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Competitive NMDA receptor antagonists raise electrically kindled generalized seizure thresholds  

Microsoft Academic Search

A sensitive method of estimation of generalized seizure thresholds (GSTs) was used to estimate the relative anticonvulsant potencies of four competitive NMDA antagonists against fully amygdala-kindled seizures. All of the antagonists tested showed potent, dose-dependent anticonvulsant activity following focal administration at doses causing no, or only minimal, overt behavioural abnormalities. These doses were similar to those which have previously been

Martin J. Croucher; Katie L. Cotterell; Henry F. Bradford



Discovery and characterization of non-competitive antagonists of group I metabotropic glutamate receptors  

Microsoft Academic Search

We have investigated the mechanism of inhibition of the new group I mGluR antagonists CPCCOEt and MPEP and determined that both compounds have a non-competitive mode of inhibition. Furthermore using chimeric\\/mutated receptors constructs we have found that these antagonists act at a novel pharmacological site located in the trans-membrane (TM). Specific non-conserved amino acid residues in the TM domain have

Fabrizio Gasparini; Philipp Floersheim; Peter Josef Flor; Micheline Heinrich; Werner Inderbitzin; David Ott; Adriana Pagano; Christine Stierlin; Natacha Stoehr; Ivo Vranesic; Rainer Kuhn



6-Amino quinazolinedione sulfonamides as orally active competitive AMPA receptor antagonists.  


A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage. PMID:22197388

Orain, David; Ofner, Silvio; Koller, Manuel; Carcache, David A; Froestl, Wolfgang; Allgeier, Hans; Rasetti, Vittorio; Nozulak, Joachim; Mattes, Henri; Soldermann, Nicolas; Floersheim, Philipp; Desrayaud, Sandrine; Kallen, Joerg; Lingenhoehl, Kurt; Urwyler, Stephan



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))



Discovery and characterization of non-competitive antagonists of group I metabotropic glutamate receptors.  


We have investigated the mechanism of inhibition of the new group I mGluR antagonists CPCCOEt and MPEP and determined that both compounds have a non-competitive mode of inhibition. Furthermore using chimeric/mutated receptors constructs we have found that these antagonists act at a novel pharmacological site located in the trans-membrane (TM). Specific non-conserved amino acid residues in the TM domain have been identified which are necessary for the inhibition by CPCCOEt and MPEP of the mGlul and mGlu5 receptors, respectively. Using molecular modeling a model of the TM domain was built for both mGlu1 and mGlu5 receptor subtypes. Docking of CPCCOEt and MPEP into their respective model allowed the modelisation of the novel binding site. PMID:11347975

Gasparini, F; Floersheim, P; Flor, P J; Heinrich, M; Inderbitzin, W; Ott, D; Pagano, A; Stierlin, C; Stoehr, N; Vranesic, I; Kuhn, R



Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self-administration  

PubMed Central

Summary Competitive dopamine receptor antagonists increase the rate of cocaine self-administration. As the rate of self-administration at a particular unit dose is determined by the satiety threshold and the elimination half-life (t1/2) of cocaine, we investigated whether dopamine receptor antagonists altered these parameters. The plasma cocaine concentration at the time of each self-administration was constant during a session demonstrating that this satiety threshold concentration represents an equiactive cocaine concentration. The plasma cocaine concentration at the time of self-administration was increased by SCH23390, consistent with pharmacological theory. In rats trained to reliably self-administer cocaine, SCH23390 had no effect on the plasma steady-state cocaine concentration produced by constant infusions of cocaine. Therefore, this antagonist had no effect on cocaine t1/2 at a dose that accelerated cocaine self-administration. A continuous cocaine infusion at a rate that maintained steady state concentrations above the satiety threshold stopped self-administration. SCH23390, or the D2 dopamine receptor antagonist (?) eticlopride, reinstated self-administration in the presence of the constant cocaine infusion. This is consistent with SCH23390 and eticlopride raising the satiety threshold above the steady state level produced by the constant cocaine infusion. It is concluded that the antagonist-induced acceleration of cocaine self-administration is the result of a pharmacokinetic/pharmacodynamic interaction whereby the rate of cocaine elimination is faster at the higher concentrations, as dictated by first-order kinetics, so that cocaine levels decline more rapidly to the elevated satiety threshold. This results in the decreased inter-injection intervals.

