suggests competitive antagonism; dose-ratio analyses show apparent dissociation constants of 0.3 and 1 microM for the cis and trans isomers, respectively. Flash-induced trans----cis concentration jumps produce the expected decrease in agonist-induced conductance; the time constant is several tens of milliseconds. From the concentration dependence of these rates, we conclude that the association and dissociation rate constants for the cis-2BQ-receptor binding are approximately 10(8) M-1 s-1 and 60 s-1 at 20 degrees C; the Q10 is 3. Flash-induced cis----trans photoisomerizations produce molecular rearrangements of the ligand-receptor complex, but the resulting relaxations probably reflect the kinetics of buffered diffusion rather than of the interaction between trans-2BQ and the receptor. Antagonists seem to bind about an order of magnitude more slowly than agonists at nicotinic receptors.



Effects of a Novel Bradykinin B1 Receptor Antagonist and Angiotensin II Receptor Blockade on Experimental Myocardial Infarction in Rats  

PubMed Central

Background The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI) and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1) receptor antagonist after MI in rats. Methodology/Principal Findings Sprague Dawley rats were subjected to permanent occlusion of the left descending coronary artery. Cardiovascular function was determined at 7 days post MI. Treatment with either B1 receptor antagonist (BI-113823) or AT1 receptor antagonist (irbesartan) alone or in combination improved post-MI cardiac function as evidenced by attenuation of elevated left ventricular end diastolic pressure (LVEDP); greater first derivative of left ventricular pressure (± dp/dt max), left ventricle ejection fraction, fractional shorting, and better wall motion; as we as reductions in post-MI up-regulation of matrix metalloproteinases 2 (MMP-2) and collagen III. In addition, the cardiac up-regulation of B1 receptor and AT1 receptor mRNA were markedly reduced in animals treated with BI 113823, although bradykinin B2 receptor and angiotensin 1 converting enzyme (ACE1) mRNA expression were not significantly affected by B1 receptor blockade. Conclusions/Significance The present study demonstrates that treatment with the novel B1 receptor antagonist, BI-113823 improves post-MI cardiac function and does not influence the cardiovascular effects of AT1 receptor antagonist following MI.

Wu, Dongmei; Lin, Xinchun; Bernloehr, Christian; Hildebrandt, Tobias; Doods, Henri



Differential locomotor interactions between dopamine D1\\/D2 receptor agonists and the NMDA antagonist dizocilpine in monoamine-depleted mice  

Microsoft Academic Search

Summary Previous work in our laboratory has shown that the non-competitive N-methyl-D-aspartate antagonist dizocilpine (MK-801) interacts synergistically with the mixed dopamine (DA) receptor agonist apomorphine and the DA D 1 agonist SKF 38393 to promote locomotion in monoamine-depleted mice. The purpose of the present study was to compare the roles of DA D 1 and DA D 2 receptors in

A. Svensson; A. Carlsson; M. L. Carlsson



The metabotropic glutamate receptor subtype 5 antagonist MPEP and the Na + channel blocker riluzole show different neuroprotective profiles in reversing behavioral deficits induced by excitotoxic prefrontal cortex lesions  

Microsoft Academic Search

Overactivation of excitatory amino acid receptors has been involved in several neurodegenerative diseases. The present study aims at investigating the potential neuroprotective action of 2-methyl-6-(phenylethylnyl)-pyridine (MPEP), a selective non-competitive antagonist of metabotropic glutamate receptor subtype 5, and 2-amino-6-trifluoro methoxy-benzothiole (riluzole), a Na+ channel blocker exhibiting anti-glutamatergic properties, on the ibotenate-induced damage to the rat medial prefrontal cortex. The neuroprotective efficacy

C. Risterucci; R. Coccurello; M. Banasr; J. M. Stutzmann; M. Amalric; A. Nieoullon



Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions  

SciTech Connect

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.

Smith, C.B.; Medzihradsky, F.; Woods, J.H.



Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties  

PubMed Central

Chronic use of mu-opioid agonists has been shown to cause neurochemical adaptations resulting in tolerance and dependence. While the analgesic effects of these drugs are mediated by mu-opioid receptors (MOR), several studies have shown that antagonism or knockdown of delta-opioid receptors (DOR) can lessen or prevent development of tolerance and dependence. Based on computational modeling of putative active and inactive conformations of MOR and DOR, we have synthesized a series of pentapeptides with the goal of developing a MOR agonist/DOR antagonist peptide with similar affinity at both receptors as a tool to probe functional opioid receptor interaction(s). The eight resulting naphthylalanine-substituted cyclic pentapeptides displayed variable mixed-efficacy profiles. The most promising peptide (9; Tyr-c(S-CH2-S)[D-Cys-Phe-2-Nal-Cys]NH2) displayed a MOR agonist and DOR partial agonist/antagonist profile and bound with equipotent affinity (Ki ~ 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity.

Purington, Lauren C.; Pogozheva, Irina D.; Traynor, John R.; Mosberg, Henry I.



Interaction of narcotic antagonist naltrexone with nicotinic acetylcholine receptor.  


The interactions of naltrexone with the nicotinic acetylcholine receptor were studied electrophysiologically using the frog sciatic nerve-sartorius muscle and biochemically using membranes from the electric organ of Torpedo ocellata. At nanomolar concentrations naltrexone increased the peak amplitude of endplate currents with little change in the decay time constant. At micromolar concentrations there was a concentration-dependent depression of endplate current and miniature endplate current amplitudes and decay time constants. Decay time constant depression was enhanced with hyperpolarization. Only marginal curvature was induced in peak endplate current amplitude versus membrane voltage plots by naltrexone. Naltrexone had no effect on single channel conductance but decreased open channel lifetime, according to fluctuation analysis. Naltrexone alone (less than or equal to 3 microM) did not impair binding of [125I]alpha-bungarotoxin to the receptor in a fast pre-equilibration assay, but increased the ability of acetylcholine to displace [125I]alpha-bungarotoxin. The drug displaced the agonist-stimulated binding of [3H]perhydrohistrionicotoxin to the channel site. Biphasic functional changes in neuromuscular transmission can be attributed to an allosteric mechanism with increased agonist binding to the nicotinic receptor at nanomolar concentrations and caused a non-competitive blockade of the ionic channel at micromolar concentrations. PMID:3653249

Oliveira, L; Madsen, B W; Kapai, N; Sherby, S M; Swanson, K L; Eldefrawi, M E; Albuquerque, E X



Intracellular Function of Interleukin-1 Receptor Antagonist in Ischemic Cardiomyocytes  

PubMed Central

Background Loss of cardiac myocytes due to apoptosis is a relevant feature of ischemic heart disease. It has been described in infarct and peri-infarct regions of the myocardium in coronary syndromes and in ischemia-linked heart remodeling. Previous studies have provided protection against ischemia-induced cardiomyocyte apoptosis by the anti-inflammatory cytokine interleukin-1 receptor-antagonist (IL-1Ra). Mitochondria triggering of caspases plays a central role in ischemia-induced apoptosis. We examined the production of IL-1Ra in the ischemic heart and, based on dual intra/extracellular function of some other interleukins, we hypothesized that IL-1Ra may also directly inhibit mitochondria-activated caspases and cardiomyocyte apoptosis. Methodology/Principal Findings Synthesis of IL-1Ra was evidenced in the hearts explanted from patients with ischemic heart disease. In the mouse ischemic heart and in a mouse cardiomyocyte cell line exposed to long-lasting hypoxia, IL-1Ra bound and inhibited mitochondria-activated caspases, whereas inhibition of caspase activation was not observed in the heart of mice lacking IL-1Ra (Il-1ra?/?) or in siRNA to IL-1Ra-interfered cells. An impressive 6-fold increase of hypoxia-induced apoptosis was observed in cells lacking IL-1Ra. IL-1Ra down-regulated cells were not protected against caspase activation and apoptosis by knocking down of the IL-1 receptor, confirming the intracellular, receptor-independent, anti-apoptotic function of IL-1Ra. Notably, the inhibitory effect of IL-1Ra was not influenced by enduring ischemic conditions in which previously described physiologic inhibitors of apoptosis are neutralized. Conclusions/Significance These observations point to intracellular IL-1Ra as a critical mechanism of the cell self-protection against ischemia-induced apoptosis and suggest that this cytokine plays an important role in the remodeling of heart by promoting survival of cardiomyocytes in the ischemic regions.

Vecile, Elena; Dobrina, Aldo; Salloum, Fadi N.; Van Tassell, Benjamin W.; Falcione, Antonella; Gustini, Edoardo; Secchiero, Samuele; Crovella, Sergio; Sinagra, Gianfranco; Finato, Nicoletta; Nicklin, Martin J.; Abbate, Antonio



Inhaled muscarinic acetylcholine receptor antagonists for treatment of COPD.  


Bronchodilators, generally administered via metered dose or dry powder inhalers, are the mainstays of pharmacological treatment of stable COPD. Inhaled long-acting beta-agonists (LABA) and anticholinergics are the bronchodilators primarily used in the chronic treatment of COPD. Anticholinergics act as muscarinic acetylcholine receptor antagonists and are frequently preferred over beta-agonists for their minimal cardiac stimulatory effects and greater efficacy in most studies. Their therapeutic efficacy is based on the fact that vagally mediated bronchoconstriction is the major reversible component of airflow obstruction in patients with COPD. However, bronchodilators are effective only on the reversible component of airflow obstruction, which by definition is limited, as COPD is characterized by a fixed or poorly reversible airflow obstruction. Inhaled anticholinergic antimuscarinic drugs approved for the treatment of COPD include ipratropium bromide, oxitropium bromide and tiotropium bromide. Ipratropium bromide, the prototype of anticholinergic bronchodilators, is a short-acting agent. Oxitropium bromide is administered twice a day. Tiotropium bromide, the only long-acting antimuscarinic agent (LAMA) currently approved, is administered once a day. Newer LAMAs including aclidinium bromide and glycopyrrolate bromide are currently in phase III development for treatment of COPD. Some new LAMAs, including glycocpyrrolate, are suitable for once daily administration and, unlike tiotropium, have a rapid onset of action. New LAMAs and their combination with ultra-LABA and, possibly, inhaled corticosteroids, seem to open new perspectives in the management of COPD. Dual-pharmacology muscarinic antagonist-beta2 agonist (MABA) molecules present a novel approach to the treatment of COPD by combining muscarinic antagonism and beta2 agonism in a single molecule. PMID:22963553

Montuschi, P; Macagno, F; Valente, S; Fuso, L



Discovery and pharmacological characterization of a small-molecule antagonist at neuromedin U receptor NMUR2.  


Neuromedin U (NMU), through its cognate receptor NMUR2 in the central nervous system, regulates several important physiological functions, including energy balance, stress response, and nociception. By random screening of our corporate compound collection with a ligand binding assay, we discovered (R)-5'-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (R-PSOP), a highly potent and selective NMUR2 antagonist. R-PSOP is a nonpeptidic small-molecule with the chemical composition C(20)N(4)O(2)H(22). In competition binding experiments, this compound was found to bind to NMUR2 with high affinity; the K(i) values were determined to be 52 and 32 nM for the human and rat NMUR2, respectively. Moreover, in functional assays measuring phosphoinositide turnover or intracellular calcium mobilization, R-PSOP strongly inhibited the responses stimulated by peptide agonists NMU-25, NMU-23, and NMU-8 in human embryonic kidney 293 cells expressing NMUR2. From Schild analyses, the functional K(b) values for R-PSOP were determined to be 92 and 155 nM at human and rat NMUR2, respectively. Highly selective for NMUR2, R-PSOP exhibited low affinity to the other subtype of NMU receptor, NMUR1, with a K(i) value >10 microM. R-PSOP in vivo attenuated NMU-23-evoked nociceptive responses in a rat spinal reflex preparation. To our knowledge, this is the first antagonist ever reported for NMU receptors. This compound could serve as a valuable tool for further understanding the physiological and pathophysiological roles of NMU system, while providing a chemical starting point that may lead to development of new therapeutics for treatment of eating disorders, obesity, pain, and stress-related disorders. PMID:19369576

Liu, Jay J; Payza, Kemal; Huang, Jian; Liu, Ruifeng; Chen, Tongming; Coupal, Martin; Laird, Jennifer M A; Cao, Chang-Qing; Butterworth, Joanne; Lapointe, Stéphanie; Bayrakdarian, Malken; Trivedi, Shephali; Bostwick, J Robert



AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist  

PubMed Central

Background and purpose: Purinoceptors containing the P2X3 subunit (P2X3 homotrimeric and P2X2/3 heterotrimeric) are members of the P2X family of ion channels gated by ATP and may participate in primary afferent sensitization in a variety of pain-related diseases. The current work describes the in vitro pharmacological characteristics of AF-353, a novel, orally bioavailable, highly potent and selective P2X3/P2X2/3 receptor antagonist. Experimental approach: The antagonistic potencies (pIC50) of AF-353 for rat and human P2X3 and human P2X2/3 receptors were determined using methods of radioligand binding, intracellular calcium flux and whole cell voltage-clamp electrophysiology. Key results: The pIC50 estimates for these receptors ranged from 7.3 to 8.5, while concentrations 300-fold higher had little or no effect on other P2X channels or on an assortment of receptors, enzymes and transporter proteins. In contrast to A-317491 and TNP-ATP, competition binding and intracellular calcium flux experiments suggested that AF-353 inhibits activation by ATP in a non-competitive fashion. Favourable pharmacokinetic parameters were observed in rat, with good oral bioavailability (%F = 32.9), reasonable half-life (t1/2 = 1.63 h) and plasma-free fraction (98.2% protein bound). Conclusions and implications: The combination of a favourable pharmacokinetic profile with the antagonist potency and selectivity for P2X3 and P2X2/3 receptors suggests that AF-353 is an excellent in vivo tool compound for study of these channels in animal models and demonstrates the feasibility of identifying and optimizing molecules into potential clinical candidates, and, ultimately, into a novel class of therapeutics for the treatment of pain-related disorders.

Gever, Joel R; Soto, Rothschild; Henningsen, Robert A; Martin, Renee S; Hackos, David H; Panicker, Sandip; Rubas, Werner; Oglesby, Ian B; Dillon, Michael P; Milla, Marcos E; Burnstock, Geoffrey; Ford, Anthony PDW



The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system.  


Thiocolchicoside (TCC) is used clinically for its muscle relaxant, anti-inflammatory, and analgesic properties, and it has been shown to interact with gamma-aminobutyric acid (GABA) type A receptors (GABAARs) and strychnine-sensitive glycine receptors in the rat central nervous system. In contrast to a proposed agonistic action at these two types of inhibitory receptors, pharmacological evidence has shown that, under certain conditions, TCC manifests convulsant activity in animals and humans. We now show that the phasic and tonic GABAAR-mediated currents recorded from Purkinje cells and granule neurons, respectively, in parasagittal cerebellar slices from adult male rats were inhibited by TCC in a concentration-dependent manner. The median inhibitory concentrations of TCC for these effects were approximately 0.15 and approximately 0.9 microM, respectively. TCC did not potentiate GABABR-mediated currents in hippocampal slices, suggesting that its muscle relaxant action is not mediated by GABABRs. Intraperitoneal injection of TCC in rats either alone or in combination with negative modulators of GABAergic transmission revealed convulsant and proconvulsant actions of this drug. Our data, consistent with clinical observations of the epileptogenic effect of this compound, suggest that TCC is a potent competitive antagonist of GABAAR function. PMID:16806306

Carta, Mario; Murru, Luca; Botta, Paolo; Talani, Giuseppe; Sechi, GianPietro; De Riu, PierLuigi; Sanna, Enrico; Biggio, Giovanni



Histamine H4 receptor antagonists as potent modulators of mammalian vestibular primary neuron excitability  

PubMed Central

BACKGROUND AND PURPOSE Betahistine, the main histamine drug prescribed to treat vestibular disorders, is a histamine H3 receptor antagonist. Here, we explored the potential for modulation of the most recently cloned histamine receptor (H4 receptor) to influence vestibular system function, using a selective H4 receptor antagonist JNJ 7777120 and the derivate compound JNJ 10191584. EXPERIMENTAL APPROACH RT-PCR was used to assess the presence of H4 receptors in rat primary vestibular neurons. In vitro electrophysiological recordings and in vivo behavioural approaches using specific antagonists were employed to examine the effect of H4 receptor modulation in the rat vestibular system. KEY RESULTS The transcripts of H4 and H3 receptors were present in rat vestibular ganglia. Application of betahistine inhibited the evoked action potential firing starting at micromolar range, accompanied by subsequent strong neuronal depolarization at higher concentrations. Conversely, reversible inhibitory effects elicited by JNJ 10191584 and JNJ 7777120 began in the nanomolar range, without inducing neuronal depolarization. This effect was reversed by application of the selective H4 receptor agonist 4-methylhistamine. Thioperamide, a H3/H4 receptor antagonist, exerted effects similar to those of H3 and H4 receptor antagonists, namely inhibition of firing at nanomolar range and membrane depolarization above 100 µM. H4 receptor antagonists significantly alleviated the vestibular deficits induced in rats, while neither betahistine nor thioperamide had significant effects. CONCLUSIONS AND IMPLICATIONS H4 receptor antagonists have a pronounced inhibitory effect on vestibular neuron activity. This result highlights the potential role of H4 receptors as pharmacological targets for the treatment of vestibular disorders.

Desmadryl, G; Gaboyard-Niay, S; Brugeaud, A; Travo, C; Broussy, A; Saleur, A; Dyhrfjeld-Johnsen, J; Wersinger, E; Chabbert, C



MK-801, phencyclidine (PCP), and PCP-like drugs increase burst firing in rat A10 dopamine neurons: comparison to competitive NMDA antagonists.  


Extracellular single-unit recordings were used to assess the effects of PCP and PCP-like drugs (MK-801 and TCP) on the burst firing of ventral tegmental A10 dopamine neurons in the rat. The effects of these noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were compared to the potent and competitive NMDA antagonists CGS 19755 and (+/-)CPP, and to BTCP, a PCP-derivative possessing little affinity for the PCP binding site within the ion channel gated by NMDA. PCP, MK-801, and TCP produced dose-dependent increases in the firing rate, which were accompanied by increases in the amount of burst activity, the number of action potentials within a burst, and the conversion of nonbursty cells to bursty. However, the coefficient of variation, a measure of the regularity of firing, was not significantly altered. These predominately excitatory effects contrast with the inhibition of firing, decrease in bursting, and regularization of pattern produced by BTCP. CGS 197555 and (+/-)CPP failed to alter any of the measured parameters. Thus, the increase in firing rate and amount of burst activity of dopamine neurons produced by PCP and PCP-like drugs, and the resultant hyperdopaminergia within the mesolimbic-mesocortical regions, could underlie the psychotomimetic properties of these compounds. Moreover, this effect would not appear to be related to a loss of activity at the NMDA recognition site, as evidenced by the lack of effect of the competitive NMDA antagonists. PMID:8446919

French, E D; Mura, A; Wang, T



Rate constants of agonist binding to muscarinic receptors in rat brain medulla. Evaluation by competition kinetics  

SciTech Connect

The method of competition kinetics, which measures the binding kinetics of an unlabeled ligand through its effect on the binding kinetics of a labeled ligand, was employed to investigate the kinetics of muscarinic agonist binding to rat brain medulla pons homogenates. The agonists studied were acetylcholine, carbamylcholine, and oxotremorine, with N-methyl-4-(TH)piperidyl benzilate employed as the radiolabeled ligand. Our results suggested that the binding of muscarinic agonists to the high affinity sites is characterized by dissociation rate constants higher by 2 orders of magnitude than those of antagonists, with rather similar association rate constants. Our findings also suggest that isomerization of the muscarinic receptors following ligand binding is significant in the case of antagonists, but not of agonists. Moreover, it is demonstrated that in the medulla pons preparation, agonist-induced interconversion between high and low affinity bindings sites does not occur to an appreciable extent.

Schreiber, G.; Henis, Y.I.; Sokolovsky, M.



Different affinity states of alpha-1 adrenergic receptors defined by agonists and antagonists in bovine aorta plasma membranes  

SciTech Connect

Evidence for a nonlinear relationship between alpha-1 adrenergic receptor occupancy and tissue responses, together with the finding of different affinity states for agonist binding, has raised the possibility of functional heterogeneity of alpha-1 adrenergic receptors. We have conducted studies to examine: 1) binding characteristics of (/sup 3/H)prazosin, 2) competition of antagonists at these sites and 3) different affinity states of the receptor for agonists and modulation of these states by 5'-guanylylimidodiphosphate (Gpp(NH)p). A plasma membrane-enriched vesicular fraction (F2; 15%/33% sucrose interphase) was prepared from the muscular medial layer of bovine thoracic aorta. (/sup 3/H)Prazosin binding was characterized by a monophasic saturation isotherm (KD = 0.116 nM, Bmax = 112 fmol/mg of protein). Antagonist displacement studies yielded a relative potency order of prazosin greater than or equal to WB4104 much greater than phentolamine greater than corynanthine greater than yohimbine greater than or equal to idazoxan greater than rauwolscine. Competition curves for unlabeled prazosin, WB4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane) and phentolamine were shallow and were best modeled to two binding sites with picomolar and nanomolar KD values. Gpp(NH)p was without effect on antagonist affinity. Agonist (epinephrine, norepinephrine and phenylephrine) competition with (/sup 3/H)prazosin binding was biphasic with pseudo-Hill slopes less than 1.0. Binding was best described by a two-site model in which the average contribution of high affinity sites was 23% of total binding. KD values for the high affinity site ranged from 2.9 to 18 nM, and 3.9 to 5.0 microM for the low affinity site.

Jagadeesh, G.; Deth, R.C.



Volunteer models for predicting antiemetic activity of 5-HT3-receptor antagonists.  

PubMed Central

1. Selective 5-HT3-receptor antagonists are highly effective in preventing nausea and vomiting associated with chemotherapy, radiotherapy and surgery. Their pharmacological activity may be determined in vitro and in animal models of emesis. However, these methods may not give an accurate indication of the antiemetic dose range of 5-HT3-receptor antagonists in patients. Two volunteer models have been used to predict more accurately clinically effective antiemetic doses of 5-HT3-receptor antagonists. 2. The flare response to intradermal 5-HT is thought to be mediated by excitation of 5-HT3-receptors on cutaneous afferents, with release of substance P and subsequent vasodilation. Antagonism of the flare response appears to provide an indication of the effective antiemetic dose of 5-HT3-receptor antagonists but data on duration of action are conflicting. 3. Ipecacuanha-induced emesis is thought to be mediated through both peripheral and central 5-HT3-receptors. Antagonism of this response has demonstrated a close correlation with clinically effective antiemetic doses of the specific 5-HT3-receptor antagonist, ondansetron, and has the advantage of being more conceptually relevant than the flare model. 4. Further work, with newer 5-HT3-receptor antagonists, will clarify the role of these models as predictive of the use of these drugs in clinical practice.

Minton, N A



The Gerbil Elevated Plus-maze II: Anxiolytic-like Effects of Selective Neurokinin NK1 Receptor Antagonists  

Microsoft Academic Search

Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human

Geoffrey B Varty; Mary E Cohen-Williams; Cynthia A Morgan; Ursula Pylak; Ruth A Duffy; Jean E Lachowicz; Galen J Carey; Vicki L Coffin



Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations  

PubMed Central

BACKGROUND AND PURPOSE The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in guinea-pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated. EXPERIMENTAL APPROACH Antagonist selectivity was assessed using a panel of human recombinant prostanoid receptor-fluorimetric imaging plate reader assays. Potencies/affinities and onset half-times of agonists and antagonists were obtained on guinea-pig-isolated aorta and vas deferens. n-Octanol-water partition coefficients were predicted. KEY RESULTS L-798106, L-826266 and the less lipophilic congener (DG)-3ap appear to behave as selective, competitive-reversible EP3 antagonists. For ligands of low to moderate lipophilicity, potency increments for EP3 and TP (thromboxane-like) agonism on guinea-pig aorta (above pEC50 of 8.0) were associated with progressively longer onset half-times; similar trends were found for TP and histamine H1 antagonism above a pA2 limit of 8.0. In contrast, L-798106 (EP3), L-826266 (EP3, TP) and the lipophilic H1 antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)-3ap (EP3) had a faster onset. Agonism and antagonism on the vas deferens EP3 system were overall much faster, although trends were similar. CONCLUSIONS AND IMPLICATIONS High affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP3 antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP3 antagonists is discussed.

Jones, RL; Woodward, DF; Wang, JW; Clark, RL



Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists  

PubMed Central

It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with ?9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already, numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB1, non-CB2 G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner. It begins with a brief description of how each of these ligands interacts with CB1 and/or CB2 receptors.

Pertwee, R.G.



Iontophoresis of Endothelin Receptor Antagonists in Rats and Men  

PubMed Central

Introduction The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis. Methods Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n?=?5). Results In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC0–20 were 44032.2±12277 and 14957.5±23818.8 %BL.s, respectively; P?=?0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans. Conclusions This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

Roustit, Matthieu; Blaise, Sophie; Arnaud, Claire; Hellmann, Marcin; Millet, Claire; Godin-Ribuot, Diane; Dufournet, Boris; Boutonnat, Jean; Ribuot, Christophe; Cracowski, Jean-Luc



Antipruritic treatment with systemic ?-opioid receptor antagonists: a review.  


During the past two decades, systemic ?-opioid receptor antagonists (MORA) have been used in the treatment of various forms of chronic pruritus. In a number of case reports, case series, and controlled trials, treatment with MORA has demonstrated considerable antipruritic effects. In double-blind controlled studies, significant antipruritic relief has been achieved by MORA in cholestatic pruritus, chronic urticaria, and atopic dermatitis. In case reports and case series, antipruritic efficacy of MORA has been reported in prurigo nodularis, mycosis fungoides, postburn pruritus, aquagenic pruritus, hydroxyethyl starch-induced pruritus, and pruritus of unknown origin. However, most of the evidence remains anecdotal, the design of these trials varies, and comparison of results is difficult. In this review we aim to present an overview of these reports and to assess the evidence for the antipruritic action of the drugs naloxone, nalmefene, and naltrexone, which are currently in use for the treatment of chronic pruritus of different origins. We will also evaluate recommendations for the use of MORA in daily medical practice. PMID:20462660

Phan, Ngoc Quan; Bernhard, Jeffrey D; Luger, Thomas A; Ständer, Sonja



Structural and pharmacological characterization of novel potent and selective monoclonal antibody antagonists of glucose-dependent insulinotropic polypeptide receptor.  


Glucose-dependent insulinotropic polypeptide (GIP) is an endogenous hormonal factor (incretin) that, upon binding to its receptor (GIPr; a class B G-protein-coupled receptor), stimulates insulin secretion by beta cells in the pancreas. There has been a lack of potent inhibitors of the GIPr with prolonged in vivo exposure to support studies on GIP biology. Here we describe the generation of an antagonizing antibody to the GIPr, using phage and ribosome display libraries. Gipg013 is a specific competitive antagonist with equally high potencies to mouse, rat, dog, and human GIP receptors with a Ki of 7 nm for the human GIPr. Gipg013 antagonizes the GIP receptor and inhibits GIP-induced insulin secretion in vitro and in vivo. A crystal structure of Gipg013 Fab in complex with the human GIPr extracellular domain (ECD) shows that the antibody binds through a series of hydrogen bonds from the complementarity-determining regions of Gipg013 Fab to the N-terminal ?-helix of GIPr ECD as well as to residues around its highly conserved glucagon receptor subfamily recognition fold. The antibody epitope overlaps with the GIP binding site on the GIPr ECD, ensuring competitive antagonism of the receptor. This well characterized antagonizing antibody to the GIPr will be useful as a tool to further understand the biological roles of GIP. PMID:23689510

Ravn, Peter; Madhurantakam, Chaithanya; Kunze, Susan; Matthews, Evelyn; Priest, Claire; O'Brien, Siobhan; Collinson, Andie; Papworth, Monika; Fritsch-Fredin, Maria; Jermutus, Lutz; Benthem, Lambertus; Gruetter, Markus; Jackson, Ronald H



Inhibiting substance p pathway for prevention of chemotherapy-induced emesis: preclinical data, clinical trials of neurokinin-1 receptor antagonists.  


Neurokinin-1 (NK-1) receptor antagonists are a new class of antiemetic agents that have activity in controlling cisplatin-induced acute and delayed emesis. Preclinical data in animal models show that the NK-1 receptor antagonists have broad antiemetic activity. The NK-1 receptor antagonists have activity in controlling emesis induced by peripherally acting and centrally acting emetogens, suggesting a mechanism of action at multiple sites. The effects at central and peripheral sites to control acute and delayed emesis cannot be determined at this time based on available studies. When added to a standard regimen of a 5-hydroxytryptamine-3 (5- HT3) receptor antagonist and dexamethasone, the NK-1 receptor antagonists improve control of acute emesis. The NK-1 receptor antagonists improve delayed emesis compared with placebo, and when used in combination with dexamethasone, compared with dexamethasone alone. Acute and delayed nausea may also be improved by the NK-1 receptor antagonists when they are used in combination with a 5-HT3 receptor antagonist and dexamethasone prechemotherapy or with daily dosing for 5 days after chemotherapy. The current data suggest that the mechanism of action of the NK-1 receptor antagonists appears to be different from that of the 5-HT3 receptor antagonists. Future studies may consider using NK-1 receptor antagonists with moderately emetogenic chemotherapy as well as bone marrow transplantation. PMID:18628185

Navari, Rudolph M



Progestins, progesterone receptor modulators, and progesterone antagonists change VEGF release of endometrial cells in culture  

Microsoft Academic Search

The influences of the synthetic progestin, medroxyprogesterone acetate (MPA), the progesterone receptor modulator J867, and the antagonist ZK137316 were studied in vitro on isolated endometrial epithelial cells, as well as endometrial fibroblasts. We evaluated the expression of estrogen receptor ? (ER) and the progesterone receptor (PR) by RT-PCR. ER and PR were strongly expressed in the fibroblasts and epithelial cells

Irmgard Classen-Linke; Joachim Alfer; Claudia A Krusche; Kristof Chwalisz; Werner Rath; Henning M Beier



Discovery and optimisation of a selective non-steroidal glucocorticoid receptor antagonist  

Microsoft Academic Search

High-throughput screening of 3.87million compounds delivered a novel series of non-steroidal GR antagonists. Subsequent rounds of optimisation allowed progression from a non-selective ligand with a poor ADMET profile to an orally bioavailable, selective, stable, glucocorticoid receptor antagonist.

Angus R. Brown; Michael Bosies; Helen Cameron; John Clark; Angela Cowley; Mark Craighead; Moira A. Elmore; Alistair Firth; Richard Goodwin; Susan Goutcher; Emma Grant; Morag Grassie; Simon J. A. Grove; Niall M. Hamilton; Hannah Hampson; Alison Hillier; Koc-Kan Ho; Michael Kiczun; Celia Kingsbury; Steven G. Kultgen; Peter T. A. Littlewood; Scott J. Lusher; Susan MacDonald; Lorraine McIntosh; Theresa McIntyre; Ashvin Mistry; J. Richard Morphy; Olaf Nimz; Michael Ohlmeyer; Jack Pick; Zoran Rankovic; Brad Sherborne; Alasdair Smith; Michael Speake; Gayle Spinks; Fiona Thomson; Lynn Watson; Mark Weston



Effects of Urotensin II Receptor Antagonist, GSK1440115, in Asthma  

PubMed Central

Background: Urotensin II (U-II) is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma. Methods: Safety, tolerability, and pharmacokinetics (PK) of single doses of GSK1440115 (1–750?mg) were assessed in a Phase I, placebo controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a two-period, single-blind crossover study and treated with single doses of 750?mg GSK1440115 or placebo and given a methacholine challenge. Results: Administration of GSK1440115 was safe and well-tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50?mg dose. In the presence of food at the 750?mg dose, the time to maximal concentration was between 2 and 6?h and the terminal half-life was short at approximately 2?h. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for ?3?h (between 4 and 7?h post-dose). There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics. Conclusion: While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population.

Portnoy, Alison; Kumar, Sanjay; Behm, David J.; Mahar, Kelly M.; Noble, Robert B.; Throup, John P.; Russ, Steven F.



Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo  

PubMed Central

Dysregulation of the 5-HT2A receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT2A receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT2A down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT2A receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT2A antagonists [ketanserin, altanserin, ?-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), ?-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT2A receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT2A antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT2A receptors and potentiated PCP-hyperlocomotion; the other 5-HT2A receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed.

Yadav, Prem N.; Kroeze, Wesley K.; Farrell, Martilias S.



Ligand competition binding assay for the androgen receptor.  


Evaluating endocrine activities of environmental chemicals or screening for new small molecule modulators of the androgen receptor (AR) transcription activity requires standardized and reliable assay procedures. Scintillation proximity assays (SPA) are sensitive and reliable techniques that are suitable for ligand competition binding assays. We have utilized a radiolabeled ligand competition binding assay for the androgen receptor (AR) that can be carried out in a 384-well format. This standardized, highly reproducible and low-cost assay has been automated for high-throughput screening (HTS) purposes. PMID:21796520

Féau, Clémentine; Arnold, Leggy A; Kosinski, Aaron; Guy, R Kiplin



Mechanisms of Radiosensitization by the Neurotensin Receptor Antagonist SR48692 in Prostate Cancer Models.  

National Technical Information Service (NTIS)

This project tests the hypothesis that blocking NTR1 receptor with antagonist SR48692 could selectively sensitize prostate cancer cells to ionizing radiation, thus improving outcomes of radiotherapy. In this second year period, we studied the molecular me...

A. S. Hosing E. V. Casarez J. DaSilva J. Dziegielewski N. C. Valerie



Fusion estrogen receptor proteins: toward the development of receptor-based agonists and antagonists.  


Estrogen-induced signaling mediated by estrogen receptors (ERs) is also affected by aberrant ERs that act as constitutively active or dominant negative modulators. Variant ERs can contribute to carcinogenesis and to the loss of estrogen responsiveness, rendering antiestrogen therapy ineffective. Determining target gene response during co-synthesis of different ER species is difficult, because dimers formed in the presence of more than one ER species are a heterogenous population of homo- or heterodimers. We engineered a homofusion ERalpha as a prototype single-chain receptor by genetically conjugating two ER monomers into a covalently fused single-chain protein to obtain a homogeneous population. This permits analysis of symmetrical or asymmetrical mutations that simulate variant homo- and heterodimers. Although a monomer, the homofusion receptor exhibited similar biochemical and functional properties to the dimeric ERalpha. We used activation function-2 (AF2) defective mutants as a model in either one or both receptor domains for a dominant-negative phenotype by suppressing the reporter activity induced by the WT receptor. When co-expressed with ERalpha, the fusion variant deficient in both AF2 functions suppressed the reporter activity effectively induced by ERalpha. These results show the utility of fusion receptors as models for generation of receptor-based agonists and antagonists. PMID:11514059

Muyan, M; Yi, P; Sathya, G; Willmert, L J; Driscoll, M D; Hilf, R; Bambara, R A



Inhibition of photocarcinogenesis by platelet-activating factor or serotonin receptor antagonists.  


The UV radiation in sunlight is the primary cause of nonmelanoma skin cancer. Moreover, UV exposure induces immune suppression. Early steps in the cascade of events leading to immune suppression are the binding of UV-induced platelet-activating factor (PAF) to its receptor and the binding of cis-urocanic acid, a photoreceptor for UVB radiation, to the serotonin (5-HT(2A)) receptor. Here, we tested the hypothesis that blocking the binding of PAF and 5-HT(2A) to their receptors would also block skin cancer induction. Hairless mice were injected with PAF or serotonin receptor antagonists and then exposed to solar-simulated UV radiation. We noted a significant and substantial decrease in skin cancer incidence in mice treated with the PAF or 5-HT(2A) receptor antagonists. Also, the PAF and/or serotonin receptor antagonists blocked skin cancer progression. The PAF and serotonin receptor antagonists worked in a synergistic fashion to block skin cancer induction. We also measured the effect that injecting PAF and 5-HT(2A) receptor antagonists had on UV-induced skin damage after a single UV exposure. We noted a significant decrease in UV-induced hypertrophy, sunburn cell formation, and apoptosis when the mice were injected with PAF and/or 5-HT(2A) receptor antagonists. These data indicate that treating UV-irradiated mice with PAF and 5-HT(2A) receptor antagonists blocks skin cancer induction in vivo, in part by reversing UV-induced damage to the skin and by preventing the induction of immune suppression. PMID:18483284

Sreevidya, Coimbatore S; Khaskhely, Noor M; Fukunaga, Atsushi; Khaskina, Polina; Ullrich, Stephen E



Chronic opioid antagonist administration upregulates mu opioid receptor binding without altering mu opioid receptor mRNA levels  

Microsoft Academic Search

Chronic administration of opioid antagonists has been shown to increase radioligand binding to brain opioid receptors. The present study was conducted to determine whether chronic exposure to the opioid antagonist naltrexone would similarly increase ? opioid receptor gene expression as measured by mRNA levels. Male Sprague-Dawley rats were administered naltrexone, 7–8 mg\\/kg\\/day, or saline by osmotic minipumps for 7 days.

Ellen M. Unterwald; Joshua M. Rubenfeld; Yasuo Imai; Jia-Bei Wang; George R. Uhl; Mary Jeanne Kreek



Endothelin-A receptor antagonists prevent amyloid-?-induced increase in ETA receptor expression, oxidative stress, and cognitive impairment.  


Alzheimer's disease is a neurodegenerative disorder associated with abnormal accumulation of amyloid-? (A?) which can release endothelin (ET). The present study was conducted to investigate the effect of ET antagonists on A?-induced changes in ETA and ETB receptor expression, oxidative stress, and cognitive impairment. Male Sprague-Dawley rats were treated with A?1-40 in the lateral cerebral ventricles and were administered vehicle or ET antagonists for 14 days. A? treatment produced an increase in ETA receptor expression in the cerebral cortex, hippocampus, and brain stem by 72%, 85%, and 90%, respectively. No change in ETB receptor expression was observed. There was an increase in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and superoxide dismutase (SOD) levels in A?-treated rats. In the Morris swim task, A? treated rats showed a significant impairment in spatial memory. ET receptor antagonists, BQ123, BMS182874, and TAK-044, significantly decreased A?-induced increase in ETA expression in the cortex, hippocampus, and brain stem. Rats treated with ET antagonists showed significant attenuation of A?-induced changes in the brain MDA, GSH, and SOD levels. Rats treated with specific ETA receptor antagonists, BQ123 and BMS182874, significantly reduced the cognitive impairment induced by A?. However, nonspecific ETA/ETB receptor antagonist TAK-044 did not show any improvement in the learning and memory parameter. This study demonstrates that ETA receptor antagonists are effective in preventing cognitive impairment, changes in ETA expression and oxidative stress induced by A?. It is concluded that ETA receptor antagonists may be useful in improving cognitive impairment due to Alzheimer's disease. PMID:21116051

Briyal, Seema; Philip, Tina; Gulati, Anil



A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression  

Microsoft Academic Search

A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. We have recently reported that renal preproendothelin-1 gene is up-regulated in rats with renal mass reduction (RMR) and that time-dependent increase in urinary excretion of the corresponding peptide correlates with renal disease progression. Here we evaluated whether a specific endothelin subtype A (ETA) receptor antagonist, FR139317,

Ariela Benigni; Carla Zoja; Daniela Corna; Silvia Orisio; Lorena Longaretti; Tullio Bertani; Giuseppe Remuzzi



PG01037, a novel dopamine D3 receptor antagonist, inhibits the effects of methamphetamine in rats  

Microsoft Academic Search

Our previous studies have shown that the selective dopamine D3 receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine- or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D3 receptor antagonist

Amanda E Higley; Krista Spiller; Peter Grundt; Amy Hauck Newman; Stephen W Kiefer; Zheng-Xiong Xi; Eliot L Gardner



1-Substituted 4-(3-Hydroxyphenyl)piperazines Are Pure Opioid Receptor Antagonists  

PubMed Central

This report describes the discovery that 1-substituted 4-(3-hydroxyphenyl)piperazines are pure opioid receptor antagonists. Compounds in this new series include N-phenylpropyl (3S)-3-methyl-4-(3-hydroxyphenyl)piperazine and (3R)-3-methyl-4-(3-hydroxyphenyl)piperazine, both of which diaplay low nanomolar potencies at ?, ?, and ? receptors and pure antagonist properties in a [35S]GTP?S assay.

Carroll, F. Ivy; Cueva, Juan Pablo; Thomas, James B.; Mascarella, S. Wayne; Runyon, Scott P.; Navarro, Hernan A.



Bismuth increases hydroxyl radical-scavenging activity of histamine H2-receptor antagonists  

Microsoft Academic Search

The effects of histamine H -receptor antagonists, alone or in a combination with bismuth, on OH-provoked degradation of deoxyribose were studied. The histamine H -receptor antagonists (cimetidine, ranitidine and roxatidine), themselves decreased the deoxyribose damage in Fenton-type systems. In combinations with bismuth, their inhibitory effect in Fenton system (Fe(III)\\/ascorbic acid + H O ) was stronger. Moreover, unlike Fe(III) and

Margarita Kirkova; Albena Alexandrova; Neli Yordanova


Identification of a GPER\\/GPR30 antagonist with improved estrogen receptor counterselectivity  

Microsoft Academic Search

GPER\\/GPR30 is a seven-transmembrane G protein-coupled estrogen receptor that regulates many aspects of mammalian biology and physiology. We have previously described both a GPER-selective agonist G-1 and antagonist G15 based on a tetrahydro-3H-cyclopenta[c]quinoline scaffold. The antagonist lacks an ethanone moiety that likely forms important hydrogen bonds involved in receptor activation. Computational docking studies suggested that the lack of the ethanone

Megan K. Dennis; Angela S. Field; Ritwik Burai; Chinnasamy Ramesh; Whitney K. Petrie; Cristian G. Bologa; Tudor I. Oprea; Yuri Yamaguchi; Shin-Ichi Hayashi; Larry A. Sklar; Helen J. Hathaway; Jeffrey B. Arterburn; Eric R. Prossnitz


Morphine tolerance does not develop in mice treated with endothelin-A receptor antagonists  

Microsoft Academic Search

Long-term use of morphine leads to development of antinociceptive tolerance. We provide evidence that central endothelin (ET) mechanisms are involved in development of morphine tolerance. In the present study, we investigated the effect of ETA receptor antagonists, BQ123 and BMS182874, on morphine antinociception and tolerance in mice. Mechanism of interaction of ETA receptor antagonists with morphine was investigated. BQ123 (3

Shaifali Bhalla; George Matwyshyn; Anil Gulati



Can a serotonin type 3 (5HT3) receptor antagonist reduce experimentally-induced itch?  

Microsoft Academic Search

Background: Serotonin type 3 (5-HT3) receptor antagonists have been reported to be a novel therapeutic principle for the treatment of cholestatic and uremic pruritus.¶Objective: To determine the antipruritic effect of a 5-HT3 receptor antagonist (tropisetron) on histamine and serotonin-induced itch under experimental conditions in comparison to native skin and after pretreatment with an orally applied antihistamine (cetirizine).¶Methods: Histamine and serotonin

E. Weisshaar; B. Ziethen; H. Gollnick



Binding characteristics of [3H]-JSM10292: a new cell membrane-permeant non-peptide bradykinin B2 receptor antagonist  

PubMed Central

BACKGROUND AND PURPOSE A 3H-labelled derivative of the novel small-molecule bradykinin (BK) B2 receptor antagonist JSM10292 was used to directly study its binding properties to human and animal B2 receptors in intact cells and to closely define its binding site. EXPERIMENTAL APPROACH Equilibrium binding, dissociation and competition studies with various B2 receptor ligands and [3H]-JSM10292 were performed at 4°C and 37°C. The experiments were carried out using HEK293 cells stably (over)expressing wild-type and mutant B2 receptors of human and animal origin. KEY RESULTS [3H]-JSM10292 bound to B2 receptors at 4°C and at 37°C with the same high affinity. Its dissociation strongly depended on the temperature and increased when unlabelled B2 receptor agonists or antagonists were added. [3H]-JSM10292 is cell membrane-permeant and thus also bound to intracellular, active B2 receptors, as indicated by the different ‘nonspecific’ binding in the presence of unlabelled JSM10292 or of membrane-impermeant BK. Equilibrium binding curves with [3H]-JSM10292 and competition experiments with unlabelled JSM10292 and [3H]-BK showed a different affinity profile for the wild-type B2 receptor in different species (man, cynomolgus, rabbit, mouse, rat, dog, pig, guinea pig). Characterization of B2 receptor mutants and species orthologues combined with homology modelling, using the CXCR4 as template, suggests that the binding site of JSM10292 is different from that of BK but overlaps with that of MEN16132, another small non-peptide B2 receptor ligand. CONCLUSIONS AND IMPLICATIONS [3H]-JSM10292 is a novel, cell membrane-permeant, high-affinity B2 receptor antagonist that allows direct in detail studies of active, surface and intracellularly located wild-type and mutant B2 receptors.

Faussner, A; Schussler, S; Feierler, J; Bermudez, M; Pfeifer, J; Schnatbaum, K; Tradler, T; Jochum, M; Wolber, G; Gibson, C



Agonist- and antagonist-induced conformational changes of loop F and their contributions to the ?1 GABA receptor function  

PubMed Central

Binding of ?-aminobutyric acid (GABA) to its receptor initiates a conformational change to open the channel, but the mechanism of the channel activation is not well understood. To this end, we scanned loop F (K210–F227) in the N-terminal domain of the ?1 GABA receptor expressed in Xenopus oocytes using a site-specific fluorescence technique. We detected GABA-induced fluorescence changes at six positions (K210, K211, L216, K217, T218 and I222). At these positions the fluorescence changes were dose dependent and highly correlated to the current dose–response, but with lower Hill coefficients. The competitive antagonist 3-aminopropyl(methyl)phosphinic acid (3-APMPA) induced fluorescence changes in the same direction at the four middle or lower positions. The non-competitive antagonist picrotoxin blocked nearly 50% of GABA-induced fluorescence changes at T218 and I222, but only <20% at K210 and K217 and 0% at K211 and L216 positions. Interestingly, the picrotoxin-blocked fraction of the GABA-induced fluorescence changes was highly correlated to the Hill coefficient of the GABA-induced dose-dependent fluorescence change. The PTX-insensitive mutant L216C exhibited the lowest Hill coefficient, similar to that in binding. Thus, the PTX-sensitive fraction reflects the conformational change related to channel gating, whereas the PTX-insensitive fraction represents a binding effect. The binding effect is further supported by the picrotoxin resistance of a competitive antagonist-induced fluorescence change. A cysteine accessibility test further confirmed that L216C and K217C partially line the binding pocket, and I222C became more exposed by GABA. Our results are consistent with a mechanism that an outward movement of the lower part of loop F is coupled to the channel activation.

Zhang, Jianliang; Xue, Fenqin; Chang, Yongchang



Highly selective fluorescent analogue of the potent delta-opioid receptor antagonist Dmt-Tic.  


A fluorescent tripeptide probe derived by coupling fluorescein to H-Dmt-Tic-Glu-NH2 was developed to interact with delta-opioid receptors with high affinity (Ki = 0.035 nM) and selectivity (Ki(mu)/Ki(delta) = 4371). It acts as an irreversible delta-opioid receptor antagonist, and binding to NG108-15 cells is blocked by the standard nonpeptidic delta-opioid receptor antagonist naltrindole. This probe should prove useful in the study of the distribution of delta-opioid receptors in tissues and the internalization of opioid peptides during signal transduction. PMID:15588089

Balboni, Gianfranco; Salvadori, Severo; Dal Piaz, Alessandro; Bortolotti, Fabrizio; Argazzi, Roberto; Negri, Lucia; Lattanzi, Roberta; Bryant, Sharon D; Jinsmaa, Yunden; Lazarus, Lawrence H



Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists.  


A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D). PMID:20889341

Yang, Zhicai; Fairfax, David J; Maeng, Jun-Ho; Masih, Liaqat; Usyatinsky, Alexander; Hassler, Carla; Isaacson, Soshanna; Fitzpatrick, Kevin; DeOrazio, Russell J; Chen, Jianqing; Harding, James P; Isherwood, Matthew; Dobritsa, Svetlana; Christensen, Kevin L; Wierschke, Jonathan D; Bliss, Brian I; Peterson, Lisa H; Beer, Cathy M; Cioffi, Christopher; Lynch, Michael; Rennells, W Martin; Richards, Justin J; Rust, Timothy; Khmelnitsky, Yuri L; Cohen, Marlene L; Manning, David D



De novo design of a picomolar nonbasic 5-HT(1B) receptor antagonist.  


We describe herein the discovery of novel, de novo designed, 5-HT(1B) receptor antagonists that lack a basic moiety and that provide improved hERG and in vitro phospholipidosis profiles. We used a known 5-HT(1B) antagonist template as our starting point and focused on replacing the piperazine moiety. Pyrazole-based ideas were designed and synthesized among a small library of piperazine replacements. To our knowledge, these are the first potent, nonbasic, functionally active antagonists of the 5-HT(1B) receptor. PMID:20088516

Nugiel, David A; Krumrine, Jennifer R; Hill, Daniel C; Damewood, James R; Bernstein, Peter R; Sobotka-Briner, Cynthia D; Liu, Jianwei; Zacco, Anna; Pierson, M Edward



Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y 6 nucleotide receptors  

Microsoft Academic Search

The physiological role of the P2Y6 nucleotide receptor may involve cardiovascular, immune and digestive functions based on the receptor tissue distribution, and selective antagonists for this receptor are lacking. We have synthesized a series of symmetric aryl diisothiocyanate derivatives and examined their ability to inhibit phospholipase C (PLC) activity induced by activation of five subtypes of recombinant P2Y receptors. Several

Liaman K Mamedova; Bhalchandra V Joshi; Zhan-Guo Gao; Ivar von Kügelgen; Kenneth A Jacobson



Study of a structurally similar kappa opioid receptor agonist and antagonist pair by molecular dynamics simulations  

Microsoft Academic Search

Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5?-GNTI is an antagonist while 6?-GNTI is an agonist\\u000a of the ?OR opioid receptor. To explore how a subtle alteration of the ligand structure influences the receptor activity, we\\u000a investigated two concurrent processes: the final steps of ligand binding at the receptor binding site and the initial steps\\u000a of receptor activation. To trace

Michal Kolinski; Slawomir Filipek



Response properties of antral mechanosensitive afferent fibers and effects of ionotropic glutamate receptor antagonists  

Microsoft Academic Search

The ionotropic glutamate receptors N-methyl-d-aspartate (NMDA) and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are present peripherally in the primary sensory afferent neurons innervating the viscera. Multiple studies have reported roles of glutamate receptors in gastric functions. However, no study has previously shown the direct influence of ionotropic glutamate receptor antagonist on vagal sensory neurons. The objective of this study was to investigate

J. N Sengupta; J Petersen; S Peles; R Shaker



Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist.  


A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3',5'-(CF(3))(2)-Bn], 20 [Ac-Aba-Gly-NMe-3',5'-(CF(3))(2)-Bn], and 23 [Ac-Tic-NMe-3',5'-(CF(3))(2)-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R. The most active NK1 antagonist of the series, 20 [Ac-Aba-Gly-NMe-3',5'-(CF(3))(2)-Bn], was then used in the design of a novel, potent chimeric opioid agonist-NK1 receptor antagonist, 35 [Dmt-D-Arg-Aba-Gly-NMe-3',5'-(CF(3))(2)-Bn], which combines the N terminus of the established Dmt(1)-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH(2)) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, that is, Dmt-D-Arg-Aba-Gly-NH(2) (36), also proved to be an extremely potent and balanced ? and ? opioid receptor agonist with subnanomolar binding and in vitro functional activity. PMID:21413804

Ballet, Steven; Feytens, Debby; Buysse, Koen; Chung, Nga N; Lemieux, Carole; Tumati, Suneeta; Keresztes, Attila; Van Duppen, Joost; Lai, Josephine; Varga, Eva; Porreca, Frank; Schiller, Peter W; Vanden Broeck, Jozef; Tourwé, Dirk



Design of novel neurokinin 1 receptor antagonists based on conformationally constrained aromatic amino acids and discovery of a potent chimeric opioid agonist-neurokinin 1 receptor antagonist  

PubMed Central

A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3?,5?-(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3?,5?-(CF3)2-Bn] and 23 [Ac-Tic-NMe-3?,5?-(CF3)2-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R. The most active NK1 antagonist of the series, 20 [Ac-Aba-Gly-NMe-3?,5?-(CF3)2-Bn], was then used in the design of a novel, potent chimeric opioid agonist-NK1 receptor antagonist, 35 [Dmt-D-Arg-Aba-Gly-NMe-3?,5?-(CF3)2-Bn], which combines the N-terminus of the established Dmt1-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH2) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, i.e. Dmt-D-Arg-Aba-Gly-NH2 36, also proved to be an extremely potent and balanced ?- and ? opioid receptor agonist with subnanomolar binding and in vitro functional activity.

Ballet, Steven; Feytens, Debby; Buysse, Koen; Chung, Nga N.; Lemieux, Carole; Tumati, Suneeta; Keresztes, Attila; Van Duppen, Joost; Lai, Josephine; Varga, Eva; Porreca, Frank; Schiller, Peter W.; Broeck, Jozef Vanden; Tourwe, Dirk



Interactions of dopamine agonists with brain D1 receptors labeled by /sup 3/H-antagonists. Evidence for the presence of high and low affinity agonist-binding states  

SciTech Connect

The interactions of dopaminergic agonists and antagonists with /sup 3/H-antagonist labeled D1 dopamine receptors of rat striatum have been characterized. (/sup 3/H)Flupentixol has been found to selectively label D1 dopamine receptors when its binding to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone. Antagonist//sup 3/H-antagonist competition curves are of uniformly steep slope (nH . 1.0) suggesting the presence of a single D1 dopamine receptor. Agonist//sup 3/H-antagonist competition curves are extremely shallow (nH less than or equal to 0.5) for agonists of high relative efficacy, suggesting the presence of heterogeneous populations of agonist-binding states of the D1 dopamine receptor. Computer-modeling techniques were used to estimate affinities and relative site densities for these heterogeneous binding states. This analysis indicates that the ratio of agonist affinities for low and high affinity agonist-binding states is correlated with agonist relative efficacies in activating adenylate cyclase in membrane homogenates. Under the assay conditions employed, the addition of saturating concentrations of guanine nucleotides reduced, but did not abolish, the relative density of high affinity agonist-binding sites. These binding data can, at least in part, be explained by postulating two states of the D1 dopamine receptor, inducible by agonists but not by antagonists and modulated by guanine nucleotides.

Leff, S.E.; Hamblin, M.W.; Creese, I.



From the first selective non-peptide AT(2) receptor agonist to structurally related antagonists.  


A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K(i) ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models. PMID:22248302

Murugaiah, A M S; Wu, Xiongyu; Wallinder, Charlotta; Mahalingam, A K; Wan, Yiqian; Sköld, Christian; Botros, Milad; Guimond, Marie-Odile; Joshi, Advait; Nyberg, Fred; Gallo-Payet, Nicole; Hallberg, Anders; Alterman, Mathias



[The potential of group II metabotropic glutamate receptor antagonists as a novel antidepressant].  


Recently, abnormalities of glutamatergic transmission have been implicated in the pathophysiology of depression. Moreover, both ketamine, an NMDA receptor antagonist, and riluzole, a modulator of glutamatergic, transmission have been reported to be effective for the treatment of patients with treatment-refractory depression. Based on these findings, extensive studies to develop agents acting on glutamatergic transmission have been conducted. Glutamate receptors are divided into two main subtypes, ionotropic glutamate receptors and metabotropic glutamate (mGlu) receptors, both of which have subtypes. Of these, much attention has been paid to mGlu2/3 receptors. mGlu2/3 receptor antagonists such as MGS0039 and LY341495 have been reported to exert antidepressant effects in animal models of depression including the forced swim test, tail suspension test, learned helplessness paradigm, olfactory bulmectomy model and isolation rearing model, and to enhance serotonin release in the prefrontal cortex and dopamine release in the nucleus accumbens. Moreover, activation of AMPA receptor and mTOR signaling have been suggested to be involved in the antidepressant effects of mGlu2/3 receptor antagonists, as demonstrated in the actions of ketamine. Thus, mGlu2/3 receptor antagonists may share some neural networks with ketamine in exerting their antidepressant effects. In addition, the potential of other agents targeting glutamatergic transmission for novel antidepressants is being investigated. PMID:23012890

Chaki, Shigeyuki



Medicinal Chemistry of the A3 Adenosine Receptor: Agonists, Antagonists, and Receptor Engineering  

PubMed Central

A3 adenosine receptor (A3AR) ligands have been modified to optimize their interaction with the A3AR. Most of these modifications have been made to the N6 and C2 positions of adenine as well as the ribose moiety, and using a combination of these substitutions leads to the most efficacious, selective, and potent ligands. A3AR agonists such as IB-MECA and Cl-IB-MECA are now advancing into Phase II clinical trials for treatments targeting diseases such as cancer, arthritis, and psoriasis. Also, a wide number of compounds exerting high potency and selectivity in antagonizing the human (h)A3AR have been discovered. These molecules are generally characterized by a notable structural diversity, taking into account that aromatic nitrogen-containing monocyclic (thiazoles and thiadiazoles), bicyclic (isoquinoline, quinozalines, (aza)adenines), tricyclic systems (pyrazoloquinolines, triazoloquinoxalines, pyrazolotriazolopyrimidines, triazolopurines, tricyclic xanthines) and nucleoside derivatives have been identified as potent and selective A3AR antagonists. Probably due to the “enigmatic” physiological role of A3AR, whose activation may produce opposite effects (for example, concerning tissue protection in inflammatory and cancer cells) and may produce effects that are species dependent, only a few molecules have reached preclinical investigation. Indeed, the most advanced A3AR antagonists remain in preclinical testing. Among the antagonists described above, compound OT-7999 is expected to enter clinical trials for the treatment of glaucoma, while several thiazole derivatives are in development as antiallergic, antiasthmatic and/or antiinflammatory drugs.