Norman, Andrew B; Norman, Mantana K; Tabet, Michael R; Tsibulsky, Vladimir L; Pesce, Amadeo J



Competitive as well as uncompetitive N-methyl-D-aspartate receptor antagonists affect cortical neuronal morphology and cerebral glucose metabolism.  


The studies examined the effects of three antagonists (CPP, CGS 19755, and CGP 37849) that act competitively at the glutamate recognition site of the NMDA receptor complex on cortical neuronal morphology and cerebral limbic glucose metabolism. Responses were compared to the effects of dizocilpine, an uncompetitive NMDA receptor ion channel antagonist as a positive control. CGS 19755 and CGP 37849 (100 mg kg-1 i.p.) caused vacuolation in cortical pyramidal neurons in the posterior cingulate cortex four hours after dosing and this dose of CGP 37849 caused a pattern of limbic glucose metabolism activation similar to that seen after dizocilpine. CPP was without effect at 100 mg/kg i.p. probably due to poor brain penetration. The data indicates that the functional consequences (structural and metabolic) of NMDA receptor blockade with NMDA antagonists acting competitively at the glutamate recognition site and uncompetitively in the receptor ion channel are ultimately the same. Comparisons of the potential therapeutic window for CGS 19755 and CGP 37849 with dizocilpine (neuroprotection versus vacuolation) suggests that the window for the competitive antagonists is greater. This indicates that the potential therapeutic window for the different classes of NMDA antagonists may vary with the site in the receptor complex at which they interact. PMID:7903796

Hargreaves, R J; Rigby, M; Smith, D; Hill, R G; Iversen, L L



Identification of WIN55212-3 as a competitive neutral antagonist of the human cannabinoid CB2 receptor  

PubMed Central

Several G protein-coupled receptors (GPCRs), including cannabinoid CB1 and CB2 receptors, show constitutive activity under heterologous expression. Such a tonic response is generated in the absence of an activating ligand, and can be inhibited by inverse agonists. Neutral antagonists, however, are silent at such receptors, but can reverse both agonist and inverse agonist responses. To date, no neutral antagonist for the CB2 receptor has been reported. Here, by monitoring receptor-dependent G protein activation, we demonstrate that WIN55212-3 acts as a neutral antagonist at the human CB2 (hCB2) receptor. WIN55212-3 alone, at concentrations ?10?4?M, behaved as a silent ligand exhibiting no agonist or inverse agonist activity. However, WIN55212-3 competitively antagonized cannabinoid agonist CP-55,940-stimulated responses (pA2 6.1). Importantly, the inverse agonism evoked by SR144528 in hCB2 was dose-dependently reversed by WIN55212-3 (pEC50 5.3±0.2), indicating true neutral antagonist behavior. Furthermore, WIN55212-3 also antagonized CB1 receptor signaling in a competitive manner (pA2 5.6), but behaved as a partial inverse agonist (pIC50 5.5±0.1) at the constitutively active human CB1. Additionally, WIN55212-3 antagonized signaling of the human melatonin MT1 receptor, with modest activity at the human muscarinic M4 receptor, but it was inactive towards several other GPCRs. These data identify WIN55212-3 as a true neutral hCB2 receptor antagonist. WIN55212-3 offers a valuable tool for further characterization of ligand activities at the CB2 receptor and may serve as a lead compound in further efforts to develop more potent and selective neutral CB2 receptor antagonists.

Savinainen, Juha R; Kokkola, Tarja; Salo, Outi M H; Poso, Antti; Jarvinen, Tomi; Laitinen, Jarmo T



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)



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



Immunochemical and immunohistochemical characterization of a synaptic membrane protein that binds the competitive antagonists of NMDA receptors.  