Jacobson, Kenneth A.; Klutz, Athena M.; Tosh, Dilip K.; Ivanov, Andrei A.; Preti, Delia; Baraldi, Pier Giovanni



Effects of 17?-Estradiol and Estrogen Receptor Antagonists on the Proliferation of Gastric Cancer Cell Lines  

PubMed Central

Purpose The aims of this study were as follow: 1) to de scribe the expression status of estrogen receptor-? and -? mRNAs in five gastric carcinoma cell lines; 2) to evaluate in vitro the effects of 17?-estradiol and estrogen receptor antagonists on the proliferation of the cell lines. Materials and Methods Detection of estrogen receptor-? and estrogen receptor-? mRNA in five human gastric cancer cell lines (AGS, KATO III, MKN28, MKN45 and MKN74) was made by the reverse transcription-polymerase chain reaction system. To evaluate the effect of 17?-estradiol and estrogen receptor antagonists on the proliferation of gastric cancer cell line, the cell lines which expressed both es trogen receptors were chosen and treated with 17?-estradiol and estrogen receptor antagonists (methyl-piperidino-pyrazole and pyrazolo [1,5-a] pyrimidine). Cell proliferation was assessed with the methylthiazol tetrazolium test. Results Estrogen receptor-? and estrogen receptor-? mRNAs were expressed in three (KATO III, MKN28 and MKN45) and all of the five gastric cancer cell lines, respectively. At higher concentrations, 17?-estradiol inhibited cell growth of MKN28, MKN45 and KATO III cell lines. Neither estrogen receptor-? nor estrogen receptor-? antagonist blocked the anti-proliferative effect of 17?-estradiol. Conclusions Our results indicate that estrogen receptor-? mRNAs are preferentially expressed in gastric cancers and also imply that hormone therapy rather than estrogen receptor blockers may be a useful strategy for the treatment of estrogen receptor-? positive gastric cancer. Its therapeutic significance in gastric cancer are, however, limited until more evidence of the roles of estrogen receptors in the gastric cancer are accumulated.

Kim, Myung-Jin; Cho, Sung-Il; Lee, Kun-Ok; Han, Hyung-Joon; Song, Tae-Jin



Transmembrane AMPA receptor regulatory protein regulation of competitive antagonism: a problem of interpretation  

PubMed Central

Abstract Synaptic AMPA receptors are greatly influenced by a family of transmembrane AMPA receptor regulatory proteins (TARPs) which control trafficking, channel gating and pharmacology. The prototypical TARP, stargazin (or ?2), shifts the blocking ability of several AMPAR-selective compounds including the commonly used quinoxalinedione antagonists, CNQX and NBQX. Stargazin's effect on CNQX is particularly intriguing as it not only apparently lowers the potency of block, as with NBQX, but also renders it a partial agonist. Given this, agonist behaviour by CNQX has been speculated to account for its weaker blocking effect on AMPAR–TARP complexes. Here we show that this is not the case. The apparent effect of stargazin on CNQX antagonism can be almost entirely explained by an increase in the apparent affinity for l-glutamate (l-Glu), a full agonist and neurotransmitter at AMPAR synapses. Partial agonism at best plays a minor role but not through channel gating per se but rather because CNQX elicits AMPAR desensitization. Our study reveals that CNQX is best thought of as a non-competitive antagonist at glutamatergic synapses due to the predominance of non-equilibrium conditions. Consequently, CNQX primarily reports the proportion of AMPARs available for activation but may also impose additional block by receptor desensitization.

MacLean, David M; Bowie, Derek



2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity  

Microsoft Academic Search

Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good

Dean G. Brown; Donna L. Maier; Mark A. Sylvester; Tiffany N. Hoerter; Elnaz Menhaji-Klotz; Celina C. Lasota; Lee T. Hirata; Deidre E. Wilkins; Clay W. Scott; Shephali Trivedi; Tongming Chen; Dennis J. McCarthy; Carla M. Maciag; Evelynjeane J. Sutton; Jerry Cumberledge; Don Mathisen; John Roberts; Anshul Gupta; Frank Liu; Charles S. Elmore; Cristobal Alhambra; Jennifer R. Krumrine; Xia Wang; Paul J. Ciaccio; Michael W. Wood; James B. Campbell; Magnus J. Johansson; Jian Xia; Xiaotian Wen; Ji Jiang; Xiaoping Wang; Zuozhong Peng; Tao Hu; Jian Wang



Screening of 5-HT1A Receptor Antagonists using Molecularly Imprinted Polymers  

PubMed Central

Molecular imprinting produces network polymers with recognition sites for imprint molecules. The high binding affinity and selectivity in conjunction with the polymers’ physical robustness positions molecular imprinted polymers (MIPs) as candidates for use as preliminary screens in drug discovery. As such, MIPs can serve as crude mimics of native receptors. In an effort to evaluate the relationship between MIPs and native receptors, imprinted polymers for WAY-100635, an antagonist of the serotonin (5-HT) receptor subtype 5-HT1A were prepared. The resulting MIP P(WAY) was evaluated as an affinity matrix in the screening of serotonin receptor antagonists with known affinities for the native receptor. Rough correlations in affinity between the synthetic P(WAY) and native receptor 5-HT1A were found. These findings provide some support for the analogy between MIPs and native receptors and their possible use as surrogates.

O'Connor, Naphtali A.; Paisner, David A.; Huryn, Donna; Shea, Kenneth J.



Cannabinoid-1 receptor antagonist rimonabant (SR141716) increases striatal dopamine D2 receptor availability  

PubMed Central

The cannabinoid 1 (CB1) receptor antagonist rimonabant (SR141716) alters rewarding properties and intake of food and drugs. Additionally, striatal dopamine D2 receptor (DRD2) availability has been implicated in reward function. This study shows that chronic treatment of rats with rimonabant (1.0 and 3.0 mg/kg/day) dose-dependently increased DRD2 availability in the dorsal striatum (14% and 23%) compared to vehicle. High-dose rimonabant also increased DRD2 availability in the ventral striatum (12%) and reduced weight gain. Thus, upregulation of striatal DRD2 by chronic rimonabant administration may be an underlying mechanism of action and confirms the interactions of the endocannabinoid and dopaminergic systems.

Crunelle, Cleo L.; van de Giessen, Elsmarieke; Schulz, Sybille; Vanderschuren, Louk J.M.J.; de Bruin, Kora; van den Brink, Wim; Booij, Jan



Antagonist but not agonist labeling of serotonin-1A receptors is decreased in major depressive disorder  

PubMed Central

Serotonin-1A receptors may play a role in the pathophysiology of depression and suicide. In postmortem brain tissue, agonist binding to serotonin-1A receptors is reportedly increased or unchanged in depression or suicide, while neuroimaging studies report a decrease in antagonist binding to these receptors in subjects with depression. In this study, both agonist and antagonist radioligand binding to serotonin-1A receptors were examined in postmortem orbitofrontal cortex from subjects with major depressive disorder (MDD). Brain tissue was collected at autopsy from 11 subjects with MDD and 11 age- and gender-matched normal control subjects. Two depressed subjects had a recent psychoactive substance use disorder. Six subjects with MDD had a prescription for an antidepressant drug in the last month of life, and, of these six, postmortem bloods from only two subjects tested positive for an antidepressant drug. There was no significant difference between cohorts for age, postmortem interval or tissue pH. The receptor agonist [3H]8-OH-DPAT or the antagonist [3H]MPPF were used to autoradiographically label serotonin-1A receptors in frozen sections from cytoarchitectonically-defined left rostral orbitofrontal cortex (area 47). There was no significant difference between depressed and control subjects in agonist binding to serotonin-1A receptors. However, antagonist binding was significantly decreased in outer layers of orbitofrontal cortex in MDD. This observation in postmortem tissue confirms reports using an antagonist radioligand in living subjects with depression. Decreased antagonist binding to serotonin-1A receptors in outer layers of orbitofrontal cortex suggests diminished receptor signaling and may be linked to corresponding neuronal changes detected previously in these depressed subjects.

Stockmeier, Craig A.; Howley, Eimear; Shi, Xiaochun; Sobanska, Anna; Clarke, Gerard; Friedman, Lee; Rajkowska, Grazyna



Subcellular localization of mineralocorticoid receptors in living cells: Effects of receptor agonists and antagonists  

PubMed Central

Results on the subcellular localization of the mineralocorticoid receptor (MR) have been controversial. To determine the subcellular distribution and trafficking of the MR in living cells after binding of agonists and antagonists, we expressed a MR-green fluorescent protein (GFP) chimera in mammalian cells lacking endogenous MR. The GFP-tagged MR (GFP-MR) remained transcriptionally active, as determined in cotransfection experiments with the MR-responsive reporter, TAT3-LUC. The subcellular localization of GFP-MR was monitored by fluorescence time-lapse microscopy. In the absence of hormone, MR was present both in the cytoplasm and nucleus. Aldosterone induced a rapid nuclear accumulation of the MR. Aldosterone-bound GFP-MR was concentrated in prominent clusters within the nucleus, whereas GFP-MR did not form clusters in the absence of hormone. Similar subnuclear distribution was observed with corticosterone, another MR agonist. In the presence of the MR antagonists spironolactone or ZK91587 the rate of nuclear translocation was significantly slower and the final nuclear-to-cytoplasmic ratio in steady state was significantly lower than with aldosterone. In addition, MR antagonists did not induce formation of nuclear GFP-MR clusters. MR antagonists also were able to disrupt pre-existing nuclear clusters formed in the presence of aldosterone. GFP-MR clusters were retained in nuclear matrix preparations after in vivo crosslinking. These data strongly suggest that hormone-activated MRs accumulate in dynamic discrete clusters in the cell nucleus, and this phenomenon occurs only with transcriptionally active mineralocorticoids.

Fejes-Toth, Geza; Pearce, David; Naray-Fejes-Toth, Aniko



A series of structurally novel heterotricyclic ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-selective antagonists  

PubMed Central

Background and purpose: A new class of heterotricyclic glutamate analogues recently was generated by incorporating structural elements of two excitotoxic marine compounds, kainic acid and neodysiherbaine A. Rather than acting as convulsants, several of these ‘IKM’ compounds markedly depressed CNS activity in mice. Here, we characterize the pharmacological profile of the series with a focus on the most potent of these molecules, IKM-159. Experimental approach: The pharmacological activity and specificity of IKM compounds were characterized using whole-cell patch clamp recording from neurons and heterologous receptor expression systems, in combination with radioligand binding techniques. Key results: The majority of the IKM compounds tested reduced excitatory synaptic transmission in neuronal cultures, and IKM-159 inhibited synaptic currents from CA1 pyramidal neurons in hippocampal slices. IKM-159 inhibited glutamate-evoked whole-cell currents from recombinant GluA2- and GluA4-containing ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors most potently, whereas kainate and NMDA receptor currents were not reduced by IKM-159. Antagonism of steady-state currents was agonist concentration dependent, suggesting that its mechanism of action was competitive, although it paradoxically did not displace [3H]-AMPA from receptor binding sites. IKM-159 reduced spontaneous action potential firing in both cultured hippocampal neurons in control conditions and during hyperactive states in an in vitro model of status epilepticus. Conclusions and implications: IKM-159 is an AMPA receptor-selective antagonist. IKM-159 and related nitrogen heterocycles represent structurally novel AMPA receptor antagonists with accessible synthetic pathways and potentially unique pharmacology, which could be of use in exploring the role of specific populations of receptors in neurophysiological and neuropathological processes.

Gill, MB; Frausto, S; Ikoma, M; Sasaki, M; Oikawa, M; Sakai, R; Swanson, GT



Adenosine A 1 receptor-dopamine D 1 receptor interaction in the rat limbic system: modulation of dopamine D 1 receptor antagonist binding sites  

Microsoft Academic Search

Antagonistic interactions between adenosine A2a and dopamine D2 receptors and between adenosine A1 and dopamine D1 receptors have been previously found in the basal ganglia. Those interactions have been proposed to be key mechanisms of action responsible for the motor depressant effects of adenosine agonists and the motor activating effects of adenosine antagonists, like caffeine. By using quantitative receptor autoradiography,

Sergi Ferré; Patrizia Popoli; Barbro Tinner-Staines; Kjell Fuxe



Change in pharmacological effect of endothelin receptor antagonists in rats with pulmonary hypertension: Role of ETB-receptor expression levels  

PubMed Central

Background and purpose The endothelin (ET) system is activated in pulmonary arterial hypertension (PAH). The therapeutic value of pharmacological blockade of ET receptors has been demonstrated in various animal models and led to the current approval and continued development of these drugs for the therapy of human PAH. However, we currently incompletely comprehend what local modifications of this system occur as a consequence of PAH, particularly in small resistance arteries, and how this could affect the pharmacological response to ET receptor antagonists with various selectivities for the receptor subtypes. Therefore, the purposes of this study were to evaluate potential modifications of the pharmacology of the ET system in rat pulmonary resistance arteries from monocrotaline (MCT)-induced pulmonary arterial hypertension. Experimental approach ET-1 levels were quantified by ELISA. PreproET-1, ETA and ETB receptor mRNA expressions were quantified in pulmonary resistance arteries using Q-PCR, while protein expression was evaluated by Western blots. Reactivity to ET-1 of isolated pulmonary resistance arteries was measured in the presence of ETA (A-147627), ETB (A-192621) and dual ETA/B (bosentan) receptor antagonists. Key results In rats with PAH, plasma ET-1 increased (p < 0.001) while pulmonary levels were reduced (p < 0.05). In PAH arteries, preproET-1 (p < 0.05) and ETB receptor (p < 0.001) gene expressions were reduced, as were ETB receptor protein levels (p < 0.05). ET-1 induced similar vasoconstrictions in both groups. In arteries from sham animals, neither bosentan nor the ETA or the ETB receptor antagonists modified the response. In arteries from PAH rats, however, bosentan and the ETA receptor antagonist potently reduced the maximal contraction, while bosentan also reduced sensitivity (p < 0.01). Conclusions and implications The effectiveness of both selective ETA and dual ETA/B receptor antagonists is markedly increased in PAH. Down-regulation of pulmonary resistance arteries ETB receptor may contribute to this finding.

Sauvageau, Stephanie; Thorin, Eric; Villeneuve, Louis; Dupuis, Jocelyn



Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists.  


Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure-activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics. PMID:23777778

Yang, Christine; Shen, Hong C; Wu, Zhicai; Chu, Hong D; Cox, Jason M; Balsells, Jaume; Crespo, Alejandro; Brown, Patricia; Zamlynny, Beata; Wiltsie, Judyann; Clemas, Joseph; Gibson, Jack; Contino, Lisa; Lisnock, Jeanmarie; Zhou, Gaochao; Garcia-Calvo, Margarita; Bateman, Tom; Xu, Ling; Tong, Xinchun; Crook, Martin; Sinclair, Peter



Analogues of the dopamine D2 receptor antagonist L741,626: Binding, Function and SAR  

PubMed Central

A series of analogues of the dopamine D2 receptor antagonist L741,626 were synthesized and evaluated for binding and function at D2 family receptor subtypes. Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity.

Grundt, Peter; Husbands, Sarah Little Jane; Luedtke, Robert R.; Taylor, Michelle; Newman, Amy Hauck



Bicyclic and tricyclic heterocycle derivatives as histamine H3 receptor antagonists for the treatment of obesity.  


A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test. PMID:24035485

de Lera Ruiz, Manuel; Zheng, Junying; Berlin, Michael Y; McCormick, Kevin D; Aslanian, Robert G; West, Robert; Hwa, Joyce; Lachowicz, Jean; van Heek, Margaret



Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl4  

Microsoft Academic Search

AIM To investigate effect o f losartan, an AT1 receptor antagonist, on hepatic fibrosis induced by CCl4; and to determine whether or not AT1 receptors are expressed on hepatic stellate cells. METHODS AND RESULTS Fifty male Sprague- Dawley rats, weighing (180 ± 20) g, were randomized into five groups (control group, model group, and three los artan treated groups), in

Hong Shan Wei; Ding Guo Li; Han Ming Lu; Yu Tao Zhan; Zhi Rong Wang; Xin Huang; Jing Zhang; Lin Cheng; Qin Fang Xu



Usefulness of 5Ht 2a Receptor Antagonists for The Treatment of Cardiovascular Complications in Diabetes  

Microsoft Academic Search

\\u000a The elevated level of 5-hydroxytryptamine (5-HT) has been reported to be asso-ciated with cardiovascular complications in\\u000a diabetes. Using different 5-HT receptor agonists and antagonists, 5-HT receptors were found to be involved in glycemic control.\\u000a Sarpogre-late, 5-HT2A receptor antagonist, was shown to produce beneficial effects in type 1 and type 2 diabetic rats. It not only reduced serum\\u000a glucose and lipid

Ramesh K. Goyal; Dhananjay N. Umrani; Dipali N. Bodiwala; Naranjan S. Dhalla


In Vitro Properties of a High Affinity Selective Antagonist of the VIP 1 Receptor  

Microsoft Academic Search

Gourlet, P., P. De Neef, J. Cnudde, M. Waelbroeck and P. Robberecht. In vitro properties of a high affinity selective antagonist of the VIP1 receptor. Peptides 18(10) 1555–1560, 1997.—A selective high affinity VIP1 receptor antagonist [Acetyl-His1, D-Phe2, Lys15, Arg16, Leu17] VIP(3-7)\\/GRF(8-27) or PG 97-269 was synthesized, by analogy with recently obtained selective VIP1 receptor agonists. The properties of the new

Philippe Gourlet; Philippe de Neef; Johnny Cnudde; Magali Waelbroeck; Patrick Robberecht



Similar behavioural effects of sigma agonists and PCP-like non-competitive NMDA antagonists in guinea-pigs  

Microsoft Academic Search

The present study examined the behavioural effects of sigma agonists and PCP-like non-competitive N-methyl-D-aspartate (NMDA) antagonists in guineapigs. Subcutaneous (SC) injection of the putative sigma agonist (+)NANM (1 and 10 mg\\/kg SC) and (?) NANM (1 and 10 mg\\/kg SC) produced a behavioural response in guinea-pigs which was characterized by sedation and exophthalmos, with locomotor depression, flattened posture and flaccidity,

Paul J. Brent



The acetylcholine receptor of the neuromuscular junction recognizes mecamylamine as a noncompetitive antagonist.  


The secondary amine, mecamylamine, interacts with the nicotinic receptor ionic channel complex as a noncompetitive antagonist. Mecamylamine (1-10 microM) blocked indirect muscle twitches with no discernible effect on the membrane potential, overshoot, or amplitude of the action potential. It also produced a voltage- and concentration-dependent depression of the peak amplitude of the endplate currents (EPC) and induced nonlinearity in the current-voltage relationship. The decay time constant of the EPC (TEPC) was significantly shortened. The linear relationship between the reciprocal of TEPC and the drug concentration suggested an open channel blockade. Patch-clamp studies, in agreement with the noise analysis results, revealed that mecamylamine (1-8 microM) shortened the lifetime of the open channels. Further, the single channel studies showed that at high concentrations mecamylamine reduced the double exponential nature of the distribution of open times characteristic of channels recorded from myoballs. Closed times had a complex distribution that could not be fitted to a single exponential function because of the presence of short closures or "flickers" during the open state. Although the frequency of channel openings progressively decreased with increasing drug concentration, the single channel conductance remained unchanged at all the concentrations tested. Biochemical studies showed that mecamylamine (up to 100 microM) did not block [3H]acetylcholine binding to the nicotinic receptor of the Torpedo electroplax, but inhibited the binding of [3H]perhydrohistionicotoxin to its channel site, both in the resting and the activated state. These results suggested that, at the nicotinic receptors of the neuromuscular junction, mecamylamine acted as a noncompetitive blocker, binding primarily to the receptor's open channel conformation. Most of the alterations of EPCs were consistent with the predictions of a sequential model for open channel blockade. Biochemical and patch-clamp results, however, could not be fully explained by this model and provided some evidence of the existence of additional blocked states most likely through pathways into desensitized species. In contrast to a competitive antagonism of acetylcholine receptors reported at autonomic ganglia, there was no such action of the drug at the neuromuscular junction; thus, mecamylamine is a useful tool to characterize the nicotinic receptors from different synapses. PMID:2410768

Varanda, W A; Aracava, Y; Sherby, S M; VanMeter, W G; Eldefrawi, M E; Albuquerque, E X



Estimation of the dissociation rate of unlabelled ligand-receptor complexes by a 'two-step' competition binding approach  

PubMed Central

BACKGROUND AND PURPOSE Because the in vivo effectiveness of ligands may also be determined by the rate by which they dissociate from their target receptors, drug candidates are being increasingly screened for this kinetic property. The dissociation rate of unlabelled ligand–receptor complexes can be estimated indirectly from their ability to slow the association of subsequently added radioligand molecules. EXPERIMENTAL APPROACH We used the ‘two-step competition’ binding approach consisting of pre-incubating the receptor preparation with a wide range of ligand concentrations, washing off free ligand molecules, adding radioligand and monitoring its receptor binding after a fixed time. Based on the rationale that binding of both ligands is mutually exclusive and that they bind according to the law of mass action to a single class of sites, the unlabelled ligand's disociation rate can be estimated from the upward shift that the competition curve experiences after washing. KEY RESULTS The relevance of the ‘two-step competition’ approach was explored by computer simulations and by comparing the dissociation behaviour of unlabelled D2 dopamine and CB1 cannabinoid receptor antagonists in this and alternative approaches. Besides providing satisfactory estimations of dissociation rates, the method also detects the ability of the unlabelled ligand molecules to be released from ‘sinks’ such as the cell membrane. CONCLUSIONS AND IMPLICATIONS As the ‘two-step competition’ requires rapid intermediate washing steps and needs radioligand binding to be measured at only one time point, this approach is particularly suited for binding studies on intact plated cells.

Packeu, A; Wennerberg, M; Balendran, A; Vauquelin, G



Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY100635, a potent, selective and silent 5HT 1 A receptor antagonist  

Microsoft Academic Search

Although considerable progress has been made in characterising the 5-HT1A receptor using agonists, partial agonists or non-selective antagonists, further studies of 5-HT1A receptor function have been hindered by the lack of highly selective antagonists. The term ‘silent’ antagonist has been used for such compounds in order to distinguish them unequivocally from several 5-HT1A receptor partial agonists which were initially designated

Allan Fletcher; Elaine A. Forster; David J. Bill; Geraldine Brown; Ian A. Cliffe; Jane E. Hartley; Deborah E. Jones; Anne McLenachan; Kelly J. Stanhope; David J. P. Critchley; Kirstie J. Childs; Vicki C. Middlefell; Laurence Lanfumey; Renato Corradetti; Anne-Marie Laporte; Henri Gozlan; Michel Hamon; Colin T. Dourish



Receptor-based QSAR studies of non-peptide human oxytocin receptor antagonists.  


In the present study, QSAR calculations were performed on the receptor-based alignment of 58 non-peptide human oxytocin receptor antagonists. With the aid of different scoring functions (AutoDock 3.05 built-in and X-Score 1.2) the evolved receptor-ligand complexes were characterized. By means of various datasets it was confirmed that the scoring functions were not capable to predict the biological activity correctly in compounds containing a rigid derivative in the variable region. To improve the pKi prediction 3D-QSAR calculation was performed. The regions related to the biological activity were determined by using cross-validated r2(q2)-guided region selection (q2-GRS) method. The predictive power of the CoMFA model [r(pred)2=0.89, q2(LMO, five groups)=0.695+/-0.034] allowed prediction of the biological activities of newly synthesized compounds and confirmed the receptor-based alignment. PMID:16857401

Jójárt, Balázs; Márki, Arpád



Site-directed mutagenesis of CC chemokine receptor 1 reveals the mechanism of action of UCB 35625, a small molecule chemokine receptor antagonist.  


The chemokine receptor CCR1 and its principal ligand, CCL3/MIP-1alpha, have been implicated in the pathology of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and asthma. As such, these molecules are the focus of much research with the ultimate aim of developing novel therapies. We have described previously a non-competitive small molecule antagonist of CCR1 (UCB 35625), which we hypothesized interacted with amino acids located within the receptor transmembrane (TM) helices (Sabroe, I., Peck, M. J., Jan Van Keulen, B., Jorritsma, A., Simmons, G., Clapham, P. R., Williams, T. J., and Pease, J. E. (2000) J. Biol. Chem. 275, 25985-25992). Here we describe an approach to identifying the mechanism by which the molecule antagonizes CCR1. Thirty-three point mutants of CCR1 were expressed transiently in L1.2 cells, and the cells were assessed for their capacity to migrate in response to CCL3 in the presence or absence of UCB 35625. Cells expressing the mutant constructs Y41A (TM helix 1, or TM1), Y113A (TM3), and E287A (TM7) were responsive to CCL3 but resistant to the antagonist, consistent with a role for the TM helices in CCR1 interactions with UCB 35625. Subsequent molecular modeling successfully docked the compound with CCR1 and suggests that the antagonist ligates TM1, 2, and 7 of CCR1 and severely impedes access to TM2 and TM3, a region thought to be perturbed by the chemokine amino terminus during the process of receptor activation. Insights into the mechanism of action of these compounds may facilitate the development of more potent antagonists that show promise as future therapeutic agents in the treatment of inflammatory disease. PMID:15548526

de Mendonça, Filipa Lopes; da Fonseca, Paula C A; Phillips, Rhian M; Saldanha, José W; Williams, Timothy J; Pease, James E



An Antagonistic Vascular Endothelial Growth Factor (VEGF) Variant Inhibits VEGF-Stimulated Receptor Autophosphorylation and Proliferation of Human Endothelial Cells  

NASA Astrophysics Data System (ADS)

Vascular endothelial growth factor (VEGF) is a potent mitogen with a unique specificity for endothelial cells and a key mediator of aberrant endothelial cell proliferation and vascular permeability in a variety of human pathological situations, such as tumor angiogenesis, diabetic retinopathy, rheumatoid arthritis, or psoriasis. VEGF is a symmetric homodimeric molecule with two receptor binding interfaces lying on each pole of the molecule. Herein we report on the construction and recombinant expression of an asymmetric heterodimeric VEGF variant with an intact receptor binding interface at one pole and a mutant receptor binding interface at the second pole of the dimer. This VEGF variant binds to VEGF receptors but fails to induce receptor activation. In competition experiments, the heterodimeric VEGF variant antagonizes VEGF-stimulated receptor autophosphorylation and proliferation of endothelial cells. A 15-fold excess of the heterodimer was sufficient to inhibit VEGF-stimulated endothelial cell proliferation by 50%, and a 100-fold excess resulted in an almost complete inhibition. By using a rational approach that is based on the structure of VEGF, we have shown the feasibility to construct a VEGF variant that acts as an VEGF antagonist.

Siemeister, Gerhard; Schirner, Michael; Reusch, Petra; Barleon, Bernhard; Marme, Dieter; Martiny-Baron, Georg



Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo.  


Dysregulation of the 5-HT(2A) receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT(2A) receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT(2A) down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT(2A) receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT(2A) antagonists [ketanserin, altanserin, ?-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), ?-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT(2A) receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT(2A) antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT(2A) receptors and potentiated PCP-hyperlocomotion; the other 5-HT(2A) receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed. PMID:21737536

Yadav, Prem N; Kroeze, Wesley K; Farrell, Martilias S; Roth, Bryan L



Identification of Receptor Ligands and Receptor Subtypes Using Antagonists in a Capillary Electrophoresis Single-Cell Biosensor Separation System  

NASA Astrophysics Data System (ADS)

A capillary electrophoresis system with single-cell biosensors as a detector has been used to separate and identify ligands in complex biological samples. The power of this procedure was significantly increased by introducing antagonists that inhibited the cellular response from selected ligand-receptor interactions. The single-cell biosensor was based on the ligand-receptor binding and G-protein-mediated signal transduction pathways in PC12 and NG108-15 cell lines. Receptor activation was measured as increases in cytosolic free calcium ion concentration by using fluorescence microscopy with the intracellular calcium ion indicator fluo-3 acetoxymethyl ester. Specifically, a mixture of bradykinin (BK) and acetylcholine (ACh) was fractionated and the components were identified by inhibiting the cellular response with icatibant (HOE 140), a selective antagonist to the BK B_2 receptor subtype (B_2BK), and atropine, an antagonist to muscarinic ACh receptor subtypes. Structurally related forms of BK were also identified based on inhibiting B_2BK receptors. Applications of this technique include identification of endogenous BK in a lysate of human hepatocellular carcinoma cells (Hep G2) and screening for bioactivity of BK degradation products in human blood plasma. The data demonstrate that the use of antagonists with a single-cell biosensor separation system aids identification of separated components and receptor subtypes.

Fishman, Harvey A.; Orwar, Owe; Scheller, Richard H.; Zare, Richard N.



Role of neurokinin-1 receptor antagonists in chemotherapy-induced emesis: summary of clinical trials.  


Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life, and although the use of 5-hydroxytryptamine3 (5-HT3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, delayed nausea and vomiting remain a significant clinical problem. Aprepitant is the first agent available in the new drug class of neurokinin-1 receptor antagonists. When added to a standard regimen of a 5-HT3 receptor antagonist and dexamethasone in patients receiving highly emetogenic chemotherapy, it improves the complete response rate of acute CINV. Aprepitant also improves the complete response of delayed CINV when used in combination with dexamethasone compared to dexamethasone alone. The use of aprepitant in patients receiving moderately emetogenic chemotherapy will await the review and analysis of recently completed phase III trials. The control of nausea is improved in some studies with the use of aprepitant when it is combined with a 5HT3 receptor antagonist and dexamethasone, but nausea control remains suboptimal. The current data suggest that the mechanism of action of the NK-1s appears to be different from the 5-HT3 receptor antagonists. Future studies may explore the use of aprepitant and other NK-1s in moderately and highly emetogenic chemotherapy, as well in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. PMID:15565815

Navari, Rudolph M



Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD  

PubMed Central

In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective ?-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit

Moulton, Bart C; Fryer, Allison D



Microglial inhibition of neuroprotection by antagonists of the EP1 prostaglandin E2 receptor  

Microsoft Academic Search

BACKGROUND: The EP1 receptor for the prostanoid PGE2 is a G-protein coupled receptor that has been shown to contribute to excitotoxic neuronal death. In this study we examined the influence of non-neuronal cells on neuroprotective properties of EP1 receptor antagonists (Ono 8711 and SC 51089). METHODS: Primary neuronal cultures systems with or without non-neuronal cells were used to examine how

Noel G Carlson; Monica A Rojas; John-David Black; Jonathan W Redd; John Hille; Kenneth E Hill; John W Rose



P2 receptor antagonist PPADS inhibits mesangial cell proliferation in experimental mesangial proliferative glomerulonephritis  

Microsoft Academic Search

P2 receptor antagonist PPADS inhibits mesangial cell proliferation in experimental mesangial proliferative glomerulonephritis.BackgroundAlthough extracellular nucleotides have been shown to confer mitogenic effects in cultured rat mesangial cells through activation of purinergic P2 receptors (P2Y receptors), thus far the in vivo relevance of these findings is unclear. Virtually all cells and in particular the dense granules of platelets contain high levels

Sylvia Rost; Christoph Daniel; Eckhard Schulze-Lohoff; Hans G Bäumert; Günter Lambrecht; Christian Hugo



Novel selective antagonist radioligands for the pharmacological study of A 2B adenosine receptors  

Microsoft Academic Search

The adenosine A2B receptor is the least well characterized of the four adenosine subtypes due to the lack of potent and selective agonists\\u000a and antagonists. Despite the widespread distribution of A2B receptor mRNA, little information is available with regard to their function. The characterization of A2B receptors, through radioligand binding studies, has been performed, until now, by using low-affinity and

Stefania Gessi; Katia Varani; Stefania Merighi; Edward Leung; Stephen Mac Lennan; Pier Giovanni Baraldi; Pier Andrea Borea



Alpha 1 receptor antagonist in the median raphe nucleus evoked hyperphagia in free-feeding rats  

Microsoft Academic Search

Serotonergic neurons in the median raphe nucleus (MnR) are stimulated by ?1-adrenergic agonists and inhibited by ?2-agonists. This study investigated the effect of the blockade of the MnR ?1-adrenergic receptors of free feeding rats as an attempt to elucidate the functional role of these receptors in the control of feeding behavior. In addition, an ?2-receptor antagonist was also administered in

Samira Schultz Mansur; Mariana Graciela Terenzi; José Marino Neto; Moacir Serralvo Faria; Marta Aparecida Paschoalini



The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept  

Microsoft Academic Search

The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I\\/II clinical trials for the indications of chronic inflammatory pain and migraine.

Daniel N. Cortright; Charles A. Blum; Samer R. Eid; Arpad Szallasi



Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration  

Microsoft Academic Search

The complement system is thought to be involved in the pathogenesis of numerous neurological diseases, although its precise role remains controver- sial. In this study we used orally active C5a receptor antagonists (PMX53 and PMX205) developed in our laboratories in a rat model of 3-nitropropionic acid (3-NP) -induced Huntington's disease. Administration of the C5a antagonists (10 mg\\/kg\\/day, oral) either 48

Trent M. Woodruff; James W. Crane; Lavinia M. Proctor; Kathryn M. Buller; Annie B. Shek; Kurt de Vos; Sandra Pollitt; Hua M. Williams; Ian A. Shiels; Peter N. Monk; Stephen M. Taylor



The clinically available NMDA receptor antagonist, memantine, exhibits relative safety in the developing rat brain  

Microsoft Academic Search

The N-methyl-d-aspartate glutamate receptor (NMDAR) has been implicated in preterm brain injury (periventricular leukomalacia (PVL)) and represents a potential therapeutic target. However, the antagonist dizocilpine (MK-801) has been reported to increase constitutive neuronal apoptosis in the developing rat brain, limiting its clinical use in the developing brain. Memantine is another use-dependent NMDAR antagonist with shorter binding kinetics and has been

Simon M. Manning; Griffin Boll; Erin Fitzgerald; Debra B. Selip; Joseph J. Volpe; Frances E. Jensen



Synthesis and SAR of selective small molecule Neuropeptide Y Y2 receptor antagonists  

PubMed Central

Highly potent and selective small molecule Neuropeptide Y Y2 receptor antagonists are reported. The systematic SAR exploration of a hit molecule N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide, identified from HTS, led to the discovery of highly potent NPY Y2 antagonists 16 (CYM 9484) and 54 (CYM 9552) with IC50 values of 19 nM and 12 nM respectively.

Mittapalli, Gopi Kumar; Vellucci, Danielle; Yang, Jun; Toussaint, Marion; Brothers, Shaun P; Wahlestedt, Claes; Roberts, Edward



Design and evaluation of xanthine based adenosine receptor antagonists: Potential hypoxia targeted immunotherapies.  


Molecular modeling techniques were applied to the design, synthesis and optimization of a new series of xanthine based adenosine A2A receptor antagonists. The optimized lead compound was converted to a PEG derivative and a functional in vitro bioassay used to confirm efficacy. Additionally, the PEGylated version showed enhanced aqueous solubility and was inert to photoisomerization, a known limitation of existing antagonists of this class. PMID:24126093

Thomas, Rhiannon; Lee, Joslynn; Chevalier, Vincent; Sadler, Sara; Selesniemi, Kaisa; Hatfield, Stephen; Sitkovsky, Michail; Ondrechen, Mary Jo; Jones, Graham B



Differential effects of NMDA and AMPA\\/KA receptor antagonists on c-Fos or Zif\\/268 expression in the rat spinal dorsal horn induced by noxious thermal or mechanical stimulation, or formalin injection  

Microsoft Academic Search

The involvement of N-methyl-d-aspartate (NMDA) and ?-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)\\/kainate (KA) receptors in the induction of c-Fos and Zif\\/268 expression in spinal dorsal horn neurons following noxious thermal or mechanical stimulation, or formalin injection into the rat hind paw was examined by intrathecal administration of a competitive NMDA receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV) or an AMPA\\/KA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or both,

Omar I. F Rahman; Ryuji Terayama; Tetsuya Ikeda; Mikako Koganemaru; Tadashi Nakamura; Ryosuke Shiba; Toshikazu Nishimori



5HT3 receptor antagonists do not block nicotine induced hyperactivity in rats.  


The effects of 5-HT3 receptor antagonists (ondansetron 0.1 mg kg-1 SC 30 min; bemesetron 0.03 mg kg-1 SC 45 min) on nicotine-induced increases in locomotor activity were measured in male Sprague-Dawley rats. Intermittent daily injections of nicotine (0.3-1.2 mg kg-1 SC 30 min) resulted in increased locomotor activity as measured by photocell counts. The effect of nicotine was not affected by administration of the 5-HT3 receptor antagonists at doses that are reported to block nicotine- and morphine-induced place-preference conditioning. Neither of the 5-HT3 receptor antagonists tested affected activity counts in vehicle treated animals. Nicotine-induced hyperactivity was blocked by the dopamine antagonist haloperidol (0.03 mg kg-1 SC 2 h) and by the nicotinic antagonist mecamylamine (1 mg kg-1 SC 1 min). The effects of a range of doses (0-1 mg kg-1) of the 5-HT3 receptor antagonists ondansetron, bemesetron, granisetron and tropisetron on hyperactivity induced by 0.6 mg kg-1 nicotine were then assessed. Only tropisetron at 1 mg kg-1 attenuated nicotine-induced hyperactivity. To demonstrate the efficacy of the present range of doses of the 5-HT3 receptor antagonists in this study, conditioned taste aversion experiments were conducted. Ondansetron (0.1 mg kg-1) failed to attenuate a conditioned taste aversion to saccharin induced by nicotine (0.6 mg kg-1), but did induce a reduction in saccharin preference in choice tests following three saccharin-ondansetron pairings.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7659769

Arnold, B; Allison, K; Ivanová, S; Paetsch, P R; Paslawski, T; Greenshaw, A J



Endothelin receptor antagonists restore morphine analgesia in morphine tolerant rats  

Microsoft Academic Search

Several neurotransmitter mechanisms have been proposed to play a role in the development of morphine tolerance. The present study provides evidence for the first time that endothelin (ET) antagonists can restore morphine analgesia in morphine tolerant rats. Tolerance to morphine was induced by subcutaneous implantation of six morphine pellets during a 7-day period. The degree of tolerance to morphine was

Shaifali Bhalla; George Matwyshyn; Anil Gulati



Angiotensin II receptor antagonists role in arterial hypertension  

Microsoft Academic Search

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT1 receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT1 receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan,

R Hernández-Hernández; B Sosa-Canache; M Velasco; M J Armas-Hernández; M C Armas-Padilla; R Cammarata



Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action  

SciTech Connect

This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 (cis-(+-)-4-((2H-tetrazol-5-yl)methyl)piperidine-2-carboxylic acid), the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of (3H) CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in (3H)alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or (3H)kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity.

Schoepp, D.D.; Ornstein, P.L.; Leander, J.D.; Lodge, D.; Salhoff, C.R.; Zeman, S.; Zimmerman, D.M. (Eli Lilly and Company, Indianapolis, IN (USA))



Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets.  


NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication. PMID:22497992

Duffy, Ruth A; Morgan, Cynthia; Naylor, Robert; Higgins, Guy A; Varty, Geoffrey B; Lachowicz, Jean E; Parker, Eric M



Bismuth increases hydroxyl radical-scavenging activity of histamine H2-receptor antagonists.  


The effects of histamine H2-receptor antagonists, alone or in a combination with bismuth, on *OH-provoked degradation of deoxyribose were studied. The histamine H2-receptor antagonists (cimetidine, ranitidine and roxatidine), themselves decreased the deoxyribose damage in Fenton-type systems. In combinations with bismuth, their inhibitory effect in Fenton system (Fe(III)/ascorbic acid + H2O2 was stronger. Moreover, unlike F(III) and Cu(II), which in the presence of ascorbic acid + H2O2 led to an increase in the *OH formation (deoxyribose damage), Bi(III) showed an opposite effect. The present results are interpreted in view of a better ( )OH scavenging activity of bismuth complexes of histamine H2-receptor antagonists as compared to that of the corresponding drugs. These findings might be one more explanation why bismuth salts, in combination with acid-reducing agents, are more effective anti-ulcer agents. PMID:16702623

Kirkova, Margarita; Alexandrova, Albena; Yordanova, Neli


Comparison of the ex vivo receptor occupancy profile of ketamine to several NMDA receptor antagonists in mouse hippocampus.  


NMDA receptor antagonists, particularly these targeting the GluN2B subunit are of therapeutic interest for the treatment of severe mood disorders. The receptor occupancy profiles of several NMDA receptor antagonists (30 mg/kg, s.c.) were compared in mouse hippocampus by ex vivo autoradiography using [(3)H]MK-801, a non-selective NMDA channel blocker, and [(3)H]ifenprodil a selective GluN2B antagonist. Subcutaneous administration of ketamine ((RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone) and memantine (3,5-dimethyladamantan-1-amine) inhibited [(3)H]MK-801 but not [(3)H]ifenprodil binding in mouse hippocampus. Ketamine reached maximal occupancy of [(3)H]MK-801 binding sites after 15 min and rapidly cleared from the brain with no significant level of occupancy measured at the 1h time point. Memantine significantly occupied [(3)H]MK-801 binding sites throughout the 6h time course. The selective GluN2B antagonist CP101,606 ((1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol) and Ro 25-6981 ((?R,?S)-?-(4-Hydroxyphenyl)-?-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate) inhibited [(3)H]ifenprodil but not [(3)H]MK-801 binding and significant levels of occupancy (above 50%) were measured throughout the 6h time course. These data highlight the unique quick pulse target engagement profile of ketamine compared to other NMDA receptor antagonists. PMID:23872376

Lord, Brian; Wintmolders, Cindy; Langlois, Xavier; Nguyen, Leslie; Lovenberg, Tim; Bonaventure, Pascal



Targeted opioid receptor antagonists in the treatment of alcohol use disorders.  


In 1994, the US Food and Drug Administration approved the ?-opioid receptor antagonist naltrexone to treat alcohol dependence. However, treatments requiring daily administration, such as naltrexone, are inconsistently adhered to in substance abusing populations, and constant medication exposure can increase risk of adverse outcomes, e.g., hepatotoxicity. This has fostered a 'targeted' or 'as needed' approach to opioid receptor antagonist treatment, in which medications are used only in anticipation of or during high-risk situations, including times of intense cravings. Initial studies of the ability of targeted naltrexone to reduce drinking-related outcomes were conducted in problem drinkers and have been extended into larger, multi-site, placebo-controlled investigations with positive results. Another ?-opioid receptor antagonist, nalmefene, has been studied on an 'as-needed' basis to reduce heavy drinking in alcohol-dependent individuals. These studies include three large multi-site trials in Europe of up to 1 year in duration, and serve as the basis for the recent approval of nalmefene by the European Medicines Agency as an 'as-needed' adjunctive treatment for alcohol dependence. We review potential moderators of opioid receptor antagonist treatment response including subjective assessments, objective clinical measures and genetic variants. In sum, the targeted or 'as-needed' approach to treatment with opioid antagonists is an efficacious harm-reduction strategy for problem drinking and alcohol dependence. PMID:23881605

Niciu, Mark J; Arias, Albert J



In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB(1) receptor antagonist for the management of obesity.  


Cannabinoid CB(1) receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB(1) receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB(1) receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CB(1) receptors in both binding (K(i)=0.7 nM) and functional assays (K(i)=0.2 nM). The compound has low affinity (K(i)=7600 nM) for human CB(2) receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CB(1) receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CB(1) receptor competitive antagonist that may further our understanding of the endocannabinoid system. PMID:20211605

Hadcock, John R; Griffith, David A; Iredale, Phillip A; Carpino, Phillip A; Dow, Robert L; Black, Shawn C; O'Connor, Rebecca; Gautreau, Denise; Lizano, Jeffrey S; Ward, Karen; Hargrove, Diane M; Kelly-Sullivan, Dawn; Scott, Dennis O



First and second generation H? histamine receptor antagonists produce different sleep-inducing profiles in rats.  


First generation H? histamine receptor antagonists, such as d-chlorpheniramine (d-CPA) and diphenhydramine, produce drowsiness in humans. They are currently used as over-the-counter sleep aids. However, the mechanisms underlying drowsiness induced by these H? histamine receptor antagonists remain obscure because they produce heterogeneous receptor-independent actions. Ketotifen is a second generation H? histamine receptor antagonist which is more permeable to the brain than newer H? histamine receptor antagonists. Therefore, to access sleep-inducing profiles by H? histamine receptor blocking actions, the present study compared the dose-dependent effects of diphenhydramine and ketotifen (1-40 mg/kg, intraperitoneal injection at dark onset time) on daily sleep-wake patterns in rats. Ketotifen dose-dependently decreased rapid-eye-movement (REM) sleep and increased non-REM sleep by amplifying slow-wave electroencephalogram powers. Diphenhydramine at 4 mg/kg transiently increased non-REM sleep and reduced REM sleep similar to the effects of ketotifen. The larger injections of diphenhydramine (10-40 mg/kg), however, reduced non-REM sleep, abolished slow-wave enhancements and facilitated wakefulness. The bi-directional action of diphenhydramine on sleep is similar to our former results using d-CPA. Taken together, the arousal effects caused by over-dose administrations of the first generation H? histamine receptor antagonists may be mediated by H? histamine receptor-independent actions. To further examine the tolerance of ketotifen-induced sleep, 3 mg/kg ketotifen was injected daily for 5 days 3 h before light onset time. These experiments consistently enhanced non-REM-sleep at the end of the active phase of rats, suggesting that ketotifen may function as a desirable sleep aid although the coincidental REM sleep reduction requires attention. PMID:22449385

Unno, Katsuya; Ozaki, Tomoya; Mohammad, Shahid; Tsuno, Saki; Ikeda-Sagara, Masami; Honda, Kazuki; Ikeda, Masayuki



Molecular mechanisms and binding site location for the noncompetitive antagonist crystal violet on nicotinic acetylcholine receptors.  


We investigated the molecular mechanisms and the binding site location for the fluorophor crystal violet (CrV), a noncompetitive antagonist of the nicotinic acetylcholine receptor (AChR). To this end, radiolabeled competition binding, fluorescence spectroscopy, Schild-type analysis, patch-clamp recordings, and molecular dynamics approaches were used. The results indicate that (i) CrV interacts with the desensitized Torpedo AChR with higher affinity than with the resting state at several temperatures (5-37 degrees C); (ii) CrV-induced inhibition of the phencyclidine (PCP) analogue [(3)H]thienylcyclohexylpiperidine binding to the desensitized or resting AChR is mediated by a steric mechanism; (iii) tetracaine inhibits CrV binding to the resting AChR, probably by a steric mechanism; (iv) barbiturates modulate CrV binding to the resting AChR by an allosteric mechanism; (v) CrV itself induces AChR desensitization; (vi) CrV decreases the peak of macroscopic currents by acting on the resting AChR but without affecting the desensitization rate from the open state; and (vii) two tertiary amino groups from CrV may bind to the alpha1-Glu(262) residues (located at position 20') in the resting state. We conclude that the CrV binding site overlaps the PCP locus in the resting and desensitized state. The noncompetitive action of CrV may be explained by an allosteric mechanism in which the binding of CrV to the extracellular mouth of the resting receptor leads to an inhibition of channel opening. Binding of CrV probably increases desensitization of the resting channel and stabilizes the desensitized state. PMID:16475790

Arias, Hugo R; Bhumireddy, Pankaj; Spitzmaul, Guillermo; Trudell, James R; Bouzat, Cecilia



Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure  

PubMed Central

Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II) heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms associated with systolic heart failure will benefit from the addition of an aldosterone receptor antagonist to the standard therapies of angiotensin-converting enzyme inhibitors and beta-blockers. This review will address the pharmacologic basis of aldosterone receptor antagonists in patients with heart failure and the clinical impact of this therapy.

Nappi, Jean M; Sieg, Adam



Identification of short-acting ?-opioid receptor antagonists with anxiolytic-like activity.  


The ?-opioid receptor plays a central role in mediating the response to stressful life events. Inhibiting ?-opioid receptor signaling is proposed as a mechanism for treating stress-related conditions such as depression and anxiety. Preclinical testing consistently confirms that disruption of ?-opioid signaling is efficacious in animal models of mood disorders. However, concerns about the feasibility of developing antagonists into drugs stem from an unusual pharmacodynamic property of prototypic ?-opioid receptor-selective antagonists; they inhibit receptor signaling for weeks to months after a single dose. Several fundamental questions include - is it possible to identify short-acting antagonists; is long-lasting inhibition necessary for efficacy; and is it safe to develop long-acting antagonists in the clinic. Here, we test representative compounds (AZ-ECPC, AZ-MTAB, and LY-DMPF) from three new chemical series of ?-opioid receptor ligands for long-lasting inhibition. Each compound dose-dependently reversed ?-opioid agonist-induced diuresis. However, unlike the prototypic antagonist, nBNI, which fully inhibited evoked diuresis for at least four weeks, the new compounds showed no inhibition after one week. The two compounds with greater potency and selectivity were tested in prenatally-stressed rats on the elevated plus maze, an exploration-based model of anxiety. Spontaneous exploration of open arms in the elevated plus maze was suppressed by prenatal stress and restored with both compounds. These findings indicate that persistent inhibition is not an inherent property of ?-opioid-selective antagonists and that post-stress dosing with transient inhibitors can be effective in a mood disorder model. This further supports ?-opioid receptor as a promising target for developing novel psychiatric medications. PMID:21539838

Peters, Matthew F; Zacco, Anna; Gordon, John; Maciag, Carla M; Litwin, Linda C; Thompson, Carolann; Schroeder, Patricia; Sygowski, Linda A; Piser, Timothy M; Brugel, Todd A



Attenuation of D-1 antagonist-induced D-1 receptor upregulation by conccomitant D-2 receptor blockade  

SciTech Connect

The effect of chronic selective D-1 and/or D-2 dopamine receptor blockade on regional D-1 receptor binding was studied in rat brain following chronic treatment with the specific D-1 antagonist SCH 23390 and/or the predominantly D-2 antagonist haloperidol. D-1 receptor density and affinity were evaluated by quantitative autoradiography using /sup 125/I-SCH 23982. Chronic SCH 23390 treatment increased D-1 receptor density by 30 to 40% in the striatum, accumbens and tuberculum olfactorium; receptor affinity remained unchanged. Haloperidol had no effect on D-1 receptor Bmax or Kd values, although, when administered with SCH 23390, reduced the D-1 receptor upregulation induced by the D-1 antagonist in striatum and tuberculum olfactorium, but not in nucleus accumbens, These results may be attributable to D-1/D-2 dopamine receptor interactions occurring in the striatum and tuberculum olfactorium and may have implications for the prevention and treatment of drug-induced extrapyramidal disorders. 34 references, 1 figure, 2 tables.

Parashos, S.A.; Barone, P.; Tucci, I.; Chase, T.N.



Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists.  


A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors. PMID:16451077

Becker, Daniel P; Flynn, Daniel L; Moormann, Alan E; Nosal, Roger; Villamil, Clara I; Loeffler, Richard; Gullikson, Gary W; Moummi, Chafiq; Yang, Dai-C



Actions of ?2 adrenoceptor ligands at ?2A and 5HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for ?2A adrenoceptors  

Microsoft Academic Search

This study examined the activity of chemically diverse ?2 adrenoceptor ligands at recombinant human (h) and native rat (r) ?2A adrenoceptors as compared with 5-HT1A receptors. First, in competition binding experiments at h?2A and h5-HT1A receptors expressed in CHO cells, several compounds, including the antagonists 1-(2-pyrimidinyl)piperazine (1-PP), (?)-idazoxan,\\u000a benalfocin (SKF 86466), yohimbine and RX 821,002, displayed preference for h?2A versus

Adrian Newman-Tancredi; Jean-Paul Nicolas; Valérie Audinot; Samantha Gavaudan; Laurence Verrièle; Manuelle Touzard; Christine Chaput; Nelly Richard; Mark J. Millan



Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists  

PubMed Central

The natural product willardiine is an AMPA receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and kainate receptors. Structure–activity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the antagonists at AMPA or kainate receptors. Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA receptor antagonist activity. To examine antagonist activity at kainate receptors, the ability of compounds to depress kainate-induced depolarisations of dorsal root fibres was assessed. Blocking ionisation of the uracil ring by adding a methyl group to the N3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N3-position of the uracil ring could antagonise AMPA and kainate receptors. S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC50 values of 287±41, 23.8±3.9 and 136±17 ?M, respectively). For kainate receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root kainate responses with apparent KD values of 73.1±4.5 and 60.5±4.1 ?M, respectively). Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at kainate receptors (UBP291 and UBP301 antagonised kainate responses on the dorsal root with apparent KD values of 9.83±1.62 and 5.94±0.63 ?M, respectively). The most useful antagonist identified in this study was UBP301, which was a potent and ?30-fold selective kainate receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated kainate response.

More, Julia C A; Troop, Helen M; Dolman, Nigel P; Jane, David E



Triamino derivatives of triazolotriazine and triazolopyrimidine as adenosine A2a receptor antagonists.  


Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been shown to be potent and selective adenosine A(2a) receptor antagonists. We now demonstrate that potent and selective A(2a) receptor antagonists could still be obtained when the arylpiperazines are separated from the triazolotriazine core structure by an ethylenediamine spacer. Selected analogs bearing this triazolotriazine or the related triazolopyrimidine core structure have been found to be orally active in a mouse catalepsy model of Parkinson's disease. PMID:15341934

Vu, Chi B; Shields, Pamela; Peng, Bo; Kumaravel, Gnanasambandam; Jin, Xiaowei; Phadke, Deepali; Wang, Joy; Engber, Thomas; Ayyub, Eman; Petter, Russell C



H 3 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing retrieval  

Microsoft Academic Search

Rationale  Accumulated evidence suggests a role for histamine in cognition and the use of H3 receptor antagonists in the treatment of learning and memory disorders.\\u000a \\u000a \\u000a \\u000a Objectives  The aim of the current study was to investigate the cognition enhancing properties of ciproxifan, an H3 receptor antagonist, after natural forgetting in normal adult rats.\\u000a \\u000a \\u000a \\u000a Materials and methods  The novel object discrimination task, a recognition memory

Vincent Pascoli; Corinne Boer-Saccomani; Jean-François Hermant



[ 3H]MRS 1754, a selective antagonist radioligand for A 2B adenosine receptors  

Microsoft Academic Search

MRS 1754 [N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide] is a selective antagonist ligand of A2B adenosine receptors. This is the least well-defined adenosine receptor subtype, and A2B antagonists have potential as antiasthmatic drugs. For use as a radioligand, MRS 1754, a p-cyanoanilide xanthine derivative, was tritiated on the propyl groups in a two-step reaction using a p-carboxamido precursor, which was dehydrated to the cyano species

Xiao-duoseqkat Ji; Yong-Chul Kim; David G Ahern; Joel Linden; Kenneth A Jacobson



Combinatorial diffusion assay used to identify topically active melanocyte-stimulating hormone receptor antagonists.  

PubMed Central

alpha-Melanocyte-stimulating hormone (alpha-MSH) is implicated in pigmentation, central nervous system and immune system functions, growth, mitogenesis, and melanoma. Evaluation of these roles has been hindered by the lack of alpha-MSH antagonists. A combinatorial chemistry-based diffusion assay is used to find random tripeptides that antagonize normal frog and human melanoma MSH receptors and to identify pharmacological groups responsible for receptor interaction. The alpha-MSH antagonist D-Trp-Arg-Leu-NH2 is used to demonstrate directly the contribution of MSH to normal skin tone in frogs following injection or topical application. Images Fig. 1 Fig. 3 Fig. 4 Fig. 6

Quillan, J M; Jayawickreme, C K; Lerner, M R



Pharmacokinetic-pharmacodynamic profile of angiotensin II receptor antagonists.  


The pharmacokinetic and pharmacodynamic properties of nonpeptide angiotensin antagonists in humans are reviewed in this paper. Representatives of this new therapeutic class share common features: lipophilia, intermediate bioavailability, high affinity for plasma proteins and liver metabolism; some have active metabolites. Angiotensin II antagonists block the blood pressure response to exogenous angiotensin II in healthy volunteers, decrease baseline blood pressure in both normal and hypertensive patients, produce a marked rise in plasma renin activity and endogenous angiotensin II and increase renal blood flow without altering glomerular filtration rate. These effects are dose-dependent, but their time course varies between the drugs owing to pharmacokinetic and pharmacodynamic differences. Additionally, the extent of blood pressure reduction is dependent on physiological factors such as sodium and water balance. The characterisation of their pharmacokinetic-pharmacodynamic relationships deserves further refinement for designing optimal therapeutic regimens and proposing dosage adaptations in specific conditions. PMID:9012554

Csajka, C; Buclin, T; Brunner, H R; Biollaz, J



Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174.  

PubMed Central

1. Conscious, Long Evans rats (n = 10), chronically instrumented for the measurement of regional haemodynamics, were studied on 3 consecutive experimental days to assess responses to angiotensin II (AII) (125 pmol kg-1, i.v.) and noradrenaline (1 nmol kg-1, i.v.) in the absence and presence of the AT2-receptor antagonist, PD 123319 (10 mg kg-1, i.v.) (day 1), the AT1-receptor antagonist, EXP 3174 (1 mg kg-1, i.v.) (day 2), and PD 123319 (10 mg kg-1, i.v.) given 24 h after EXP 3174 (day 3). 2. In naive rats (day 1), PD 123319 did not antagonize the haemodynamic effects of AII or noradrenaline. EXP 3174 (day 2) caused a marked, prolonged blockade of the haemodynamic effects of AII but not those of noradrenaline. Twenty four h after administration of EXP 3174 (day 3) there was still significant attenuation of the haemodynamic effects of AII. However, administration of PD 123319 at this time caused a further inhibition (lasting 1 h) of the effects of AII but not those of noradrenaline. 3. An identical 3 day protocol was used in a separate group of rats (n = 6) in which the AT2-receptor antagonist, PD 123177, was given instead of PD 123319, and the results were essentially the same, i.e., PD 123177 significantly attenuated the haemodynamic effects of AII but only when given 24 h after EXP 3174.(ABSTRACT TRUNCATED AT 250 WORDS)

Widdop, R. E.; Gardiner, S. M.; Kemp, P. A.; Bennett, T.



Dopamine receptor agonistic and antagonistic effects of 3PPP enantiomers  

Microsoft Academic Search

The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (-)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of

J. Arnt; K. P. Bøgesø; A. V. Christensen; J. Hyttel; J.-J. Larsen; O. Svendsen



The serotonin 5-HT2A receptors antagonist M100907 prevents impairment in attentional performance by NMDA receptor blockade in the rat prefrontal cortex.  


We investigated whether 5-HT2A receptors contribute to the control of attentional performance by glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC). We examined the effects of NMDA receptor blockade in the mPFC on attentional performance by infusing a competitive glutamate NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) into the mPFC of rats performing a task of divided and sustained visual attention. The five-choice serial reaction time task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responses) and speed. A dose of 10 ng CPP injected bilaterally into the mPFC increased anticipatory and perseverative responding; 50 ng reduced accuracy. Increasing the stimulus duration alleviated the CPP-induced accuracy deficit but did not reduce its effects on anticipatory and perseverative responses. CPP at 50 ng caused motor hyperactivity whereas lower doses had no effect. [R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol] (M100907) (M100907), a 5-HT2A receptor antagonist, injected subcutaneously at 10 and 40 microg/kg, had no effect on accuracy but dose dependently reversed the impairment induced by 50 ng CPP. Both doses of M100907 completely abolished CPP-induced anticipatory but not perseverative over-responding. At the dose of 40 microg/kg M100907 reversed CPP-induced motor hyperactivity. This study provides evidence that the prefronto-cortical glutamate NMDA system may make an important contribution to the control of attention and executive functions. It also indicates that 5-HT2A receptors may serve to optimize attentional selectivity and improve some aspects of executive control. PMID:15127084

Mirjana, Carli; Baviera, Marta; Invernizzi, Roberto W; Balducci, Claudia



Corticotropin-releasing hormone receptor antagonists: framework design and synthesis guided by ligand conformational studies.  


As described in the preceding paper (Arvanitis et al. J. Med. Chem. 1999, 42), anilinopyrimidines I were identified as potent antagonists of corticotropin-releasing hormone-1 receptor (CRH1-R, also referred to as corticotropin-releasing factor, CRF1-R). Our next goal was to understand the receptor-bound conformation of the antagonists and to use this information to help guide preclinical optimization of the series and to develop new leads. Since receptor structural information was not available, we assumed that these small, high-affinity antagonists would tend to bind in conformations at or energetically close to their global minima and that rigid analogues that maintained the important stereoelectronic features of the bound anilinopyrimidine would also bind tightly. Conformational preferences and barriers to rotation of the anilinopyrimidines were determined by semiempirical methods, and X-ray and variable-temperature NMR spectroscopy provided experimental results that correlated well with calculated structures. Using these data, a key dihedral angle was constrained to design fused-ring analogues, substituted N-arylpyrrolopyridines II, synthesis of which provided CRH1 receptor antagonists with potency equal to that of the initial congeneric leads (Ki = 1 nM) and which closely matched the conformation held by the original compound, as determined by crystallography. In addition to providing a useful template for further analogue synthesis, the study unequivocally determined the active conformation of the anilinopyrimidines. Theoretical and spectroscopic studies, synthesis, and receptor binding data are presented. PMID:10072680

Hodge, C N; Aldrich, P E; Wasserman, Z R; Fernandez, C H; Nemeth, G A; Arvanitis, A; Cheeseman, R S; Chorvat, R J; Ciganek, E; Christos, T E; Gilligan, P J; Krenitsky, P; Scholfield, E; Strucely, P



A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist  

SciTech Connect

Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Met-binding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors.

Tolbert, W. David; Daugherty, Jennifer; Gao, ChongFeng; Xie, Qian; Miranti, Cindy; Gherardi, Ermanno; Vande Woude, George; Xu, H. Eric (Van Andel); (MRCLMB)



P2X receptor antagonists for pain management: examination of binding and physicochemical properties.  


Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors. PMID:22086553

Gum, Rebecca J; Wakefield, Brian; Jarvis, Michael F



Discovery and development of orexin receptor antagonists as therapeutics for insomnia.  


Insomnia persistently affects the quality and quantity of sleep. Currently approved treatments for insomnia primarily target ?-aminobutyric acid-A (GABA-A) receptor signalling and include benzodiazepines and GABA-A receptor modulators. These drugs are used to address this sleep disorder, but have the potential for side effects such as tolerance and dependence, making them less attractive as maintenance therapy. Forward and reverse genetic approaches in animals have implicated orexin signalling (also referred to as hypocretin signalling) in the control of vigilance and sleep/wake states. Screening for orexin receptor antagonists using in vitro and in vivo methods in animals has identified compounds that block one or other of the orexin receptors (single or dual orexin receptor antagonists [SORAs and DORAs], respectively) in animals and humans. SORAs have primarily been used as probes to further elucidate the roles of the individual orexin receptors, while a number of DORAs have progressed to clinical development as pharmaceutical candidates for insomnia. The DORA almorexant demonstrated significant improvements in a number of clinically relevant sleep parameters in animal models and in patients with insomnia but its development was halted. SB-649868 and suvorexant have demonstrated efficacy and tolerability in Phase II and III trials, respectively. Furthermore, suvorexant is currently under review by the FDA for the treatment of insomnia. Based on the publication of recent nonclinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well-tolerated new class of medications for insomnia. PMID:23731216

Winrow, C J; Renger, J J



Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance\\/dependence liability  

Microsoft Academic Search

Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism

Stanley M Crain; Ke-Fei Shen



Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801  

NASA Astrophysics Data System (ADS)

The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.

Trujillo, Keith A.; Akil, Huda



Interleukin1 Receptor Antagonist Gene Polymorphism, Vaginal Interleukin1 Receptor Antagonist Concentrations, and Vaginal Ureaplasma urealyticum Colonization in Pregnant Women  

Microsoft Academic Search

Ureaplasma urealyticum is the microorganism most frequently isolated from amniotic fluids of women in preterm labor. The relationship between vaginal colonization with U. urealyticum, vaginal interleukin-1 recep- tor antagonist (IL-1ra) levels, and the IL-1ra genotype in pregnant women was examined. Vaginal specimens, obtained with a cotton swab from 207 women in their first trimester of pregnancy, were tested for IL-1ra

Parrin T. Barton; Stefan Gerber; Daniel W. Skupski; Steven S. Witkin



New bicyclic cannabinoid receptor-1 (CB1-R) antagonists.  


A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB(1)-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity. PMID:16263283

Carpino, Philip A; Griffith, David A; Sakya, Subas; Dow, Robert L; Black, Shawn C; Hadcock, John R; Iredale, Philip A; Scott, Dennis O; Fichtner, Michael W; Rose, Colin R; Day, Robert; Dibrino, Joseph; Butler, Mary; Debartolo, Demetria B; Dutcher, Darrin; Gautreau, Denise; Lizano, Jeff S; O'connor, Rebecca E; Sands, Michelle A; Kelly-Sullivan, Dawn; Ward, Karen M



Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss.  


Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss. PMID:17656463

Esler, William P; Rudolph, Joachim; Claus, Thomas H; Tang, Weifeng; Barucci, Nicole; Brown, Su-Ellen; Bullock, William; Daly, Michelle; Decarr, Lynn; Li, Yaxin; Milardo, Lucinda; Molstad, David; Zhu, Jian; Gardell, Stephen J; Livingston, James N; Sweet, Laurel J



A comparison of 5-hydroxytryptamine receptors mediating contraction in rabbit aorta and dog saphenous vein: evidence for different receptor types obtained by use of selective agonists and antagonists.  

PubMed Central

Using recently available selective agonists and antagonists we have examined further our postulate (Apperley et al., 1980) that 5-hydroxytryptamine (5-HT) mediates contraction of dog saphenous vein via a different 5-HT receptor type from that in the rabbit aorta. In the rabbit isolated aorta, ketanserin and spiperone were potent, specific, competitively-acting antagonists of the contractile effects of 5-HT. In contrast, in the dog isolated saphenous vein neither ketanserin nor spiperone caused any rightward displacement of concentration-response curves to 5-HT although the maximum response was reduced by about 10%. In the rabbit aorta 5-carboxamidotryptamine (5-CONH2-T) was a weak agonist whilst the 5-N,N-dimethyl and 5-N-ethyl derivatives were even weaker or inactive. The contractile effect of 5-CONH2-T in the rabbit aorta was potently and competitively antagonized by ketanserin. In contrast, in the dog saphenous vein 5-CONH2-T and its 5-N,N-dimethyl and 5-N-ethyl derivatives were all potent agonists. The contractile effect of 5-CONH2-T was not markedly affected by ketanserin. The profile of action of ketanserin and spiperone in the rabbit aorta is consistent with the view that 5-HT2 receptors mediate contraction in this preparation. However, the 5-HT receptor mediating contraction in the dog saphenous vein appears to be '5-HT1-like', sharing a number of characteristics with the 5-HT1 recognition site identified from [3H]-5-HT ligand binding studies in brain tissue.

Feniuk, W.; Humphrey, P. P.; Perren, M. J.; Watts, A. D.



Structure-based design of eugenol analogs as potential estrogen receptor antagonists.  


Eugenol is an essential oil mainly found in the buds and leaves of clove (Syzygium aromaticum (L.) Merrill and Perry), which has been reported to have activity on inhibition of cell proliferation and apoptosis induction in human MCF-7 breast cancer cells. This biological activity is correlated to its activity as an estrogen receptor antagonist. In this article, we present the construction and validation of structure-based virtual screening (SBVS) protocols to identify the potent estrogen receptor ? (ER) antagonists. The selected protocol, which gave acceptable enrichment factors as a virtual screening protocol, subsequently used to virtually screen eugenol, its analogs and their dimers. Based on the virtual screening results, dimer eugenol of 4-[4-hydroxy-3-(prop-2-en-1- yl)phenyl]-2-(prop-2-en-1-yl)phenol is recommended to be developed further in order to discover novel and potent ER antagonists. PMID:23144548

Anita, Yulia; Radifar, Muhammad; Kardono, Leonardus Bs; Hanafi, Muhammad; Istyastono, Enade P



Discriminative stimulus effects in rats of SR141716 (rimonabant), a cannabinoid CB 1 receptor antagonist  

Microsoft Academic Search

Objective To examine the discriminative stimulus effects of (i) the cannabinoid CB 1 receptor antagonist SR-141716 (SR, 5.6 mg\\/kg) and vehicle, and (ii) the cannabinoid receptor agonist ? 9-THC (THC, 1.8 mg\\/kg) and vehicle using a discriminated taste aversion (DTA) procedure. Methods Two groups of rats ( n=6) were trained to discriminate between these drugs and vehicle in DTA ( t?=20 min). The

Torbjörn U. C. Järbe; Michele Y. Harris; Chen Li; Qian Liu; Alexandros Makriyannis



A proposed common spatial pharmacophore and the corresponding active conformations of some peptide leukotriene receptor antagonists  

Microsoft Academic Search

Molecular modeling studies were carried out by a combined use of conformational analysis and 3D-QSAR methods to identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetophenone (non-HAP) peptide leukotriene (pLT) receptor antagonists. In attempts to develop a ligand-binding model for the pLT receptor, the Apex-3D program was used to identify biophoric structural patterns that are common to

V. Hariprasad; Vithal M. Kulkarni



SR 144528, the First Potent and Selective Antagonist of the CB2 Cannabinoid Receptor  

Microsoft Academic Search

Based on both binding and functional data, this study intro- duces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki 5 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki 5 400 nM) for both the rat



Functional potencies of dopamine agonists and antagonists at human dopamine D 2 and D 3 receptors  

Microsoft Academic Search

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D2 and D3 receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D2L and D2S receptors (hD2L-Low,

Yoshihiro Tadori; Robert A. Forbes; Robert D. McQuade; Tetsuro Kikuchi



A selective orexin-1 receptor antagonist reduces food consumption in male and female rats  

Microsoft Academic Search

A variety of evidence implicates the orexins, especially orexin-A, in the regulation of food intake, but it has not been established whether this effect is mediated by the orexin-1 or orexin-2 receptor. In the present study, a selective orexin-1 receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride (SB-334867-A), was administered intraperitoneally to rats under various conditions, and food consumption was subsequently measured over

Andrea C. Haynes; Brian Jackson; Helen Chapman; Mohammed Tadayyon; Amanda Johns; Roderick A. Porter; Jonathan R. S. Arch



Synthesis and SAR studies of benzimidazolone derivatives as histamine H3-receptor antagonists.  


A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9?Mh. PMID:24050887

Zeng, Qingbei; Rosenblum, Stuart B; Yang, Zhaoxia; Jiang, Yueheng; McCormick, Kevin D; Aslanian, Robert G; Duguma, Luli; Kozlowski, Joseph A; Shih, Neng-Yang; Hey, John A; West, Robert E; Korfmacher, Walter A; Berlin, Michael; Boyce, Christopher W



Characterization of RWJ-351647, a novel nonpeptide vasopressin V2 receptor antagonist.  


1. Antagonists of the V(2) vasopressin (AVP) receptor are aquaretic agents, inhibiting water resorption without stimulating electrolyte excretion. In this set of experiments, a novel V(2) receptor antagonist, RWJ-351647, was characterized in vitro and in vivo. 2. RWJ-351647 displaced (3)H-AVP binding from cloned human V(2) and V(1A) receptors with Ki values of 1 nmol/L and 24 nmol/L. In assays using transfected HEK293 cells expressing either human or rat V(2) receptors, RWJ-351647 inhibited AVP-induced cAMP accumulation with Ki values of 3 nmol/L and 6 nmol/L, respectively. 3. RWJ-351647 was very selective in binding assays and showed only weak functional antagonist activity at either the cloned human V(1B) and oxytocin receptors or the human platelet V(1A) receptor. No agonist activity was seen with the compound at any receptor. 4. Pharmacokinetic studies in rats showed RWJ-351647 to be 41.9% bioavailable after a single oral administration. After repeated daily dosing over 5 days, the oral bioavailability remained at 43.9% with no change in the compound peak plasma levels or clearance rate. 5. In efficacy studies, RWJ-351647 increased urine output and decreased urine osmolality with oral doses as low as 0.1 mg/kg and 1.0 mg/kg in rats and cynomolgus monkeys, respectively. In a multiple dose study in primates, RWJ-351647 maintained a consistent aquaretic effect over 10 days without increasing sodium or potassium excretion. 6. In summary, RWJ-351647 was shown to be a selective and potent V(2) receptor antagonist with sustainable aquaretic activity in both rats and primates. The preclinical data suggest that RWJ-351647 is a potent and effective aquaretic agent with potential for use in diseases characterized by water retention. PMID:16620295

Gunnet, Joseph W; Matthews, Jay M; Maryanoff, Bruce E; de Garavilla, Lawrence; Andrade-Gordon, Patricia; Damiano, Bruce; Hageman, William; Look, Richard; Stahle, Paul; Streeter, Anthony J; Wines, Pamela G; Demarest, Keith T



Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y 13 receptor  

Microsoft Academic Search

We have synthesized a series of derivatives of the known P2 receptor antagonist PPADS (pyridoxal-5?-phosphate-6-azo-phenyl-2,4-disulfonate) and examined their ability to inhibit functional activity of the recombinant human P2Y13 nucleotide receptor expressed in 1321N1 human astrocytoma cells co-expressing G?16 protein (AG32). Analogues of PPADS modified through substitution of the phenylazo ring, including halo and nitro substitution, and 5?-alkyl phosphonate analogues were

Yong-Chul Kim; Jung-Sun Lee; Katrin Sak; Frederic Marteau; Liaman Mamedova; Jean-Marie Boeynaems; Kenneth A. Jacobson



The metabotropic glutamate receptor antagonist l-2-amino-3-phosphonopropionic acid inhibits phosphoserine phosphatase  

Microsoft Academic Search

Phosphoserine phosphatase catalyzes the final step in the major pathway of l-serine biosynthesis in brain. Using d-phosphoserine as substrate, the metabotropic glutamate receptor antagonist l-2-amino-3-phosphonopropionic acid (l-AP3) inhibits phosphoserine phosphatase partially purified from rat brain with a Ki of 151 ?M. In contrast to AP3 enantioselectivity at metabotropic receptors, d-AP3 (Ki 48 ?m) is more potent as an inhibitor of

Jon E. Hawkinson; Manuel Acosta-Burruel; Paul L. Wood



Adenosine A 1 receptor antagonist versus montelukast on airway reactivity and inflammation  

Microsoft Academic Search

Adenosine produces bronchoconstriction in allergic rabbits, primates, and humans by activating adenosine A1 receptors. Previously, it is reported that a high dose of L-97-1, a water-soluble, small molecule adenosine A1 receptor antagonist, blocks early and late allergic responses, and bronchial hyper-responsiveness to histamine in a hyper-responsive rabbit model of allergic asthma. Effects of a lower dose of L-97-1 are compared

Ahmed Nadeem; Peter C. M. Obiefuna; Constance N. Wilson; S. Jamal Mustafa



Expression Profiling to Understand Actions of NMDA\\/Glutamate Receptor Antagonists in Rat Brain  

Microsoft Academic Search

Agents acting as noncompetitive N-methyl-d-aspartate (NMDA)\\/glutamate receptor antagonists induce the expression of several genes in limbic cortical regions, such as the cingulate, retrosplenial, and entorhinal cortices. These include important regulatory genes such as the neurotrophin brain–derived neurotrophic factor (BDNF), its receptor trkB, and c-fos. We applied expression profiling methods to find genes coregulated with BDNF following treatment with the prototypical

Petri Törönen; Marcus Storvik; Anni-Maija Lindén; Outi Kontkanen; Markéta Marvanová; Merja Lakso; Eero Castrén; Garry Wong




PubMed Central

Experimental evidence suggests that metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists affect cognitive function, although contradictory findings have been reported. To clarify the role of mGlu2/3 receptor antagonists in one aspect of cognition, the present study investigated the effects of a broad range of doses of the mGlu2/3 receptor antagonist LY341495 on post-training recognition memory components (storage and/or retrieval) in rats. The efficacy of LY341495 in antagonizing the extinction of recognition memory was also investigated. The novel object recognition test was used as the memory test. The highest LY341495 doses administered (0.3, 1, and 3 mg/kg) disrupted performance in this recognition memory procedure in rats at all delay conditions tested, whereas administration of lower doses (0.05 and 0.1 mg/kg) did not impair recognition memory. Moreover, administration of the low LY341495 doses (0.05 and 0.1 mg/kg) counteracted the extinction of recognition memory. The present results indicate that administration of the mGlu2/3 receptor antagonist LY341495 can either impair or enhance recognition memory in rats, depending on the dose of the compound and delay period used. Thus, together with previously reported findings, the present data suggest complex effects of this compound on cognitive function, particularly recognition memory.

Pitsikas, Nikolaos; Kaffe, Eleanna; Markou, Athina



I. Effects of a Dopamine Receptor Antagonist on Fathead Minnow, Pimephales promelas ,Reproduction  

EPA Science Inventory

This study used a 21 d fathead minnow (Pimephales promelas) reproduction assay to test the hypothesis that exposure to the dopamine 2 receptor (D2R) antagonist, haloperidol, would impair fish reproduction. Additionally, a 96 h experiment with fathead minnows and zebrafish (Danio ...


Dual action molecules: bioassays of combined novel antioxidants and angiotensin II receptor antagonists.  


In this study we have investigated the in vitro angiotensin II receptor antagonist and antioxidant activity of a series of compounds in which the antioxidant pharmacophores (selenium, phenol, benzothiophene, ebselen or nitroxide) have been incorporated into the AT(1) receptor antagonist (sartan) milfasartan. Activity of these compounds was assessed in tissue-based assays. The novel molecules (30nM), nitrasartan or phenol-milfasartan, retained AT(1) receptor antagonist potency in rat isolated right atria. Antioxidant capacity of the substituted sartans was examined in an AAPH (2,2'-azobis (2-amidinopropane) hydrochloride)-induced haemolysis assay (mouse C57/BL6 isolated erythrocytes). Each of the antioxidant pharmacophores (10?M), except benzothiophene, protected against radical-mediated lysis. Of the novel sartans, only analogues incorporating selenium, phenol or nitroxide (nitrasartan) protected against radical-induced haemolysis. In the tissue-based assay using mouse isolated paced left atria, the free radical generator doxorubicin (30?M) resulted in a decrease in left atrial force over 90min. In this assay the phenol, nitroxide or ebselen antioxidant pharmacophores protected against doxorubicin-induced negative inotropy but selenocystine and benzothiophene did not. Nitrasartan (10?M) was the only novel analogue to protect against radical-induced negative inotropy. Nitrasartan also antagonised angiotensin II responses and decreased superoxide production in a concentration-dependent manner in rat isolated carotid arteries and aortae, respectively. In conclusion, nitrasartan is a dual action molecule demonstrating both AT(1) receptor antagonist potency and antioxidant properties in vitro. PMID:22975712

Jani, Nitya V; Ziogas, James; Angus, James A; Schiesser, Carl H; Macdougall, Phoebe E; Grange, Rebecca L; Wright, Christine E



Substituted thieno[2,3-d]pyrimidines as adenosine A2A receptor antagonists.  


A novel series of benzyl substituted thieno[2,3-d]pyrimidines were identified as potent A2A receptor antagonists. Several five- and six-membered heterocyclic replacements for the optimized methylfuran were explored. Select compounds effectively reverse catalepsy in mice when dosed orally. PMID:23522563

Shook, Brian C; Chakravarty, Devraj; Barbay, J Kent; Wang, Aihua; Leonard, Kristi; Alford, Vernon; Powell, Mark T; Rassnick, Stefanie; Scannevin, Robert H; Carroll, Karen; Wallace, Nathaniel; Crooke, Jeffrey; Ault, Mark; Lampron, Lisa; Westover, Lori; Rhodes, Kenneth; Jackson, Paul F



Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior.  


Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 microg, 20 microg, 2 mg/kg or vehicle. When tested 90-120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse. PMID:16504276

Ferris, Craig F; Lu, Shi-Fang; Messenger, Tara; Guillon, Christophe D; Heindel, Ned; Miller, Marvin; Koppel, Gary; Robert Bruns, F; Simon, Neal G



Progesterone receptor modulators and progesterone antagonists in women’s health  

Microsoft Academic Search

Both progesterone receptor modulators (PRMs) as well as pure progesterone antagonists (PAs) have numerous proven and potential therapeutic applications in female health care. Mifepristone, a PRM with only marginal agonistic activity, together with a prostaglandin can terminate pregnancies of less than 9 weeks duration; mifepristone is also used in the preparation of women at later gestational stages whose pregnancies are

Irving M Spitz; Kristof Chwalisz



Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma  

Microsoft Academic Search

BACKGROUND: Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown. METHODS: The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an

D. J. Evans; P. J. Barnes; S. M. Spaethe; E. L. van Alstyne; M. I. Mitchell; B. J. OConnor



Discovery techniques for calcitonin gene-related peptide receptor antagonists for potential antimigraine therapies.  


Introduction: Calcitonin gene-related peptide (CGRP) exerts a key function in migraine pathophysiology through the trigeminovascular system. Influencing this system via CGRP receptor antagonists seems to be an important new option in treating migraine attacks. To characterize new compounds, models are used to study the vascular effects as well as their effects on the central nervous system. Areas covered: The authors review the clinical trials and many different in vitro and in vivo experimental models that have been used to investigate the effects and side effects in animals, healthy subjects and patients. These experimental models are essential, not only in characterizing new CGRP receptor antagonists, but also in gaining more insight into the pathophysiological mechanisms behind migraines. Expert opinion: Although triptans were a major breakthrough in migraine treatment, they are not effective for every patient and contraindicated in patients with cardiovascular disease. There is still a demand for other acute antimigraine acting drugs with CGRP receptor antagonists being the most promising candidates. CGRP plays a role in protection against ischemia, but CGRP receptor antagonists do not seem to affect this protection to a harmfull extent, when used incidentally as acute antimigraine treatment. In order for drug specificity to be increased, the site of action needs to be identified; this consequently may lead to a decrease in dosing with fewer side effects. PMID:23962310

Labruijere, Sieneke; Ibrahimi, Khatera; Chan, Kayi Y; Maassenvandenbrink, Antoinette



A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant.  


A patient with severe capillary leakage syndrome caused by a Puumala hantavirus infection was treated with a single dose of icatibant, a bradykinin receptor antagonist, with a dramatic positive response. We suggest that this drug should be tested in a larger number of patients with severe hantavirus infection. PMID:23294035

Antonen, Jaakko; Leppänen, Ilona; Tenhunen, Jyrki; Arvola, Pertti; Mäkelä, Satu; Vaheri, Antti; Mustonen, Jukka



New azole antagonists with high affinity for the P2Y(1) receptor.  


Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent. PMID:23668989

Ruel, Réjean; L'Heureux, Alexandre; Thibeault, Carl; Daris, Jean-Paul; Martel, Alain; Price, Laura A; Wu, Qimin; Hua, Ji; Wexler, Ruth R; Rehfuss, Robert; Lam, Patrick Y S



Tetrahydro-4-quinolinamines identified as novel P2Y 1 receptor antagonists  

Microsoft Academic Search

High-throughput screening of the GSK compound collection against the P2Y1 receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.

Ángel I. Morales-Ramos; John S. Mecom; Terry J. Kiesow; Todd L. Graybill; Gregory D. Brown; Nambi V. Aiyar; Elizabeth A. Davenport; Lorena A. Kallal; Beth A. Knapp-Reed; Peng Li; Allyn T. Londregan; Dwight M. Morrow; Shobha Senadhi; Reema K. Thalji; Steve Zhao; Cynthia L. Burns-Kurtis; Joseph P. Marino



Effect of VEGF Receptor Antagonist (VGA1155) on Brain Edema in the Rat Cold Injury Model  

Microsoft Academic Search

Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and a strong vascular permeability factor. Blockade of VEGF may have a potential to treat brain edema after brain injury. In the rat cold injury model, the VEGF receptor antagonist VGA1155 significantly reduced the brain water content and the maximum effect was obtained when given at 30 minutes after




Eryloside F, a novel penasterol disaccharide possessing potent thrombin receptor antagonist activity.  


We report the discovery of Eryloside F, a novel disaccharide of the steroidal carboxylic acid penasterol, isolated from an extract of the marine sponge Erylus formosus. The compound is a potent thrombin receptor antagonist, and furthermore inhibits human platelet aggregation in vitro. PMID:10762048

Stead, P; Hiscox, S; Robinson, P S; Pike, N B; Sidebottom, P J; Roberts, A D; Taylor, N L; Wright, A E; Pomponi, S A; Langley, D



Attenuation of antagonist-induced impairment of dopamine receptors by L-prolyl-L-leucyl-glycinamide  

SciTech Connect

The present study was undertaken in order to determine whether chronic,long-term postnatal challenge of rat pups per se, with specific dopamine D1 and D2 receptor antagonists, would modify the ontogeny of the respective receptor types. Since the neuropeptide L-prolyl-L-leucyl-glycinamide (PLG) attenuates the effect of haloperidol on dopamine D2 receptors in adult rats it was of interest to determine whether PLG would modulate antagonists-induced alterations in the ontogeny of striatal dopamine D1 and D2 receptors. Half of the rats were treated daily for 32 days from birth with SCH-23390, a selective dopamine D1 antagonist; or spiroperidol, a selective dopamine D2 antagonists; or both SCH-23390 and spiroperidol; or saline. The other half of the litters were treated with PLG, in combination with the other treatments. Animals were decapitated at 5, 8, and 12 weeks from birth for neurochemical analysis of the striatum. Chronic SCH-23390 treatment produced a 70-80% decrease in the binding of ({sup 3}H) SCH-23390 to striatal homogenates. The alteration at 5 weeks was associated with a 78% decrease in the Bmax for ({sup 3}H) SCH-23390 binding, and no change in the K{sub D}. Similarly, at 5, 8, and 12 weeks, chronic spiroperidol treatment reduced the binding of ({sup 3}H) spiroperidol to striatal homogenates by 70-80%.

Saleh, M.I.M.



Improvement of memory in rodents by the selective CB1 cannabinoid receptor antagonist, SR 141716  

Microsoft Academic Search

Social short-term memory in rodents is based on the recognition of a juvenile by an adult conspecific when the juvenile is presented on two successive occasions. Cannabimimetics are claimed to induce memory deficits in both humans and animals. In the brain, they mainly bind to CB1 receptors for which anandamide is a purported endogenous ligand. SR 141716, a specific antagonist

J.-P. Terranova; J.-J. Storme; N. Lafon; A Pério; M. Rinaldi-Carmona; G. Le Fur; P. Soubrié



A new nonpeptide tachykinin NK1 receptor antagonist isolated from the plants of Compositae.  