An approximately 54-kDa protein that has binding sites for the competitive N-methyl-D-aspartate (NMDA) receptor antagonists 3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP) and (+-)-(E)-2-amino-4-propyl-5-phosphonopentenoic acid (CGP 39653) was purified from rat brain synaptic membranes. Polyclonal antibodies to this protein reacted specifically with an approximately 54-kDa protein in synaptic membranes and immunoextracted approximately 60% of [3H]CGP 39653 binding sites associated with solubilized membrane proteins. The antibodies also labeled antigenic sites in the perikaryon and apical and basilar dendrites of pyramidal neurons of the hippocampus and cerebral cortex. PMID:7901820

Eggeman, K T; Pal, R; Walsh, J; Kumar, K N; Michaelis, E K



Attenuation of nociceptive responses by ACEA-1021, a competitive NMDA receptor/glycine site antagonist, in the mice.  


Intrathecal administration of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists has been shown to produce antinociception in various animal models of pain. In the present study we examined the effect of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021), a competitive NMDA receptor/glycine site antagonist, on nociceptive responses in the tail flick and formalin tests in mice. Swiss Webster mice were injected with ACEA-1021 intraperitoneally (1-60 mg/kg), or intrathecally (1-40 micrograms/mouse), and tested for antinociception. Systemic administration of ACEA-1021 attenuated the nociceptive responses solely in the formalin test. Nevertheless, intrathecal administration of ACEA-1021 showed equally potent attenuation of nociceptive responses in both animal models of pain. The effect of ACEA-1021 was also examined on caudally directed biting and scratching (CDBS) behaviors induced by intrathecal administration of NMDA. Microinjections of NMDA (1-1000 microM) in the spinal cord produced dose-dependent CDBS behaviors. Mice pretreated with ACEA-1021 (0.5-40 micrograms/mouse) showed dose-dependent protection against CDBS behaviors induced by intrathecal NMDA. Taken together, the results suggest that ACEA-1021 may block spinal NMDA receptors to attenuate nociceptive responses, however, our data cannot exclude the involvement of non-NMDA receptors. PMID:9017225

Lutfy, K; Weber, E



Putative TRP channel antagonists, SKF 96365, flufenamic acid and 2-APB, are non-competitive antagonists at recombinant human ?1?2?2 GABA(A) receptors.  


Although transient receptor potential (TRP) channel biology research has expanded rapidly in recent years, the field is hampered by the widely held, but relatively poorly investigated, belief that most of the pharmacological tools used to investigate TRP channel function may not be particularly selective for their intended targets. The objective of this study was therefore to determine if this was indeed the case by systematically evaluating the effects of three routinely used putative TRP channel antagonists, SKF 96365, flufenamic acid (FF) and 2-aminoethoxydiphenyl borate (2-APB) against one of the most widely expressed CNS receptor subtypes CNS, the human ?1?2?2 GABA(A) receptor. Using whole cell patch-clamp recording to record responses to rapidly applied GABA in the absence and presence of the three putative antagonists in turn we found that SKF 96365 (1-100 ?M) and FF (1-100 ?M) significantly inhibited GABA responses of recombinant human ?1?2?2 GABA(A) receptor stably expressed in HEK293 cells with IC(50) values of 13.4 ± 5.1 and 1.9 ± 1.4 ?M, respectively, suppressing the maximal response to GABA at all concentrations used in a manner consistent with a non-competitive mode of action. SKF 96365 and FF also both significantly reduced desensitisation and prolonged the deactivation kinetics of the receptors to GABA (1mM; P<0.05). 2-APB (10-1000 ?M) also inhibited responses to GABA at all concentrations used with an IC(50) value of 16.7 ± 5.4 ?M (n=3-5) but had no significant effect on the activation, desensitisation or deactivation kinetics of the GABA responses. Taken together this investigation revealed that these widely utilised TRP channel antagonists display significant 'off-target' effects at concentrations that are routinely used for the study of TRP channel function in numerous biological systems and as such, data which is obtained utilising these compounds should be interpreted with caution. PMID:22369768

Rae, M G; Hilton, J; Sharkey, J



Quinazolin-4-one derivatives: A novel class of non-competitive NR2C/D subunit-selective N-methyl-D-aspartate receptor antagonists  

PubMed Central

We describe a new class of subunit-selective antagonists of N-methyl D-Aspartate (NMDA)-selective ionotropic glutamate receptors that contain the (E)-3-phenyl-2-styrylquinazolin-4(3H)-one backbone. The inhibition of recombinant NMDA receptor function induced by these quinazolin-4-one derivatives is non-competitive and voltage-independent, suggesting that this family of compounds does not exert action on the agonist binding site of the receptor or block the channel pore. The compounds described here resemble CP-465,022 ((S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one), a non-competitive antagonist of AMPA-selective glutamate receptors. However, modification of ring substituents resulted in analogues with greater than 100-fold selectivity for recombinant NMDA receptors over AMPA and kainate receptors. Furthermore, within this series of compounds, analogues were identified with 50-fold selectivity for recombinant NR2C/D-containing receptors over NR2A/B containing receptors. These compounds represent a new class of non-competitive subunit-selective NMDA receptor antagonists.

Mosley, Cara A.; Acker, Timothy M.; Hansen, Kasper B.; Mullasseril, Praseeda; Andersen, Karen T.; Le, Phuong; Vellano, Kimberly M.; Brauner-Osborne, Hans; Liotta, Dennis C.; Traynelis, Stephen F.



2-Guanidine-4-methylquinazoline acts as a novel competitive antagonist of A type ?-aminobutyric acid receptors.  


The pentameric A type ?-aminobutyric acid receptors (GABAARs) are the major inhibitory neurotransmitter receptors in the nervous system and have long been considered as important pharmaceutical targets for the treatment of multiple neurological or psychological disorders. Here, we show that 2-guanidine-4-methylquinazoline (GMQ), a recently identified acid-sensing ion channel (ASIC) modulator, strongly and preferentially inhibits GABAAR among the major neurotransmitter-gated ion channels in cultured rat hippocampal neurons. GMQ inhibited GABA (1 ?M)-induced currents in a competitive manner, with an IC50 (0.39±0.05 ?M) comparable to that of bicuculline. Schild analysis revealed a slope of 1.04±0.06 for GMQ on ?1?2 GABAARs expressed in HEK293T cells. Single-channel analysis showed that GMQ decreased open probability of GABAARs without affecting conductance. Moreover, GMQ inhibited GABAergic neurotransmission in hippocampal neurons, while having no significant effect on the basal field excitatory postsynaptic potentials (fEPSPs) and the intrinsic excitability of neurons. Using site-directed mutagenesis, we further demonstrated that mutations at Glu155 of ?2 subunit and Phe64 of ?1 subunit, both located inside the GABA binding pocket, profoundly decreased the sensitivity of the receptor to both GABA and GMQ. Interestingly, these mutations did not significantly affect the inhibition by amiloride, a diuretic structurally similar to GMQ and a known GABAAR inhibitor. We conclude that GMQ represents a novel chemical structure that acts, possibly, by competing with GABA binding to GABAARs. It is anticipated that GMQ and its analogs will facilitate the development of new chemical probes for GABAARs. PMID:23916476

Xiao, Xian; Zhu, Michael X; Xu, Tian-Le



Leukotriene-receptor antagonists.  


Leukotriene-receptor antagonists are the first novel class of antiasthma drugs to become available over the past three decades. They have an unique profile in that they are a hybrid of an anti-inflammatory and bronchodilator drug, and they can be taken as a tablet once or twice daily. The published data with leukotriene-receptor antagonists such as montelukast or zafirlukast show good antiasthmatic activity over a wide spectrum of asthma severity either as monotherapy or with inhaled steroids. Another potential spin-off of leukotriene-receptor antagonists is that they also seem to be effective in treating allergic rhinitis, which commonly coexists in patients with asthma. Here I overview the clinical pharmacology of leukotriene antagonists and appraise the published data from clinical trials, and look at the appropriate position of these agents in asthma management guidelines. PMID:10023966