To find new tachykinin NK1 receptor antagonists from natural sources, we examined the tachykinin antagonist activity in the extracts of approximately 200 species of plants by the use of isolated guinea pig ileum. As a result, we discovered a novel and potent NK1 receptor antagonist in the extract of dried flowers of Matricaria chamomilla L. (chamomile). The structure of the antagonist was established as N1,N5,N10,N14-tetrakis[3-(4-hydroxyphenyl)-2-propenoyl]-1,5,10,14-tetraazatetradecane (tetracoumaroyl spermine, 1a). The Ki values of 1a, estimated from the inhibitory action on the substance P (SP)-induced contraction of the guinea pig ileum and the inhibition of the binding of [3H][Sar9, Met(O2)11]SP to human NK1 receptors, were 21.9 nM and 3.3 nM, respectively. 1a is the first potent NK1 receptor antagonist from natural sources and it has a unique structure of a polyacylated spermine. 1a was concentrated in pollen of Matricaria chamomilla L. and was also found in the extracts of flowers of other four species of Compositae. In addition, we found N1,N5,N10-tris[3-(4-hydroxyphenyl)-2-propenoyl]-1,5,10,14-tetraazatetradecane (2) as a new compound in the extract of flowers of Matricaria chamomilla L., which did not exhibit any tachykinin antagonist activity. A number of related compounds were synthesized, and the structure-activity relationship was studied. PMID:11824584

Yamamoto, Atsushi; Nakamura, Ko; Furukawa, Kazuhito; Konishi, Yukari; Ogino, Takashi; Higashiura, Kunihiko; Yago, Hisashi; Okamoto, Kaoru; Otsuka, Masanori



In vitro characterization of ZK 230211--A type III progesterone receptor antagonist with enhanced antiproliferative properties.  


The progesterone receptor (PR) is a key regulator of female reproductive functions. Compounds with progesterone inhibiting effects (PR antagonists) have found numerous utilities in female reproductive health, ranging from contraception to potential treatment of progesterone-dependent diseases like uterine leiomyomas. Based on in vitro characteristics such as DNA binding activity and partial agonistic transcriptional behavior in the presence of protein kinase A activators (cyclic-AMP), three types of PR modulators with antagonistic properties have been defined. In this study, we analyzed the in vitro characteristics of the PR antagonist ZK 230211 in comparison to the classical antagonists onapristone and mifepristone. We focused on PR actions in genomic signaling pathways, including DNA binding activity, nuclear localization and association with the nuclear receptor corepressor (NCoR) as well as actions in non-genomic signaling, such as the activation of c-Src kinase signaling and cyclin D1 gene promoter activity. ZK 230211 represents a type of PR antagonist with increased inhibitory properties in comparison to mifepristone and onapristone. When liganded to the progesterone receptor, ZK 230211 induces a strong and persistent binding to its target response element (PRE) and increases NCoR recruitment in CV-1 cells. Furthermore, ZK 230211 displays less agonistic properties with regard to the association of PR isoform B and the cytoplasmic c-Src kinase in HeLa cells. It represses T47D cell cycle progression, in particular estradiol-induced S phase entry. In summary, our studies demonstrate ZK 230211 to be a type III progesterone receptor antagonist which is characterized by very strong DNA binding activity and strong antiproliferative effects in the cancer cell lines HeLa and T47D. PMID:20043998

Afhüppe, Wiebke; Beekman, Johanna M; Otto, Christiane; Korr, Daniel; Hoffmann, Jens; Fuhrmann, Ulrike; Möller, Carsten



Agonist and antagonist protect sulfhydrals in the binding site of the D-1 dopamine receptor  

SciTech Connect

An iodinated compound (/sup 125/I)-SCH 23982 (8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) has been characterized as a specific, high affinity (Kd = 0.7 nM) ligand for the D-1 dopamine receptor. The ligand binding site of the D-1 receptor in rat striatum was inactivated by N-ethylmaleimide (NEM) in a time and concentration dependent manner. The inactivation was rapid and irreversible with a 70% net loss of binding sites. Scatchard analysis of binding to NEM-treated tissue showed a decrease both in receptor number and in radioligand affinity. The remaining receptors retained their selectivity for stereoisomers of both agonist and antagonist. Receptor occupancy by either a D-1 specific agonist or antagonist protected in a dose dependent manner the binding sites from inactivation by NEM; the agonist was more effective than the antagonist. The agonist high affinity site, however, was abolished in the absence or presence of protective compound, presumably because of inactivation of the GTP-binding component of adenylate cyclase. In this regard, there was a total loss of agonist- and forskolin-stimulated adenylate cyclase activity after NEM treatment. The authors conclude that the D-1 dopamine receptor contains NEM-sensitive sulfhydral group(s) at or near the vicinity of the ligand binding site.

Sidhu, A.; Kebabian, J.W.; Fishman, P.H.



Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist  

SciTech Connect

The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu; Yurugi-Kobayashi, Takami; Shiroishi, Mitsunori; Zhang, Cheng; Weis, William I.; Okada, Tetsuji; Kobilka, Brian K.; Haga, Tatsuya; Kobayashi, Takuya (Stanford-MED); (Kyoto); (Gakushuin); (Kyushu)



Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist  

PubMed Central

The parasympathetic limb of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G protein coupled receptors (GPCRs) that mediate the response to acetylcholine released from parasympathetic nerves.1–5 Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiologic control of cardiovascular function through activation of G protein-coupled inwardly-rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of antagonist-bound M2 receptor, the first human acetylcholine receptor to be characterized structurally. The antagonist QNB binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all 5 muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The M2 receptor structure provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu; Yurugi-Kobayashi, Takami; Shiroishi, Mitsunori; Zhang, Cheng; Weis, William I.; Okada, Tetsuji; Kobilka, Brian K.; Haga, Tatsuya; Kobayashi, Takuya



AM-251 and Rimonabant Act as Direct Antagonists at Mu-Opioid Receptors: Implications for Opioid/Cannabinoid Interaction Studies  

PubMed Central

Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). AM-251 and rimonabant are CB1R antagonist/inverse agonists employed to validate opioid-cannabinoid interactions, presumed to act selectively at CB1Rs. Therefore, the potential for direct action of these antagonists at MORs is rarely considered. This study determined if AM-251 and/or rimonabant directly bind and modulate the function of MORs. Surprisingly, AM-251 and rimonabant, but not a third CB1R inverse agonist AM-281, bind with mid-nanomolar affinity to human MORs with a rank order of affinity (Ki) of AM-251 (251 nM) > rimonabant (652 nM) > AM281 (2135 nM). AM-251 and rimonabant, but not AM-281, also competitively antagonize morphine induced G-protein activation in CHO-hMOR cell homogenates (Kb = 719 or 1310 nM, respectively). AM-251 and rimonabant block morphine inhibition of cAMP production, while only AM-251 elicits cAMP rebound in CHO-hMOR cells chronically exposed to morphine. AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent actions of these antagonists may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.

Seely, Kathryn A.; Brents, Lisa K.; Franks, Lirit N.; Rajasekaran, Maheswari; Zimmerman, Sarah M.; Fantegrossi, William E.; Prather, Paul L.



( sup 3 H)SCH39166, a D1 dopamine receptor antagonist: Binding characteristics and localization  

SciTech Connect

Schering-Plough Research has developed a new, more specific analogue of SCH23390. This compound, SCH39166, has been shown to be a potent, specific, D1 receptor antagonist with several features which are advantageous over its predecessor. In this report, the binding characteristics of (3H)SCH39166 are described by in vitro analysis in rat brain tissues. The binding was shown to be of high affinity (Kd in the low nM range), saturable, and specific (readily displaceable with SCH23390, but not with the D2 receptor antagonists sulpiride or haloperidol). The binding of SCH39166 is more selective for binding to D1 receptors than SCH23390 with regard to overlap of the latter compound onto 5HT2 and 5HT1C receptors. Autoradiographic localization of D1 receptor sites labeled with (3H)SCH39166 showed a very specific distribution in areas known to contain high quantities of D1 receptors. These regions included the deepest layer of the cerebral cortex, the caudate-putamen, nucleus accumbens, olfactory tubercle, entopeduncular nucleus, and substantia nigra-pars reticulata, as well as less dense binding in a few other areas. At the concentration of ligand used (1 nM), there was a noticeable paucity of labeling in lamina IV of the cerebral cortex and in the choroid plexus, regions of high 5HT2 and 5HT1C receptor binding, respectively. Thus, SCH39166 represents a new D1 receptor antagonist which shows a greater specificity for the D1 receptor than its predecessor SCH23390. As previously shown, another distinct advantage of this compound is its stability in primates which should allow the determination of the effects and utility of D1 receptor antagonism in vivo.

Wamsley, J.K.; Hunt, M.E.; McQuade, R.D.; Alburges, M.E. (Neuropsychiatric Research Institute, Fargo, ND (USA))



Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix.  

PubMed Central

Antagonists of luteinizing hormone-releasing hormone (LH-RH), unlike the LH-RH agonists, suppress gonadotropins and sex steroid secretion immediately after administration, without initial stimulatory effects. [Ac-D-Nal(2)1,D-Ph(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]LH-R H (SB-75; Cetrorelix) is a modern, potent antagonistic analog of LH-RH. In this study, the binding characteristics of receptors for LH-RH in membrane fractions from rat anterior pituitaries were investigated after a single injection of Cetrorelix at a dose of 100 microg per rat. To determine whether the treatment with Cetrorelix can affect the concentration of measurable LH-RH binding sites, we applied an in vitro method to desaturate LH-RH receptors by chaotropic agents such as manganous chloride (MnCl2) and ammonium thiocyanate (NH4SCN). Our results show that the percentages of occupied LH-RH receptors at 1, 3, and 6 h after administration of Cetrorelix were approximately 28%, 14%, and 10%, respectively, of total receptors. At later time intervals, we could not detect occupied LH-RH binding sites. Ligand competition assays, following in vitro desaturation, demonstrated that rat pituitary LH-RH receptors were significantly (P < 0.01) down-regulated for at least 72 h after administration of Cetrorelix. The lowest receptor concentration was found 3-6 h after Cetrorelix treatment and a recovery in receptor number began within approximately 24 h. The down-regulation of LH-RH binding sites induced by Cetrorelix was accompanied by serum LH and testosterone suppression. Higher LH-RH receptor concentrations coincided with elevated serum hormone levels at later time intervals. Our results indicate that administration of LH-RH antagonist Cetrorelix produces a marked down-regulation of pituitary receptors for LH-RH and not merely an occupancy of binding sites.

Halmos, G; Schally, A V; Pinski, J; Vadillo-Buenfil, M; Groot, K



Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders  

PubMed Central

Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D3 receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D3 receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D3 receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D2/D3 receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D3 versus D2 receptor, and their efficacy profile is related primarily to functional antagonism at D2 receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D3 receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.

Heidbreder, Christian A.; Newman, Amy H.



Synthesis and Evaluation of [11C]LY2795050 as a Novel Kappa Opioid Receptor Antagonist Radiotracer for PET Imaging  

PubMed Central

Kappa opioid receptors (KOR) are believed to be involved in the pathophysiology of depression, anxiety disorders, drug abuse and alcoholism. To date, only one tracer, the kappa opioid receptor agonist [11C]GR103545, has been reported to be able to image KOR in primates. The goal of the present study was to synthesize the selective KOR antagonist [11C]LY2795050 and evaluate its potential as a PET tracer to image KOR in vivo. METHODS In vitro binding affinity of LY2795050 was measured in radioligand competition binding assays. Ex vivo experiments were conducted using microdosing of the unlabelled ligand in Sprague-Dawley rats, as well as wild-type and KOR knock-out mice, to assess the ligand’s potential as a tracer candidate. Imaging experiments with [11C]LY2795050 in monkeys were carried out on the Focus-220 PET scanner with arterial blood input function measurement. Binding parameters were determined with kinetic modeling analysis. RESULTS LY2795050 displays full antagonist activity and high binding affinity and selectivity for KOR. Microdosing studies in rodents and ex vivo analysis of tissue concentrations with LC/MS/MS identified LY2795050 as an appropriate tracer candidate able to provide specific binding signals in vivo. [11C]LY2795050 was prepared in an average yield of 12% and >99% radiochemical purity. In rhesus monkeys, [11C]LY2795050 displayed a moderate rate of peripheral metabolism, with ?40% of parent compound remaining at 30 min postinjection. In the brain, [11C]LY2795050 displayed fast uptake kinetics (regional activity peak times < 20 min) and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, iv) resulted in a uniform distribution of radioactivity. Further, specific binding of [11C]LY2795050 was reduced by the selective KOR antagonist LY2456302 in a dose-dependent manner. CONCLUSION [11C]LY2795050 displayed favorable pharmacokinetic properties and binding profiles in vivo, and therefore is a suitable ligand for imaging the KOR in primates. This newly developed KOR antagonist tracer has since been advanced to PET imaging of KOR in humans and constitutes the first successful KOR antagonist radiotracer.

Zheng, Ming-Qiang; Nabulsi, Nabeel; Kim, Su Jin; Tomasi, Giampaolo; Lin, Shu-fei; Mitch, Charles; Quimby, Steven; Barth, Vanessa; Rash, Karen; Masters, John; Navarro, Antonio; Seest, Eric; Morris, Evan E.; Carson, Richard E.; Huang, Yiyun



Formation of an active dimer during storage of interleukin-1 receptor antagonist in aqueous solution.  

PubMed Central

The degradation products of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) formed during storage at 30 degrees C in aqueous solution were characterized. Cationic exchange chromatography of the stored sample showed two major, new peaks eluting before (P1) and after (L2) the native protein, which were interconvertible. Size-exclusion chromatography and electrophoresis documented that both the P1 and L2 fractions were irreversible dimers, formed by noncovalent interactions. A competition assay with interleukin-1 indicated that on a per monomer basis the P1 and L2 dimers retained about two-thirds of the activity of the native monomer. Infrared and far-UV circular dichroism spectroscopies showed that only minor alterations in secondary structure arose upon the formation of the P1 dimer. However, alteration in the near-UV circular dichroism spectrum suggested the presence of disulfide bonds in the P1 dimer, which are absent in the native protein. Mass spectroscopy and tryptic mapping, before and after carboxymethylation, demonstrated that the P1 dimer contained an intramolecular disulfide bond between Cys-66 and Cys-69. Although conversion of native protein to the P1 dimer was irreversible in buffer alone, the native monomer could be regained by denaturing the P1 dimer with guanidine hydrochloride and renaturing it by dialysis, suggesting that the intramolecular disulfide bond does not interfere with refolding. Analysis of the time course of P1 formation during storage at 30 degrees C indicated that the process followed first-order, and not second-order, kinetics, suggesting that the rate-limiting step was not dimerization. It is proposed that a conformational change in the monomer is the rate-limiting step in the formation of the P1 dimer degradation product. Sucrose stabilized the native monomer against this process. This result can be explained by the general stabilization mechanism for this additive, which is due to its preferential exclusion from the protein surface.

Chang, B S; Beauvais, R M; Arakawa, T; Narhi, L O; Dong, A; Aparisio, D I; Carpenter, J F



SR 121787, a new orally active fibrinogen receptor antagonist.  


The aim of this study was to describe the pharmacological properties of SR 121787, a new antiaggregating drug which is metabolized in vivo into SR 121566, a potent non-peptide antagonist of Gp IIb/IIIa. In vitro, SR 121566 antagonized the binding of [125I]-fibrinogen (IC50 = 19.8+/-6.3 nM) and of [125I]-L-692,884, an RGD-containing peptide (IC50 = 291+/-96 nM) to activated human platelets. SR 121566 inhibited the aggregation of human platelets induced by ADP, collagen, thrombin, arachidonic acid and PAF at concentrations lower than 0.1 microM. Adhesion of human platelets to adhesive proteins was inhibited by SR 121566 (IC50 = 40.3+/-2.5 nM) only when Gp IIb/IIIa and fibrinogen were involved. No effect was found with regard to other adhesive proteins and/or other integrins. SR 121787 demonstrated a potent and sustained antiaggregating effect when administered intravenously to baboons at a dose 50 microg/kg, and eight hours after the administration of 100 microg/kg, ADP-induced aggregation was still strongly inhibited (more than 80%). A single oral administration of 2 mg/kg of SR 121787 produced a nearly complete inhibition of platelet aggregation for up to 8 h (ED50 at 8 h = 193+/-20 microg/kg), a significant residual antiaggregating activity being still observed 24h after the administration. When administered orally to rabbits, SR 121787 exhibited a potent antiaggregating (ED50 = 2.3+/-0.3 mg/kg) and antithrombotic activity in an arterio-venous shunt thrombosis model (ED50 = 10.4+/-0.8 mg/kg). After oral and IV administration, SR 121787 was well tolerated suggesting that SR 121787, the most potent and long lasting orally active Gp IIb/IIIa antagonist described to date, is a promising antithrombotic compound. PMID:9759629

Savi, P; Badorc, A; Lalé, A; Bordes, M F; Bornia, J; Labouret, C; Bernat, A; de Cointet, P; Hoffmann, P; Maffrand, J P; Herbert, J M



Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate.  


The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties. PMID:24075145

Di Fabio, Romano; Alvaro, Giuseppe; Braggio, Simone; Carletti, Renzo; Gerrard, Philip A; Griffante, Cristiana; Marchioro, Carla; Pozzan, Alfonso; Melotto, Sergio; Poffe, Alessandro; Piccoli, Laura; Ratti, Emiliangelo; Tranquillini, Elvira; Trower, Michael; Spada, Simone; Corsi, Mauro



Structure-based design and synthesis of a thyroid hormone receptor (TR) antagonist.  


Antagonists have been developed for several nuclear receptors but not for others, including TRs. TR antagonists may have significant clinical utility for treating hormone excess states and other conditions. A structure derived "extension hypothesis" was applied to synthesize a TR antagonist. The principal design feature was to attach an extension group to a TR agonist whose structure would perturb formation of the TR coactivator-binding surface. The compound, 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid, has no (TRalpha) or very weak partial (TRbeta) TR agonist activity and blocks TR binding of T3, formation of the coactivator-binding surface, and both a positive T3 response on a thyroid hormone response element and a negative T3 response on the TSHbeta promoter in cultured cells. The results suggest that 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid is a TR antagonist for thyroid hormone response element-mediated responses, this approach can be used more generally to generate nuclear receptor antagonists, and this compound or analogues may have medical and research utility. PMID:11796506

Baxter, John D; Goede, Patrick; Apriletti, James W; West, Brian L; Feng, Weijun; Mellstrom, Karin; Fletterick, Robert J; Wagner, Richard L; Kushner, Peter J; Ribeiro, Ralff C J; Webb, Paul; Scanlan, Thomas S; Nilsson, Stefan



A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose-Stimulated Chemotaxis of Human Neutrophils  

PubMed Central

The nucleotide-sugar–activated P2Y14 receptor (P2Y14-R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y14-R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y14-R was shifted to the right in a concentration-dependent manner by PPTN. Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a KB of 434 pM observed. In contrast, 1 ?M PPTN exhibited no agonist or antagonist effect at the P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, or P2Y13 receptors. UDP-glucose–promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the KB determined with recombinant P2Y14-R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose–promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y14-R that is useful for interrogating the action of this receptor in physiologic systems.

Barrett, Matthew O.; Sesma, Juliana I.; Ball, Christopher B.; Jayasekara, P. Suresh; Jacobson, Kenneth A.; Lazarowski, Eduardo R.



A selective high-affinity antagonist of the P2Y14 receptor inhibits UDP-glucose-stimulated chemotaxis of human neutrophils.  


The nucleotide-sugar-activated P2Y14 receptor (P2Y14-R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y14-R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y14-R was shifted to the right in a concentration-dependent manner by PPTN. Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a KB of 434 pM observed. In contrast, 1 ?M PPTN exhibited no agonist or antagonist effect at the P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, or P2Y13 receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the KB determined with recombinant P2Y14-R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose-promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y14-R that is useful for interrogating the action of this receptor in physiologic systems. PMID:23592514

Barrett, Matthew O; Sesma, Juliana I; Ball, Christopher B; Jayasekara, P Suresh; Jacobson, Kenneth A; Lazarowski, Eduardo R; Harden, T Kendall



Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist.  


SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases. PMID:8981918

Serradeil-Le Gal, C; Lacour, C; Valette, G; Garcia, G; Foulon, L; Galindo, G; Bankir, L; Pouzet, B; Guillon, G; Barberis, C; Chicot, D; Jard, S; Vilain, P; Garcia, C; Marty, E; Raufaste, D; Brossard, G; Nisato, D; Maffrand, J P; Le Fur, G



Role of 5-HT2A receptor antagonists in the treatment of insomnia  

PubMed Central

Insomnia encompasses a difficulty in falling asleep (sleep-onset insomnia) and/or a difficulty in staying asleep (SMI). Several selective serotonin-2A (5-HT2A) receptor antagonists have been in development as potential treatments for SMI. However, none have shown a sufficiently robust benefit-to-risk ratio, and none have reached market approval. We review the role of the 5-HT2A mechanism in sleep, the preclinical and clinical data supporting a role for 5-HT2A receptor antagonism in improving sleep maintenance, and the status of 5-HT2A receptor antagonists in clinical development. Overall, the polysomnography data strongly support an increase in slow-wave sleep and a decrease in waking after sleep onset following treatment with 5-HT2A receptor antagonists, although it has been more difficult to show subjective improvements in sleep with these agents. The incidence and prevalence of SMI, whether primary or secondary to psychiatric, neurologic, or other medical conditions, will increase as our population ages. There will be an increased need for safe and efficacious treatments of insomnia characterized by difficulty maintaining sleep, and there remains much promise for 5-HT2A receptor antagonism to play a role in these future treatments.

Vanover, Kimberly E; Davis, Robert E



Sitaxsentan: a novel endothelin-A receptor antagonist for pulmonary arterial hypertension.  


Sitaxsentan is an orally active, selective endothelin-A receptor antagonist that may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictive effects of endothelin-A receptors, while maintaining the vasodilator and endothelin-1 clearance functions of the endothelin-B receptors. In its first randomized, placebo-controlled study, sitaxsentan improved exercise capacity assessed by the 6-min walk test, New York Heart Association functional class, cardiac index and pulmonary vascular resistance in New York Heart Association Class II, III and IV patients with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension related to connective tissue disease or congenital heart disease. Although doses of 100 and 300 mg once daily demonstrated equivalent efficacy, the lower dose had a better safety profile. Additional studies are ongoing to assess the relative safety and efficacy of 50 and 100 mg once-daily dosing. The most common side effects include rhinitis, headache, peripheral edema, chest pain, nausea, constipation, increased prothrombin time/international normalized ratio (in patients on warfarin), flushing and insomnia. As with other endothelin receptor antagonists, increases in hepatic transaminases have been observed with sitaxsentan. Initial studies using the selective oral endothelin-A receptor antagonist sitaxsentan in pulmonary arterial hypertension patients have revealed a favorable risk-benefit therapeutic profile with the 100 mg once-daily dose. PMID:16292989

Widlitz, Allison C; Barst, Robyn J; Horn, Evelyn M



Analgesic effects of morphine and loperamide in the rat formalin test: interactions with NMDA receptor antagonists.  


To reveal peripheral components of opiate analgesia, effects of loperamide, opioid agonist which does not penetrate the blood-brain barrier, were examined in formalin and acute thermal pain tests in comparison with morphine. Formalin administration induces pain behaviour such licking/biting of injected paw expressed as two phases. The first phase is caused by C-fibre activation due to peripheral stimulation, the second phase attributed to ongoing input from peripheral site, leading to spinal hyperexcitability, which is dependent on N-methyl-D-aspartate (NMDA) receptor activation. Loperamide (3-10 mg/kg) and morphine (6 mg/kg) reduced formalin-induced nociceptive behaviours and these effects were reversed by naloxone methiodide (0.03-10 mg/kg), opioid receptor antagonist which poorly penetrates the blood-brain barrier. Loperamide action was enhanced only by centrally active NMDA receptor antagonists memantine (3 mg/kg) and CGP 37849 (3 mg/kg), but not by NMDA/glycineB receptor antagonists showing weak or no central nervous system (CNS) activity. Present results suggest that central NMDA receptor blockade may be necessary to enhance analgesia induced through peripheral opioid mechanisms in formalin-evoked nociception. PMID:16297905

Sevostianova, Natalja; Danysz, Wojciech; Bespalov, Anton Y



In vivo evaluation of a novel, orally bioavailable, small molecule growth hormone receptor antagonist.  


IGF-I is regarded as the most sensitive marker of growth hormone (GH) secretion in both GH deficient individuals and in individuals with excessive GH production. Studies on the effect of inhibitors of GH action in normal experimental animals are difficult to evaluate due to the complex relationship and feed back mechanisms of the GH/IGF-I system and the hypothalamo-pituitary axis. To circumvent the GH/IGF-I feedback mechanisms, we have used hypophysectomized (HX) rats treated with GH to assess the potential of a new low molecular weight compound, BVT-A ((N-[5-(aminosulfonyl)-2-methylphenyl]-5-bromo-2-furamide), to act as a GH receptor antagonist in vivo. GH treatment of HX rats induced serum IGF-I, body weight and hepatic mRNA levels of IGF-I, IGFBP-3, ALS and the IGF-I and GH receptors. Co-treatment with BVT-A suppressed all the GH-induced effects. We conclude that the GH substituted HX rat is a useful model for studies on GH receptor antagonists, and for the first time, a small molecule GH receptor antagonist with in vivo activity has been revealed. This opens up for development of new drugs for diseases in which lowering of GH receptor activity would be beneficial. PMID:17161642

Rosengren, Linda; Parrow, Vendela; Chmielewska, Joanna; Mode, Agneta; Fhölenhag, Karin



Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist.  


Orexins/hypocretins are key neuropeptides responsible for regulating central arousal and reward circuits. Two receptors respond to orexin signaling, orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R) with partially overlapping nervous system distributions. Genetic studies suggest orexin receptor antagonists could be therapeutic for insomnia and other disorders with disruptions of sleep and wake. Suvorexant (MK-4305) is a potent, selective, and orally bioavailable antagonist of OX(1)R and OX(2)R currently under clinical investigation as a novel therapy for insomnia. Examination of Suvorexant in radioligand binding assays using tissue from transgenic rats expressing the human OX(2)R found nearly full receptor occupancy (>90%) at plasma exposures of 1.1 ?M. Dosed orally Suvorexant significantly and dose-dependently reduced locomotor activity and promoted sleep in rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and rhesus monkeys (10 mg/kg). Consistent cross-species sleep/wake architecture changes produced by Suvorexant highlight a unique opportunity to develop dual orexin antagonists as a novel therapy for insomnia. PMID:21473737

Winrow, Christopher J; Gotter, Anthony L; Cox, Christopher D; Doran, Scott M; Tannenbaum, Pamela L; Breslin, Michael J; Garson, Susan L; Fox, Steven V; Harrell, Charles M; Stevens, Joanne; Reiss, Duane R; Cui, Donghui; Coleman, Paul J; Renger, John J



Opposite modulation of apomorphine- or amphetamine-induced stereotypy by antagonists of CCK receptors.  


Stereotyped behavior is elicited by activation of dopaminergic systems with drugs such as apomorphine and amphetamine. In previous studies, we have reported that the sulfated cholecystokinin octapeptide (CCK-8) decreased apomorphine-induced stereotypy in animals with normal and supersensitive dopamine receptors. The aim of the present study was to evaluate the effects of CCK(1) and CCK(2) receptor antagonists on stereotyped behavior induced by apomorphine or amphetamine. Rats were pretreated with the CCK(1) (SR 27897B; 1-[[2-(4-(2-chlorophenyl) thiazol-2-yl) aminocarbonyl]indolyl]acetic acid; 500 microg/kg; i.p.) or CCK(2) (L-365,260; 3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5 phenyl-1H-1, 4-benzodiazepine-3-yl)-N'-(3-methyl phenyl)-urea; 500 microg/kg; i.p. ) receptor antagonists or saline 15 min before apomorphine (0.6 mg/kg; s.c.) or amphetamine (9.0 mg/kg; i.p.) injection. Both CCK(1) and CCK(2) receptor antagonists significantly increased apomorphine-induced stereotypy. In contrast, only the blockade of CCK(2) receptors significantly decreased amphetamine-induced stereotypy. The results suggest a dual opposite mechanism for CCK-dopamine interactions. These data also suggest that both apomorphine- and amphetamine-induced stereotypy should be used whenever effects of drugs acting on dopaminergic systems are being assessed. PMID:10650159

Tieppo, C A; Ferreira, F S; Sassatani, A S; Felicio, L F; Nasello, A G




Microsoft Academic Search

Synopsis Prognosis in congestive heart failure is directly linked to neurohormonal activation. Angiotensin II through the activation of the renin angiotensin aldosterone system has been the principal focus of therapy over the last two decades. New agents that target selective blockade of the angiotensin II receptor have been introduced in clinical trials for the treatment of heart failure. Aldosterone has

Alan B. Miller; Pankaj Srivastava



An antagonist of GABA-B receptors potentiates activity of cortical epileptic foci.  


Cortical epileptic foci elicited by local application of bicuculline methiodide represent a model of interictal epileptic activity with a transition into ictal phases. We studied a role of GABA-B receptors in this model using GABA-B receptor antagonist CGP35348 in adult rats with implanted cortical electrodes and cannula. CGP35348 (100 or 200 mg/kg i.p.) did not affect interictal discharges but it augmented ictal activity. Latency to the first ictal episode was decreased by the lower dose of CGP35348, duration of episodes was increased by the higher dose. GABA-B receptor antagonist did not influence purely cortical epileptic phenomenon but it is proconvulsant in ictal activity generated with participation of subcortical structures. PMID:22480419

Mareš, P; Bernášková, K; Kubová, H



Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks  

NASA Astrophysics Data System (ADS)

Insulin is thought to elicit its effects by crosslinking the two extracellular -subunits of its receptor, thereby inducing a conformational change in the receptor, which activates the intracellular tyrosine kinase signaling cascade. Previously we identified a series of peptides binding to two discrete hotspots on the insulin receptor. Here we show that covalent linkage of such peptides into homodimers or heterodimers results in insulin agonists or antagonists, depending on how the peptides are linked. An optimized agonist has been shown, both in vitro and in vivo, to have a potency close to that of insulin itself. The ability to construct such peptide derivatives may offer a path for developing agonists or antagonists for treatment of a wide variety of diseases.

Schäffer, Lauge; Brissette, Renee E.; Spetzler, Jane C.; Pillutla, Renuka C.; Østergaard, Søren; Lennick, Michael; Brandt, Jakob; Fletcher, Paul W.; Danielsen, Gillian M.; Hsiao, Ku-Chuan; Andersen, Asser S.; Dedova, Olga; Ribel, Ulla; Hoeg-Jensen, Thomas; Hertz Hansen, Per; Blume, Arthur J.; Markussen, Jan; Goldstein, Neil I.



The cannabinoid CB1 receptor antagonist AM251 does not modify methamphetamine reinstatement of responding  

PubMed Central

Cannabinoid CB1 receptor antagonists can decrease methamphetamine self administration. This study examined whether the CB1 receptor antagonist AM251 [N-(piperidin-1-yl)-5-(4-indophonyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] modifies reinstatement in rats that previously self-administered methamphetamine. Rats (n=10) self administered methamphetamine (0.1 mg/kg/infusion) under a fixed ratio 2 schedule. Non-contingent methamphetamine (0.01-1.78 mg/kg, i.v.) yielded responding for saline (reinstatement) that was similar to responding for self-administered methamphetamine. AM251 (0.032-0.32, i.v.) did not affect methamphetamine-induced reinstatement but significantly attenuated ?9-tetrahydrocannabinol (2.0 mg/kg, i.p.)-induced hypothermia. These data fail to support a role for endogenous cannabinoids or cannabinoid CB1 receptors in reinstatement and, therefore, relapse to stimulant abuse.

Boctor, Sherin Y.; Martinez, Joe L.; Koek, Wouter; France, Charles P.



Separation of alpha-glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LXRalpha-selective antagonists.  


Liver X receptor (LXR) alpha/beta dual agonists are candidate medicaments for the treatment of metabolic syndrome, because their biological actions include increasing cholesterol efflux mediated by LXRbeta. However, their clinical application is currently limited by their enhancing effect on triglyceride (TG) synthesis mediated by LXRalpha. Combination of an LXRalpha-selective antagonist with an LXRalpha/beta dual agonist may overcome this disadvantage. In the present work, structural development studies of phenethylphenyl phthalimide 9, which possesses LXRalpha/beta dual-antagonistic activity and alpha-glucosidase-inhibitory activity, led to the LXRalpha-selective antagonist 23f. Specific alpha-glucosidase inhibitors were also obtained. PMID:19539483

Motoshima, Kazunori; Noguchi-Yachide, Tomomi; Sugita, Kazuyuki; Hashimoto, Yuichi; Ishikawa, Minoru



A model for the antagonist binding site on the adenosine A1 receptor, based on steric, electrostatic, and hydrophobic properties.  


With the aid of molecular modeling, both adenosine and adenosine A1 receptor antagonists belonging to various chemical classes were compared with respect to their minimum-energy conformations and molecular electrostatic potentials, as computed by the semiempirical molecular orbital program MOPAC. Distinct steric and electrostatic similarities between adenosine and the prototypic adenosine antagonist theophylline are evident when both compounds are superimposed, with theophylline in a so-called flipped orientation. Similar patterns were found for all other A1 antagonists investigated in this study. A model for the antagonist binding site on the adenosine A1 receptor, based on steric, electrostatic, and hydrophobic properties contributing to potency, is proposed. PMID:2342066

van Galen, P J; van Vlijmen, H W; IJzerman, A P; Soudijn, W



5HT3Receptor Antagonists in the Management of Nausea and Vomiting in Cancer and Cancer Treatment  

Microsoft Academic Search

The 5-HT3-receptor antagonists, considered as ‘gold standard’ therapy for cancer patients, are generally perceived to have similar efficacy and safety profiles, andmost antiemetic guidelines do not distinguish between agents. However, important pharmacological differences exist between agents, which may translate into potential benefits for some patients. In particular, 5-HT3-receptor antagonists vary in the nature of their receptor antagonism and plasma half-lives,

Matti Aapro



GR 38032F (Ondansetron), a selective 5HT 3 receptor antagonist, slows colonic transit in healthy man  

Microsoft Academic Search

The newly recognized class of 5-hydroxytryptamine receptors (5HT3) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT3 receptors are present on enteric neurons, and 5HT3 blockers may produce mild constipation; we thus hypothesized that 5HT3 receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT3 antagonist

N. J. Talley; S. F. Phillips; A. Haddad; L. J. Miller; C. Twomey; A. R. Zinsmeister; R. L. MacCarty; A. Ciociola



Analgesic effects of mGlu1 and mGlu5 receptor antagonists in the rat formalin test  

Microsoft Academic Search

mGlu1 and mGlu5 receptors have been implicated in pain associated with inflammation. In the present study, the formalin test was used to measure sustained pain with components of tissue injury. The aims of the present study were to assess: (i) the role of mGlu1 and mGlu5 receptors in inflammatory pain using selective antagonist EMQMCM, 1.25–5mg\\/kg, as the mGlu1 receptor antagonist,

N. Sevostianova; W. Danysz



CysLT 1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors  

Microsoft Academic Search

Montelukast and pranlukast are orally active leukotriene receptor antagonists selective for the CysLT1 receptor. Conversely, the hP2Y1,2,4,6,11,12,13,14 receptors represent a large family of GPCRs responding to either adenine or uracil nucleotides, or to sugar-nucleotides. Montelukast and pranlukast were found to inhibit nucleotide-induced calcium mobilization in a human monocyte-macrophage like cell line, DMSO-differentiated U937 (dU937). Montelukast and pranlukast inhibited the effects

Liaman Mamedova; Valérie Capra; Maria Rosa Accomazzo; Zhan-Guo Gao; Silvia Ferrario; Marta Fumagalli; Maria P. Abbracchio; G. Enrico Rovati; Kenneth A. Jacobson



Postweaning social isolation exacerbates neurotoxic effects of the NMDA receptor antagonist MK-801 in rats.  


The glutamate hypothesis of schizophrenia postulates NMDA receptor hypofunction as important pathophysiological mechanism. In rodents, NMDA receptor antagonists induce together with psychosis-like effects cortical injury. Stress during adolescence can trigger schizophrenia by unknown mechanisms. Here we show in rats that juvenile chronic isolation significantly increases MK-801-triggered expression of heat shock protein 70, a marker of neuronal injury, in the retrosplenial cortex. These data suggest an additive effect of juvenile stress and NMDA receptor blockade, with possible relevance for schizophrenia. PMID:23736946

Inta, Dragos; Renz, Peter; Lima-Ojeda, Juan M; Dormann, Christof; Gass, Peter



Blonanserin, an antipsychotic and dopamine D(2)/D(3) receptor antagonist, and ameliorated alcohol dependence.  


Blonanserin (BNS) is used for treatment of both positive and negative symptoms of schizophrenia in Japan and Korea. Because BNS has weak ?(1) receptor blocking activities and is almost devoid of histamine H1 and muscarinic M1 antagonist activity, BNS is better tolerated than other atypical antipsychotics. A high degree of D3 receptor blockage is reported to be predictive of drug abuse and alcoholism, and BNS has strong D3 receptor antagonism. Thus, BNS may be useful in the treatment of alcoholism. We present a case in which BNS ameliorated alcohol dependence. PMID:23503552

Takaki, Manabu; Ujike, Hiroshi


N-methyl-D-aspartate receptor antagonists disrupt the formation of a mammalian neural map.  

PubMed Central

The topographic ordering of retinal connections in the rat superior colliculus emerges during early postnatal life from an initially diffuse projection. Disruption of N-methyl-D-aspartate (NMDA) receptor activity in the superior colliculus during this period interferes with map remodeling. In rats chronically treated with NMDA receptor antagonists during the first two postnatal weeks, aberrant axons remain and arborize at topographically incorrect sites. These results indicate that, at a stage preceding visually evoked activity, normal NMDA receptor function is important for the development of an ordered neural map in the mammalian brain. Images

Simon, D K; Prusky, G T; O'Leary, D D; Constantine-Paton, M



LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors  

Microsoft Academic Search

The in vitro pharmacology of a structurally novel compound, LY341495, was investigated at human recombinant metabotropic glutamate (mGlu) receptor subtypes expressed in non-neuronal (RGT, rat glutamate transporter) cells. LY341495 was a nanomolar potent antagonist of 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD)-induced inhibition of forskolin-stimulated cAMP formation at mGlu2 and mGlu3 receptors (respective IC50s of 0.021 and 0.014 ?M). At group I mGlu receptor

A. E Kingston; P. L Ornstein; R. A Wright; B. G Johnson; N. G Mayne; J. P Burnett; R Belagaje; S Wu; D. D Schoepp



Design, synthesis, and biological evaluation of phenylpropanamides as novel transient receptor potential vanilloid 1 antagonists.  


Synthesis and structure-activity relationship of N-benzyl-3-phenylpropanamides as transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of substituents such as halide, ester, nitro, and alkyl groups at 2 or 3-position of 4-(methylsulfonylamino) benzyl unit were examined. These compounds exhibited potent 45Ca2+ uptake inhibition in rat DRG neuron via TRPV1 blockade. Especially compound 28c, has been identified as a potent antagonist with IC50 of 38 nM. PMID:19784574

Li, Fu-Nan; Kim, Nam-Jung; Nam, Yeon-Hee; Kim, Seung-Hee; Seo, Seung-Yong; Jeong, Yeon-Su; Kim, Sun-Young; Park, Young-Ho; Suh, Young-Ger



Synthesis and pharmacological evaluation of dimeric follicle-stimulating hormone receptor antagonists.  


A series of homo- and heterodimeric compounds encompassing the follicle-stimulating hormone receptor (FSHR) antagonist (R)-1 and its inactive conformer (S)-1 connected through ethylene glycol spacers of various lengths is described. Evaluation of these compounds reveals that dimeric compounds, with a spacer of sufficient length, bearing two active copies of the antagonist are more potent relative to dimeric compounds in which one of the active pharmacophores is replaced by an inactive conformer. Interestingly, the opposite trend is observed if a short spacer is used, indicating that these compounds may be valuable tools to study FSHR dimerization in greater detail. PMID:19902448

Bonger, Kimberly M; Hoogendoorn, Sascha; van Koppen, Chris J; Timmers, Cornelis M; Overkleeft, Herman S; van der Marel, Gijsbert A



Progress in the proxifan class: heterocyclic congeners as novel potent and selective histamine H(3)-receptor antagonists.  


Histamine H(3) receptors are critically involved in the pathophysiology of several disorders of the central nervous system (CNS). Among other families of H(3)-receptor ligands, the proxifan class has recently been described to contain numerous potent histamine H(3)-receptor antagonists, e.g. ciproxifan or imoproxifan. In the present study, we report on the design of novel heterocyclic proxifan analogues and their antagonist potencies at histamine H(3) receptors. The new compounds were tested for in vitro and in vivo H(3)-receptor antagonist potencies in different species as well as for H(3)-receptor selectivity vs. H(1) and H(2) receptors. In vitro, all compounds investigated proved to be potent H(3)-receptor antagonists in the rat as well as in the guinea-pig. In addition, they showed good to high oral CNS potency in vivo in mice. Especially, oxadiazole derivatives 24-26 displayed nanomolar antagonist activity in vitro and high potency in vivo (ED(50)=0.47-0.57 mg/kg). The results show that the additional heteroaromatic moieties might act as bioisosteres of the ketone or oxime moieties of ciproxifan or imoproxifan, respectively, and might cause divergent pharmacokinetic properties. Thus, these novel H(3)-receptor antagonists are interesting leads for further development. PMID:11988398

Grassmann, Sven; Sadek, Bassem; Ligneau, Xavier; Elz, Sigurd; Ganellin, C Robin; Arrang, Jean-Michel; Schwartz, Jean-Charles; Stark, Holger; Schunack, Walter



The therapeutic potential of endothelin receptor antagonists in cardiovascular disease  

Microsoft Academic Search

Endothelin (ET)-1, a 21-amino acid peptide, is the predominant isoform of the endothelin peptide family. ET-1 is ubiquitously expressed and stimulates vasoconstriction and cell proliferation. Enzymes such as endothelin converting enzymes (ECE), chymases, and non-ECE metalloproteinases contribute to the synthesis of ET-1, which is regulated in an autocrine fashion in vascular and nonvascular cells. Endothelin ET(A) receptors mediate vasoconstriction and

Matthias Barton; Wolfgang Kiowski



Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders.  


Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D(2) receptors by antipsychotics, respectively. Adenosine A(2A) receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D(2) receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A(2A) receptor activation contributes to the overdrive of the indirect pathway. A(2A) receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A(2A) receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A(2A) receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A(2A) receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders. PMID:20655910

Hodgson, Robert A; Bedard, Paul J; Varty, Geoffrey B; Kazdoba, Tatiana M; Di Paolo, Therese; Grzelak, Michael E; Pond, Annamarie J; Hadjtahar, Abdallah; Belanger, Nancy; Gregoire, Laurent; Dare, Aurelie; Neustadt, Bernard R; Stamford, Andrew W; Hunter, John C



3-Dimensional structures of G protein-coupled receptors and binding sites of agonists and antagonists.  


We summarize here recent progress in predicting the 3-dimensional (3D) structure of G protein-coupled receptors (GPCR) and in predicting the binding sites for various agonists and antagonists. These receptors play a critical role in cell communications (dopamine, histamine, epinephrine, and serotonin) and in sensing the outside world (vision, smell, taste, and pain). There are no experimental 3D structures available for human GPCR despite their vital function and importance as therapeutic targets. Indeed, considering every form of life, there is an experimental structure for only 1 GPCR: bovine rhodopsin. Consequently, we developed the MembStruk method to predict the 3D structure without using homology. We then validated our predicted structures by using them to predict their binding sites and binding energies for strongly binding agonists and antagonists. The results were in excellent agreement with available binding and mutation experiments. We will summarize the results for adrenergic receptors, dopamine receptors, chemokine receptors, muscarinic acetylcholine receptors, and a tetrapeptide receptor (mas-related gene C11). PMID:17513420

Goddard, William A; Abrol, Ravinder



A new frontier in the treatment of cancer: NK-1 receptor antagonists.  


The past two decades have witnessed an exponential increase in research into cancer. This effort, however, has not been translated into better perspectives as regards the problem, although several fields of research have certainly been promising (the human genome project, gene therapy, the search for new cytostatic agents and stem cell research). New pathways must be opened up to offer future hope to oncologic patients. Thus, there is a need to explore other research initiatives in cancer ways to improve this chronic global problem. Substance P (SP) has a widespread distribution in both the central and peripheral nervous systems. It is known that after binding to the specific neurokinin-1 (NK-1) receptor, SP regulates biological functions related to cancer, such as tumour cell proliferation, angiogenesis, and migration of the tumour cells for invasion and metastasis. By contrast, it is also known that after binding to NK-1 receptors, the NK-1 receptor antagonists specifically inhibit tumour cell proliferation (tumour cells die by apoptosis), angiogenesis and the migration of the tumour cells. It is also known that NK-1 receptors are overexpressed in tumours. All these observations suggest that the SP/NK-1 receptor system could play an important role in the development of cancer and metastasis; that the NK-1 receptor could be a new promising target in the treatment of cancer, and that NK-1 receptor antagonists could improve cancer treatment. PMID:20015033

Muñoz, M; Rosso, M; Coveñas, R



Inverse agonist and neutral antagonist actions of synthetic compounds at an insect 5-HT1 receptor  

PubMed Central

Background and purpose: 5-Hydroxytryptamine (5-HT) has been shown to control and modulate many physiological and behavioural functions in insects. In this study, we report the cloning and pharmacological properties of a 5-HT1 receptor of an insect model for neurobiology, physiology and pharmacology. Experimental approach: A cDNA encoding for the Periplaneta americana 5-HT1 receptor was amplified from brain cDNA. The receptor was stably expressed in HEK 293 cells, and the functional and pharmacological properties were determined in cAMP assays. Receptor distribution was investigated by RT-PCR and by immunocytochemistry using an affinity-purified polyclonal antiserum. Key results: The P. americana 5-HT1 receptor (Pea5-HT1) shares pronounced sequence and functional similarity with mammalian 5-HT1 receptors. Activation with 5-HT reduced adenylyl cyclase activity in a dose-dependent manner. Pea5-HT1 was expressed as a constitutively active receptor with methiothepin acting as a neutral antagonist, and WAY 100635 as an inverse agonist. Receptor mRNA was present in various tissues including brain, salivary glands and midgut. Receptor-specific antibodies showed that the native protein was expressed in a glycosylated form in membrane samples of brain and salivary glands. Conclusions and implications: This study marks the first pharmacological identification of an inverse agonist and a neutral antagonist at an insect 5-HT1 receptor. The results presented here should facilitate further analyses of 5-HT1 receptors in mediating central and peripheral effects of 5-HT in insects.

Troppmann, B; Balfanz, S; Baumann, A; Blenau, W



A systematic review of the effects of NMDA receptor antagonists on oscillatory activity recorded in vivo.  


Distinct frequency bands can be differentiated from neuronal ensemble recordings, such as local field potentials or electrocorticogram recordings. Recent years have witnessed a rapid acceleration of research examining how N-methyl-D-aspartate receptor (NMDAR) antagonists influence fundamental frequency bands in cortical and subcortical brain regions. Herein, we systematically review findings from in vivo studies with a focus on delta, theta, gamma and more recently identified high-frequency oscillations. We also discuss some of the current hypotheses that are considered to account for the actions of NMDAR antagonists on these frequency bands. The data emphasize a close relationship between altered oscillatory activity and NMDAR blockade, with both local and large-scale networks accounting for their effects. These findings may have fundamental implications for the psychotomimetic effects produced by NMDAR antagonists. PMID:23863924

Hunt, Mark J; Kasicki, Stefan



Fumaroylamino-4,5-epoxymorphinans and Related Opioids with Irreversible ? Opioid Receptor Antagonist Effects  

PubMed Central

We have previously shown that cinnamoyl derivatives of 14?-amino-17-cyclopropylmethyl-7,8-dihydronormorphinone and 7?-aminomethyl-6,14-endoethanonororipavine have pronounced pseudoirreversible ? opioid receptor (MOR) antagonism. The present communication describes the synthesis and evaluation of fumaroylamino analogues of these cinnamoylamino derivatives together with some related fumaroyl derivatives. The predominant activity of the new ligands was MOR antagonism. The fumaroylamino analogues (2a, 5a) of the pseudoirreversible antagonist cinnamoylamino morphinones and oripavines (2b, 5b) were themselves irreversible antagonists in vivo. However the fumaroylamino derivatives had significantly higher MOR efficacy than the cinnamoylamino derivatives in mouse antinociceptive tests. Comparison of 2a and 5a with the prototypic fumaroylamino opioid ?-FNA (1a) shows that they have similar MOR irreversible antagonist actions but differ in the nature of their opioid receptor agonist effects; 2a is a predominant MOR agonist and 5a shows no opioid receptor selectivity, whereas the agonist effect of ?-FNA is clearly ? opioid receptor (KOR) mediated.



Activity of new NOP receptor ligands in a rat peripheral mononeuropathy model: Potentiation of Morphine anti-allodynic activity by NOP receptor antagonists  

PubMed Central

The effect of new NOP receptor agonists and antagonists in the rat chronic constriction injury model was investigated. Intraperitoneally administered NOP receptor agonist SR14150 and antagonists SR16430 and SR14148, had no effect on mechanical allodynia when given alone. The nonselective NOP/mu-opioid receptor agonist SR16435, however, produced an anti-allodynic response, similar to morphine and reversible by naloxone. Notably, co-administration of the NOP receptor antagonists potentiated the anti-allodynic activity of both morphine and SR16435. Increased levels of the NOP receptor are implicated in the reduced efficacy of morphine in neuropathic pain. Our results suggest the utility of NOP receptor antagonists for potentiating opioid efficacy in chronic pain.

Khroyan, Taline V.; Polgar, Willma E.; Orduna, Juan; Jiang, Faming; Olsen, Cris; Toll, Lawrence; Zaveri, Nurulain T.



RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists  

PubMed Central

Prostacyclin (PGI2) possesses various physiological functions, including modulation of nociception, inflammation and cardiovascular activity. Elucidation of these functions has been hampered by the absence of selective IP receptor antagonists. Two structurally distinct series of IP receptor antagonists have been developed: 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) and R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO3244794). RO1138452 and RO3244794 display high affinity for IP receptors. In human platelets, the receptor affinities (pKi) were 9.3±0.1 and 7.7±0.03, respectively; in a recombinant IP receptor system, pKi values were 8.7±0.06 and 6.9±0.1, respectively. Functional antagonism of RO1138452 and RO3244794 was studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinities (pKi) of RO1138452 and RO3244794 were 9.0±0.06 and 8.5±0.11, respectively. Selectivity profiles for RO1138452 and RO3244794 were determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at I2 (8.3) and PAF (7.9) receptors, while RO3244794 was highly selective for the IP receptor: pKi values for EP1 (<5), EP3 (5.38), EP4 (5.74) and TP (5.09). RO1138452 (1–10?mg?kg?1, i.v.) and RO3244794 (1–30?mg?kg?1, i.v.) significantly reduced acetic acid-induced abdominal constrictions. RO1138452 (3–100?mg?kg?1, p.o.) and RO3244794 (0.3–30?mg?kg?1, p.o.) significantly reduced carrageenan-induced mechanical hyperalgesia and edema formation. RO3244794 (1 and 10?mg?kg?1, p.o.) also significantly reduced chronic joint discomfort induced by monoiodoacetate. These data suggest that RO1138452 and RO3244794 are potent and selective antagonists for both human and rat IP receptors and that they possess analgesic and anti-inflammatory potential.

Bley, Keith R; Bhattacharya, Anindya; Daniels, Don V; Gever, Joel; Jahangir, Alam; O'Yang, Counde; Smith, Steven; Srinivasan, Dinesh; Ford, Anthony P D W; Jett, Mary-Frances



Persistent anxiolytic affects after chronic administration of the CRF1 receptor antagonist R121919 in rats  

PubMed Central

Corticotropin-releasing factor (CRF) functions as one of the major mediators of the mammalian stress response and appears to play a key role in the pathophysiology of mood and anxiety disorders. Small molecule CRF1 receptor antagonists may represent a novel form of pharmacotherapy for these disorders. The therapeutic success of CRF1 receptor antagonists will depend, in part, upon whether tolerance develops to the actions of these compounds and whether appropriate patterns of HPA axis function is maintained. This study evaluated the effects of long term (~4 week) treatment with the CRF1 receptor antagonist R121919, on CRF receptor function, HPA axis activity, behavioral measures, adrenal gland size, and body weight gain. Animals treated with 20 mg/kg/day of R121919 spent significantly more time in the open field in a defensive withdrawal test (138±36 seconds for R121919 vs 52±12 seconds for vehicle, p=0.01). No significant effect of chronic CRF1 receptor blockade on basal ACTH or corticosterone concentrations were detected, nor were significant changes detected in an elevated plus maze test. Both vehicle- and R121919- treated rats showed increases in AUC and peak ACTH and corticosterone concentrations following air puff startle stress, without any overall group differences, although a clear but non-significant attenuation in HPA axis response was observable in R121919 treated animals. Chronic CRF1 receptor blockade increased CRF peptide mRNA expression in the PVN and decreased CRF peptide mRNA expression in the central nucleus of the amygdala. Overall our results suggest that anxiolytic effects of chronic CRF1 receptor antagonism persist following chronic administration without significant attenuation of the HPA axis’s ability to mount a stress response.

Gutman, David A.; Owens, Michael J.; Thrivikraman, K.V.; Nemeroff, Charles B.



Antagonistic-synergistic muscle action at the knee during competitive weightlifting  

Microsoft Academic Search

A sagittal-plane model of the knee, which takes account of the movements of the flexion axis relative to the femur and tibia\\u000a and considers the possibility of antagonistic and synergistic muscle action, is used to determine the values of the forces\\u000a transmitted by the muscles, cruciate ligaments and intra-articular surfaces during the clean phase of the clean-and-jerk weightlift.\\u000a The theoretical

J. J. Collins



[3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors.  


ATP-sensitive P2X7 receptors are localized on cells of immunological origin including peripheral macrophages and glial cells in the CNS. Activation of P2X7 receptors leads to rapid changes in intracellular calcium concentrations, release of the pro-inflammatory cytokine IL-1beta, and following prolonged agonist exposure, the formation of cytolytic pores in plasma membranes. Data from gene knockout studies and recently described selective antagonists indicate a role for P2X7 receptor activation in inflammation and pain. While several species selective P2X7 antagonists exist, A-804598 represents a structurally novel, competitive, and selective antagonist that has equivalent high affinity at rat (IC50 = 10 nM), mouse (IC50 = 9 nM) and human (IC50 = 11 nM) P2X7 receptors. A-804598 also potently blocked agonist stimulated release of IL-1beta and Yo-Pro uptake from differentiated THP-1 cells that natively express human P2X7 receptors. A-804598 was tritiated ([3H]A-804598; 8.1Ci/mmol) and utilized to study recombinant rat P2X7 receptors expressed in 1321N1 cells. [3H]A-804598 labeled a single class of high affinity binding sites (Kd=2.4 nM and apparent Bmax=0.56 pmol/mg). No specific binding was observed in untransfected 1321N1 cells. The pharmacological profile for P2X antagonists to inhibit [3H]A-804598 binding correlated with their ability to block functional activation of P2X7 receptors (r=0.95, P<0.05). These data demonstrate that A-804598 is one of the most potent and selective antagonists for mammalian P2X7 receptors described to date and [3H]A-804598 is a high affinity antagonist radioligand that specifically labels rat P2X7 receptors. PMID:18602931

Donnelly-Roberts, Diana L; Namovic, Marian T; Surber, Bruce; Vaidyanathan, Srirajan X; Perez-Medrano, Arturo; Wang, Ying; Carroll, William A; Jarvis, Michael F



MIBE acts as antagonist ligand of both estrogen receptor ? and GPER in breast cancer cells  

PubMed Central

Introduction The multiple biological responses to estrogens are mainly mediated by the classical estrogen receptors ER? and ER?, which act as ligand-activated transcription factors. ER? exerts a main role in the development of breast cancer; therefore, the ER antagonist tamoxifen has been widely used although its effectiveness is limited by de novo and acquired resistance. Recently, GPR30/GPER, a member of the seven-transmembrane G protein-coupled receptor family, has been implicated in mediating the effects of estrogens in various normal and cancer cells. In particular, GPER triggered gene expression and proliferative responses induced by estrogens and even ER antagonists in hormone-sensitive tumor cells. Likewise, additional ER ligands showed the ability to bind to GPER eliciting promiscuous and, in some cases, opposite actions through the two receptors. We synthesized a novel compound (ethyl 3-[5-(2-ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]but-2-enoate), referred to as MIBE, and investigated its properties elicited through ER? and GPER in breast cancer cells. Methods Molecular modeling, binding experiments and functional assays were performed in order to evaluate the biological action exerted by MIBE through ER? and GPER in MCF7 and SkBr3 breast cancer cells. Results MIBE displayed the ability to act as an antagonist ligand for ER? and GPER as it elicited inhibitory effects on gene transcription and growth effects by binding to both receptors in breast cancer cells. Moreover, GPER was required for epidermal growth factor receptor (EGFR) and ERK activation by EGF as ascertained by using MIBE and performing gene silencing experiments. Conclusions Our findings provide novel insights on the functional cross-talk between GPER and EGFR signaling. Furthermore, the exclusive antagonistic activity exerted by MIBE on ER? and GPER could represent an innovative pharmacological approach targeting breast carcinomas which express one or both receptors at the beginning and/or during tumor progression. Hence, the simultaneous inhibition of both ER? and GPER may guarantee major therapeutic benefits in respect to the use of a selective estrogen receptor antagonist.



Effect of the tachykinin receptor antagonists, SR 140333, FK 888, and SR 142801, on capsaicin-induced mouse ear oedema  

Microsoft Academic Search

We examined the effect of SR 140333, a nonpeptide NK1 receptor antagonist, FK 888, a peptide NK1 antagonist, and SR 142801, a non-peptide NK3 antagonist, on ear oedema induced by topical application of capsaicin (250 g\\/ear) in mice. SR 140333 (ED50: 39 g\\/kg, i.v.) dose-dependently inhibited the oedema response to capsaicin, whereas FK 888 (1.0 mg\\/kg, i.v.) and SR 142801

H. Inoue; N. Nagata; Y. Koshihara



3-amino-2-hydroxy-N-(4-nitrophenyl)-propanesulphonamide, a new class of GABAB receptor antagonist in central and peripheral preparations.  


Racemic 3-amino-2-hydroxy-N-(4-nitrophenyl)-propanesulphonamide (AHPNS), a sulphonamide analog of GABA, reversibly and competitively antagonised the concentration-dependent depression of cholinergic twitch contractions by baclofen, in the electrically stimulated guinea-pig isolated ileum, with a pA2 of 4.0 +/- 0.2. In the rat neocortex, maintained in Mg(2+)-free medium, AHPNS (100-500 microM) also reversibly antagonised the baclofen (10 microM)-induced suppression of spontaneous discharges. AHPNS is a new class of GABAB receptor antagonist that has central and peripheral blocking actions. PMID:8788452

Kerr, D I; Ong, J; Hughes, R; Prager, R H



Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration.  


The complement system is thought to be involved in the pathogenesis of numerous neurological diseases, although its precise role remains controversial. In this study we used orally active C5a receptor antagonists (PMX53 and PMX205) developed in our laboratories in a rat model of 3-nitropropionic acid (3-NP) -induced Huntington's disease. Administration of the C5a antagonists (10 mg/kg/day, oral) either 48 h pre- or 48 h post-toxin significantly reduced body weight loss, anorexia, and behavioral and motor deficits associated with 3-NP intoxication. Striatal lesion size, apoptosis, neutrophil infiltration, and hemorrhage were also significantly reduced in C5a antagonist-treated rats. Immunohistochemical analysis demonstrated marked deposition of C3 and C9, and up-regulation of C5a receptors on neuronal cells at the time of lesion formation. Inhibition of prostaglandins or TNF-alpha with ibuprofen or infliximab had no effect in this model. The C5a antagonists did not affect 3-NP-induced cell death when added directly to rat striatal neuronal cultures, indicating a secondary mechanism of action in vivo. Our findings demonstrate for the first time that complement activation in the brain, particularly C5a, is a key event in the pathogenesis of this disease model, and suggest a future role for inhibitors of C5a in the treatment of neurodegenerative diseases. PMID:16816116

Woodruff, Trent M; Crane, James W; Proctor, Lavinia M; Buller, Kathryn M; Shek, Annie B; de Vos, Kurt; Pollitt, Sandra; Williams, Hua M; Shiels, Ian A; Monk, Peter N; Taylor, Stephen M



Identification of surrogate agonists and antagonists for orphan G-protein-coupled receptor GPR139.  


GPR139 is an orphan G-protein-coupled receptor (GPCR) that is expressed nearly exclusively in the central nervous system and may play a role in the control of locomotor activity. The signal transduction pathway and pharmacological function of GPR139, however, are still controversial due to the lack of natural or synthetic ligands. The authors report the characterization of human GPR139 signaling pathway and identification of surrogate agonists and antagonists. In both transient and stable transfections of HEK293F cells, overexpression of GPR139 increased basal intracellular cAMP concentrations compared to control cells. Furthermore, forskolin and isoproterenol-stimulated cAMP responses were enhanced in GPR139-expressing cells, suggesting that GPR139 is predominantly coupled to Galpha(s). The authors screened a large library of small molecules for compounds that increase cAMP levels in GPR139-expressing cells and identified a compound with GPR139 agonist activity. This compound increased cAMP production specifically in cells expressing GPR139 but not in cells expressing its highly homologous receptor GPR142. Furthermore, this compound did not induce calcium mobilization in GPR139 cells, indicating no Galpha(q)-mediated response. In addition, antagonist screening with the identified agonist yielded 2 classes of compounds as antagonists. The identification of surrogate agonists and antagonists of human GPR139 provides important tools for further study of this orphan GPCR. PMID:19525486

Hu, Liaoyuan A; Tang, Pauline M; Eslahi, Nima K; Zhou, Tian; Barbosa, Joseph; Liu, Qingyun



Selective and Brain Penetrant Neuropeptide Y Y2 Receptor Antagonists Discovered by Whole-Cell High-Throughput ScreeningS?  

PubMed Central

The role of neuropeptide Y Y2 receptor (Y2R) in human diseases such as obesity, mood disorders, and alcoholism could be better resolved by the use of small-molecule chemical probes that are substantially different from the currently available Y2R antagonist, N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide) (BIIE0246). Presented here are five potent, selective, and publicly available Y2R antagonists identified by a high-throughput screening approach. These compounds belong to four chemical scaffolds that are structurally distinct from the peptidomimetic BIIE0246. In functional assays, IC50 values between 199 and 4400 nM against the Y2R were measured, with no appreciable activity against the related NPY-Y1 receptor (Y1R). Compounds also displaced radiolabeled peptide YY from the Y2R with high affinity (Ki values between 1.55 and 60 nM) while not displacing the same ligand from the Y1R. In contrast to BIIE0246, Schild analysis with NPY suggests that two of the five compounds behave as competitive antagonists. Profiling against a panel of 40 receptors, ion channels, and transporters found in the central nervous system showed that the five Y2R antagonists demonstrate greater selectivity than BIIE0246. Furthermore, the ability of these antagonists to penetrate the blood-brain barrier makes them better suited for pharmacological studies of Y2R function in both the brain and periphery.

Brothers, Shaun P.; Saldanha, S. Adrian; Spicer, Timothy P.; Cameron, Michael; Mercer, Becky A.; Chase, Peter; McDonald, Patricia; Wahlestedt, Claes



Antagonist for PET Imaging of Somatostatin Receptor-Positive Tumors  

Microsoft Academic Search

TE2A-sst2-ANT) as a PET radiopharmaceutical for the in vivo imaging of SSTR2-positive tumors. Methods: Receptor-binding studies were performed to determine the dissociation con- stant of the radiopharmaceutical 64Cu-CB-TE2A-sst2-ANT using AR42J rat pancreatic tumor cell membranes. The internaliza- tion of 64Cu-CB-TE2A-sst2-ANT was compared with that of the 64Cu-labeled agonist 64Cu-CB-TE2A-tyrosine3-octreotate (64Cu-CB-TE2A-Y3-TATE) in AR42J cells. Both radiopharma- ceuticals were also compared in

Thaddeus J. Wadas; Martin Eiblmaier; Alexander Zheleznyak; Christopher D. Sherman; Riccardo Ferdani; Kexian Liang; Samuel Achilefu; Carolyn J. Anderson


Structure-activity relationships of arodyn, a novel acetylated kappa opioid receptor antagonist.  


We previously reported that the novel dynorphin A (Dyn A, Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln) analog arodyn (Ac[Phe(1,2,3),Arg(4),d-Ala(8)]Dyn A-(1-11)NH(2), Bennett, M.A., Murray, T.F. & Aldrich, J.V. (2002) J. Med. Chem. vol. 45, pp. 5617-5619) is a kappa opioid receptor-selective peptide [K(i)(kappa) = 10 nm, K(i) ratio (kappa/mu/delta) = 1/174/583] which exhibits antagonist activity at kappa opioid receptors. In this study, a series of arodyn analogs was prepared and evaluated to explore the structure-activity relationships (SAR) of this peptide; this included an alanine scan of the entire arodyn sequence, sequential isomeric d-amino acid substitution in the N-terminal 'message' sequence, NMePhe substitution individually in positions 1-3, and modifications in position 1. The results for the Ala-substituted derivatives indicated that Arg(6) and Arg(7) are the most important residues for arodyn's nanomolar binding affinity for kappa opioid receptors. Ala substitution of the other basic residues (Arg(4), Arg(9) and Lys(11)) resulted in lower decreases in affinity for kappa opioid receptors (three- to fivefold compared with arodyn). Of particular interest, while [Ala(10)]arodyn exhibits similar kappa opioid receptor binding as arodyn, it displays higher kappa vs. mu opioid receptor selectivity [K(i) ratio (kappa/mu) = 1/350] than arodyn because of a twofold loss in affinity at mu opioid receptors. Surprisingly, the Tyr(1) analog exhibits a sevenfold decrease in kappa opioid receptor affinity, indicating that arodyn displays significantly different SAR than Dyn A; [Tyr(1)]arodyn also unexpectedly exhibits inverse agonist activity in the adenylyl cyclase assay using Chinese hamster ovary cells stably expressing kappa opioid receptors. Substitution of NMePhe in position 1 gave [NMePhe(1)]arodyn which exhibits high affinity [K(i)(kappa) = 4.56 nm] and exceptional selectivity for kappa opioid receptors [K(i) ratio (kappa/mu/delta) = 1/1100/>2170]. This peptide exhibits antagonistic activity in the adenylyl cyclase assay, reversing the agonism of 10 nm Dyn A-(1-13)NH(2). Thus [NMePhe(1)]arodyn is a highly kappa opioid receptor-selective antagonist that could be a useful pharmacological tool to study kappa opioid receptor-mediated activities. PMID:15787962

Bennett, M A; Murray, T F; Aldrich, J V



[Are IL2 receptor antagonist useful in high risk acute tubular necrosis kidney recipients?].  


The questions are if old recipients from old donor have more incidence of delayed graft function and if antagonists of Il-2 receptors use decreased the incidence of NTA post-transplant. To answer the first question we have come to information from registry and uni or multicenter studies. We have used the Irish normograme that included 16 clinical questions from donors, recipients and kidney transplant. We concluded that age of donors increases likelihood of delayed graft function. The second question is answered in the literature with information of a meta-analysis with 38 clinical studies. Of them 9 (1.380 patients) studied delayed graft function and are against placebo. The odds ratio for delayed graft function was 0.87(IC 95% 0,72 a 1,06). Therefore, at the moment, we can conclude that the utilization of antagonists of Il-2 receptors does not have protective effect to NTA. PMID:18045028

Fernández, A; Royuela, A; Quintás, A; Zamora, J



Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists  

PubMed Central

The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential. In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive. The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision. We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered.

Greineisen, William E.; Turner., Helen



Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists.  


The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential. In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive. The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision. We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered. PMID:20219697

Greineisen, William E; Turner, Helen



Treatment and prevention of various therapeutic conditions using OX receptor antagonistic activity (WO2012081692).  


Application WO2012081692 from Taisho Pharmaceutical Co. Ltd. claims pyrazole-based antagonists of the orexin-1 and orexin-2 receptors. Utility in a number of therapeutic areas is claimed, including the treatment of sleep disorders; the most likely use of the claimed compounds. Data from in vitro functional assays are presented, with the claimed compounds typically being dual orexin receptor antagonists (DORAs) or having moderate selectivity for orexin-1. Structurally, the claimed compounds represent a variation on established DORA SAR themes and translate features of clinical compounds into a pyrazole-based scaffold. Example 52, the most potent molecule in the application, has similar molecular weight and lipophilicity to suvorexant, the most advanced DORA, with broadly comparable potency in functional assays. PMID:23282091

Christopher, John A; Congreve, Miles S



Identification of renal natriuretic peptide receptor subpopulations by use of the non-peptide antagonist, HS-142-1.  

PubMed Central

1. The renal actions of natriuretic peptides are dictated by the distribution of guanylyl cyclase-linked (NPRA and NPRB) and non-guanylyl cyclase-linked (NPRC) receptors. Natriuretic peptide receptors have previously been distinguished on the basis of their differential affinity for peptide fragments and analogues; however, most of the available ligands are not fully selective. We have used the specific guanylyl cyclase-linked receptor antagonist, HS-142-1, to investigate the differential distribution of natriuretic peptide receptor subtypes in the human, bovine and rat kidney. 2. Specific, high affinity 3-([125I]-iodotyrosyl)-rat-ANP-(1-28)([125I]-rANP1-28) binding sites were identified in all three species, localized to glomeruli, inner medulla, intrarenal arteries and regions in the outer medulla corresponding to vasa recta bundles. Binding sites were also identified in the smooth muscle lining of the hilar region in the bovine and rat kidney. 3. In the rat, [125I]-rANP1-28 binding was inhibited by unlabelled peptide sequences with a rank order of potency (rANP1-28 > pCNP1-22 > C-ANP4-23). The glomeruli exhibited a heterogeneous population of binding sites, C-ANP4-23 and pCNP1-22 producing a significantly better fit to a two component inhibition curve compared to the single component curve for rANP1-28. 4. Competitive inhibition experiments with the receptor selective ligands, C-ANP4-23 and HS-142-1, suggested that, like the rat, human and bovine glomeruli possessed a heterogeneous population of binding sites, whilst those in the inner medulla and intrarenal arteries of all three species represented a homogeneous population.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 2 Figure 3

Rutherford, R A; Matsuda, Y; Wilkins, M R; Polak, J M; Wharton, J



Structure activity relationship studies of carboxamido-biaryl ethers as opioid receptor antagonists (OpRAs). Part 2.  


A series of 6-bicycloaryloxynicotinamides were identified as opioid receptor antagonists at mu, kappa, and delta receptors. Compounds in the 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide scaffold exhibited potent in vitro functional antagonism at all three receptors. PMID:17980586

Takeuchi, Kumiko; Holloway, William G; Mitch, Charles H; Quimby, Steven J; McKinzie, Jamie H; Suter, Todd M; Statnick, Michael A; Surface, Peggy L; Emmerson, Paul J; Thomas, Elizabeth M; Siegel, Miles G



Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors.  


Metabotropic glutamate (mGlu) receptors are implicated in many neurological and psychiatric diseases and are the targets of therapeutic agents currently in clinical development. Their activation has diverse effects in the central nervous system (CNS) that includes an involvement in synaptic plasticity. We previously reported that the brief exposure of hippocampal slices to dihydroxyphenylglycine (DHPG) can result in a long-term depression (LTD) of excitatory synaptic transmission. Surprisingly, this LTD could be fully reversed by mGlu receptor antagonists in a manner that was itself fully reversible upon washout of the antagonist. Here, 15 years after the discovery of DHPG-LTD and its reversible reversibility, we summarise these initial findings. We then present new data on DHPG-LTD, which demonstrates that evoked epileptiform activity triggered by activation of group I mGlu receptors can also be reversibly reversed by mGlu receptor antagonists. Furthermore, we show that the phenomenon of reversible reversibility is not specific to group I mGlu receptors. We report that activation of group II mGlu receptors in the temporo-ammonic pathway (TAP) and mossy fibre pathway within the hippocampus and in the cortical input to neurons of the lateral amygdala induces an LTD that is reversed by LY341495, a group II mGlu receptor antagonist. We also show that activation of group III mGlu8 receptors induces an LTD at lateral perforant path inputs to the dentate gyrus and that this LTD is reversed by MDCPG, an mGlu8 receptor antagonist. In conclusion, we have shown that activation of representative members of each of the three groups of mGlu receptors can induce forms of LTD than can be reversed by antagonists, and that in each case washout of the antagonist is associated with the re-establishment of the LTD. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID:23542080

Lodge, David; Tidball, Patrick; Mercier, Marion S; Lucas, Sarah J; Hanna, Lydia; Ceolin, Laura; Kritikos, Minos; Fitzjohn, Stephen M; Sherwood, John L; Bannister, Neil; Volianskis, Arturas; Jane, David E; Bortolotto, Zuner A; Collingridge, Graham L



Endothelin-A receptor antagonist BQ123 potentiates acetaminophen induced hypothermia and reduces infarction following focal cerebral ischemia in rats  

Microsoft Academic Search

Endothelin antagonists are being investigated to prevent neuronal loss after cerebral ischemia. Acetaminophen has been tried in stroke patients to produce hypothermia so that injury following cerebral ischemia can be reduced. The aim of this study was to assess the effect of BQ123, an endothelin-A receptor antagonist, alone and in combination with acetaminophen on neurological outcome, oxidative stress and infarct

Seema Briyal; Anil Gulati



The Epistatic Interrelationships of IL1, IL1 Receptor Antagonist, and the Type I IL1 Receptor1  

Microsoft Academic Search

Mice lacking the gene for the IL-1R antagonist (IL-1ra) show abnormal development and homeostasis as well as altered responses to infectious and inflammatory stimuli. A reduction in the level of IL-1 signaling, either by deletion of the receptor or increased expression of IL-1ra, does not affect development or homeostasis, but does alter immune responses. In this study we use genetic

Vera M. Irikura; Mouna Lagraoui; David Hirsh



PubMed Central

Chemokine receptor CCR3 is highly expressed by eosinophils and signals in response to binding of the eotaxin family of chemokines, which are upregulated in allergic disorders. Consequently, CCR3 blockade is of interest as a possible therapeutic approach for the treatment of allergic disease. We have described previously a bi-specific antagonist of CCR1 and CCR3 named UCB35625, which was proposed to interact with the transmembrane residues Y41, Y113 and E287 of CCR1, all of which are conserved in CCR3. Here, we show that cells expressing the CCR3 constructs Y113A and E287Q are insensitive to antagonism by UCB35625 and also exhibit impaired chemotaxis in response to CCL11/Eotaxin suggesting that these residues are important for antagonist binding and also receptor activation. Furthermore, mutation of the residue Y113 to alanine was found to turn the antagonist UCB35625 into a CCR3 agonist. Screens of small molecule libraries identified a novel specific agonist of CCR3 named CH0076989. This was able to activate eosinophils and transfectants expressing both wild-type CCR3 and a CCR1:CCR3 chimaeric receptor lacking the CCR3 amino-terminus, indicating that this region of CCR3 is not required for CH0076989 binding. A direct interaction with the transmembrane helices of CCR3 was supported by mutation of the residues Y41, Y113 and E287 which resulted in complete loss of CH0076989 activity, suggesting that the compound mimics activation by CCL11. We conclude that both agonists and antagonists of CCR3 appear to occupy overlapping sites within the transmembrane helical bundle, suggesting a fine line between agonism and antagonism of chemokine receptors.

Wise, Emma L.; Duchesnes, Cecile; da Fonseca, Paula C.A.; Allen, Rodger A.; Williams, Timothy J.; Pease, James E.



Fosaprepitant: a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting.  


Chemotherapy-induced nausea and vomiting (CINV) is a distressing and common adverse event associated with cancer treatment. Updated antiemetic guidelines were published in 2008 by the National Comprehensive Cancer Network and, in 2006, by the American Society of Clinical Oncology, which have included the use of the new and more effective antiemetic agents 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonist and neurokinin (NK)-1 receptor antagonist. Aprepitant is a selective NK-1 receptor antagonist approved as part of combination therapy with a corticosteroid and a 5-HT(3) receptor antagonist for the prevention of acute and delayed CINV in patients receiving moderately and highly emetogenic chemotherapy. Fosaprepitant (also known as MK-0517 and L-758,298) is a water-soluble phosphoryl prodrug for aprepitant, which, when administered intravenously, is converted to aprepitant within 30 min of intravenous administration via the action of ubiquitous phosphatases. Owing to the rapid conversion of fosaprepitant to the active form (aprepitant), fosaprepitant 115 mg provided the same aprepitant exposure in terms of AUC as aprepitant 12 mg orally, and fosaprepitant is expected to provide a correspondingly similar antiemetic effect as aprepitant. Clinical studies have suggested that fosaprepitant could be appropriate as an intravenous alternative to the aprepitant oral capsule. In a study in healthy subjects, fosaprepitant 115 mg was generally well tolerated at a final drug concentration of 1 mg/ml, and fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg. Fosaprepitant in the dose of 115 mg has been approved by the US FDA, the EU and the Australian authorities on day 1 of a 3-day oral aprepitant regimen, with oral aprepitant administered on days 2 and 3. Fosaprepitant may be a useful parenteral alternative to oral aprepitant. Further study is needed to clarify the utility of fosaprepitant in the prevention of CINV and to clarify optimal dosing regimens that may be appropriate substitutes for oral aprepitant. PMID:18983233

Navari, Rudolph M



The Leukotriene Receptor Antagonist Zafirlukast Inhibits Sulfur Dioxide-induced Bronchoconstriction in Patients with Asthma  

Microsoft Academic Search

Inhalation of sulfur dioxide (SO 2 ) causes bronchoconstriction in most people with asthma. To exam- ine the role of leukotrienes in this response, the antagonism of SO 2 -induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, pla- cebo-controlled, two-period crossover trial in 12 subjects with mild-to-moderate asthma. Subjects had




Small molecule antagonists of the TGF-?1\\/TGF-? receptor binding interaction  

Microsoft Academic Search

Excessive and inappropriate action of transforming growth factor (TGF)-? has been implicated in the pathogenesis of several\\u000a disease processes, especially cancer and fibrosis. To identify antagonists of the TGF-? ligand-binding domain that may have\\u000a therapeutic potential, we screened the National Cancer Institute open access chemical repository for molecules that inhibited\\u000a binding of TGF-? to the type II receptor (T?RII). About

James K. Burmester; Sherry A. Salzman; Kai Qi Zhang; Richard A. Dart



Development of Chronic Inflammatory Arthropathy Resembling Rheumatoid Arthritis in Interleukin 1 Receptor Antagonist-deficient Mice  

Microsoft Academic Search

Interleukin (IL)-1 is a proinflammatory cytokine that plays important roles in inflammation, host defense, and the neuro-immuno-endocrine network. IL-1 receptor antagonist (ra) is an endogenous inhibitor of IL-1 and is supposed to regulate IL-1 activity. However, its patho- physiological roles in a body remain largely unknown. To elucidate the roles of IL-1ra, IL-1ra- deficient mice were produced by gene targeting,

Reiko Horai; Shinobu Saijo; Hidetoshi Tanioka; Susumu Nakae; Katsuko Sudo; Akihiko Okahara; Toshimi Ikuse; Masahide Asano; Yoichiro Iwakura



Regulatory immune responses induced by IL1 receptor antagonist in rheumatoid arthritis  

Microsoft Academic Search

Anakinra, a human recombinant IL-1 receptor antagonist, is approved for the treatment of RA. In this study, 12 patients received the placebo plus MTX treatment, 38 patients received Anakinra combined with MTX treatment. Compared with the placebo plus MTX group, serum levels of IL-17, IFN-?, IL-21 and IL-1? significantly decreased, the percentages of Th17 cells and Th1 cells were lower

Xiaoyin Niu; Dongyi He; Shaohua Deng; Weiyi Li; Yebin Xi; Changyi Xie; Ting Jiang; Jingwu Z. Zhang; Chen Dong; Guangjie Chen



Variant interleukin 1 receptor antagonist gene alleles in sudden infant death syndrome  

Microsoft Academic Search

ObjectiveTo investigate if carriage of interleukin 1 (IL-1) receptor antagonist gene variants are associated with sudden infant death syndrome (SIDS) in a large cohort of case–control demographically matched infants.Design118 SIDS and 233 control infants, who were matched to each SIDS infant by date of birth, sex, birth weight (±500 g), gestational age and ethnicity, were genotyped for an IL-1RN 89

Amanda R Highet; Catherine S Gibson; Paul N Goldwater



Gastric emptying in non-responders to H 2 -receptor antagonists  

Microsoft Academic Search

Summary H2-receptor antagonists are known to fail to increase the intragastric pH in some patients (so-called non-responders), and we have recently found a higher frequency of non-responders among cirrhotics. Since intragastric pH is also affected by gastric emptying, in the present study we determined the gastric emptying of 300 ml orange juice labelled with [99mTc]-Solco Nanocoll using a gamma camera.

S. Walker; J. Meinke; U. Klotz; G. Treiber; J. C. Bode



P2 receptor antagonist PPADS confers neuroprotection against glutamate\\/NMDA toxicity  

Microsoft Academic Search

The present study investigated the role of pyridoxal phosphate-6-azophenyl-2?,4?-disulfonic acid tetrasodium salt (PPADS), a P2 receptor antagonist, in protecting mouse cerebellar granule neurons (CGNs) against glutamate\\/NMDA-induced neuronal death. Neurotoxicity caused by 50?M glutamate or 200?M NMDA was significantly reduced in CGNs treated with PPADS. Such neuroprotection was in a time- and dose-dependent manner. The possibility that PPADS may block glutamate\\/NMDA-mediated

Yanpeng Lin; Angele Desbois; Susan Jiang; Sheng T. Hou



Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks  

Microsoft Academic Search

The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence,

Gilbert Y. Wong; Narender R. Gavva



Umbilical Cord Levels of Interleukin1 Receptor Antagonist and Neonatal Outcome  

Microsoft Academic Search

Background: Previous studies indicate that there may be infant gender differences in cytokine expression associated with differences in neonatal morbidity. Objective: We tested the hypothesis that umbilical cord interleukin-1 receptor antagonist (IL-1ra) correlates with infant gender and neonatal outcome in preterm infants. Study Design: IL-1ra was measured in cord blood taken from 58 preterm infants (33 males, 25 females) with

Emma Elsmén; David Ley; Corrado M. Cilio; Ingrid Hansen-Pupp; Lena Hellström-Westas



Constitutional isomers of Reactive Blue 2 – selective P2Y-receptor antagonists?  

Microsoft Academic Search

The anthraquinone derivative Reactive Blue 2 (RB 2) is one of the most widely used P2-receptor antagonists, still claimed to be P2Y-selective. RB 2 is defined as a mixture of two constitutional isomers and commercially available in different identity and purity. A sample of RB 2, offered for sale by RBI, purchased from Biotrend, Köln, Germany, was chromatographically purified and

Markus Glänzel; Ralph Bültmann; Klaus Starke; August W Frahm



Ritanserin, a serotonin-2 receptor antagonist, improves ultradian sleep rhythmicity in young poor sleepers  

Microsoft Academic Search

Objectives: To determine the effect on sleep electroencephalographic (EEG) activity of ritanserin, a serotonin-2 (5-HT2) receptor antagonist in young poor sleepers.Methods: Eight male subjects underwent two randomized night studies after receiving either a placebo or 5mg ritanserin administered in the morning. The overnight variations in the delta (0.5–4.0Hz) and sigma (12.25–15.0Hz) frequency bands were characterized using a peak analysis which

Antoine U. Viola; Gabrielle Brandenberger; Michel Toussaint; Philippe Bouhours; Jean Paul Macher; Remy Luthringer



PEGylated PPI dendritic architectures for sustained delivery of H 2 receptor antagonist  

Microsoft Academic Search

The present study was aimed at synthesizing and exploring the use of long circulating biocompatible PEGylated PPI 5.0G dendrimers for sustained delivery of a H2 receptor antagonist, Famotidine. PPI 5.0G dendrimers were synthesized and PEGylated using dicarboxylic acid PEG 2000. PEGylation was confirmed by SEC, IR, NMR and MASS spectroscopies. Famotidine was loaded in PEGylated dendritic system and confirmed by

Virendra Gajbhiye; P. Vijayaraj Kumar; Rakesh Kumar Tekade; N. K. Jain



Identification and optimisation of novel sulfonamide, selective vasopressin V 1B receptor antagonists  

Microsoft Academic Search

The synthesis and preliminary structure–activity relationships (SAR) of a novel class of vasopressin V1B receptor antagonists are described. Hit compound 5, identified via high throughput screening of the corporate collection, showed good activity in a V1B binding assay (Ki 63nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A ‘deletion approach’ on the HTS

James Baker; Matilda Bingham; Ruth Blackburn-Munro; Jiaqiang Cai; Mark Craighead; Robert Gilfillan; Kate Goan; David Jaap; Rachel Milne; J. Richard Morphy; Susan Napier; Jeremy Presland; Gayle Spinks; Fiona Thomson



Chlamydia pneumoniae Growth Inhibition in Cells by the Steroid Receptor Antagonist RU486 (Mifepristone)  

Microsoft Academic Search

Since steroids are powerful anti-inflammatory agents and increase susceptibility to a variety of infections, including Chlamydia (Chlamydophila) pneumoniae respiratory tract infections, the effect of the steroid receptor antagonist RU486 (mifepristone) on C. pneumoniae growth in epithelial HEp-2 cells was examined. Treatment of HEp-2 cells with RU486 significantly inhibited the growth of C. pneumoniae in a dose-dependent manner. Electron microscopic studies

Hiroyuki Yamaguchi; Shigeru Kamiya; Tomonori Uruma; Takako Osaki; Haruhiko Taguchi; Tomoko Hanawa; Minoru