Lipworth, B J



6?-Azidohex-2?-yne-cannabidiol: a potential neutral, competitive cannabinoid CB 1 receptor antagonist  

Microsoft Academic Search

Previous experiments with the mouse vas deferens have shown that cannabidiol produces surmountable antagonism of cannabinoid CB1 receptor agonists at concentrations well below those at which it binds to cannabinoid CB1 receptors and antagonizes ?1-adrenoceptor agonists insurmountably. It also enhances electrically evoked contractions of this tissue. We have now found that subtle changes in the structure of cannabidiol markedly influence

Adèle Thomas; Ruth A Ross; Bijali Saha; Anu Mahadevan; Raj K Razdan; Roger G Pertwee



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



Effects of LY274614, a competitive NMDA receptor antagonist, on the micturition reflex in the urethane-anaesthetized rat.  

PubMed Central

1. The effects of 3 competitive N-methyl-D-aspartate (NMDA) receptor antagonists, LY274614, LY233536 and LY235723, on the micturition reflex and external urethral sphincter EMG activity, were examined either under isovolumetric conditions or during continuous filling cystometry in urethane-anaesthetized (1.2 g kg-1, s.c.) rats. 2. Intravenous administration of LY274614 (3-30 mg kg-1) inhibited in a dose-dependent fashion both bladder and sphincter activity in the intact rats. In addition, the volume threshold for inducing micturition was increased and voided volume was decreased. 3. Intrathecal administration of LY274614 (0.06-30 micrograms) similarly inhibited bladder and sphincter activity during cystometry in intact rats. 4. In chronic spinal cord (T6-T8) transected rats LY274614 (0.1-30 mg kg-1, i.v.) did not alter bladder activity under isovolumetric conditions but decreased the amplitude of micturition contractions and sphincter EMG activity during cystometry at a dose of 10-30 mg kg-1. 5. The inhibitory effects of i.v. administration of LY274614, on bladder and sphincter activity induced by infusion of chemical irritant (0.1% acetic acid) or saline, were similar; except that a slightly larger dose was needed to inhibit sphincter activity during acetic acid infusion. 6. Peak amplitude of micturition contractions recovered to 50% of control 3 h following i.v. (30 mg kg-1) or i.t. (6 micrograms) administration of LY274614. 7. Two other chemically related NMDA antagonists, LY233536 and LY235723 produced similar but less potent effects than LY274614 when given i.v. 8. These data indicate that glutamatergic transmitter mechanisms at the level of the spinal cord are important in modulating bladder activity in the intact animal, but that these mechanisms do not contribute to bladder reflexes in the chronic spinal rat. These mechanisms may, however, contribute to sphincter activity in both intact or chronic spinal rats.

Yoshiyama, M.; Roppolo, J. R.; Thor, K. B.; de Groat, W. C.



The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor.  


As the Ah receptor target gene products play a critical role in chemical carcinogenesis, antagonists are considered as potential chemopreventive agents. It is demonstrated in this paper that the isothiocyanates R,S-sulforaphane and erucin are non-competitive antagonists of the aryl hydrocarbon (Ah) receptor. Both isothiocyanates were poor agonists for the receptor and elevated CYP1A1 mRNA levels only modestly when incubated with precision-cut rat liver slices. In contrast, the classical Ah receptor agonist benzo[a]pyrene was a potent inducer of CYP1A1 mRNA levels, with this effect being effectively antagonized by the two isothiocyanates. In further studies, it was demonstrated that R,S-sulforaphane could both prevent the interaction of and displace already bound benzo[a]pyrene from the Ah receptor, but no concentration dependency was observed with respect to the isothiocyanate. Both erucin and R,S-sulforaphane antagonized the benzo[a]pyrene-mediated increase in the CYP1A-mediated O-deethylation of ethoxyresorufin in rat precision-cut liver slices. Of the two isomers of R,S-sulforaphane, the naturally occurring R-isomer was more effective than the S-isomer in antagonizing the activation of the Ah receptor by benzo[a]pyrene. Antagonism of the Ah receptor may be a major contributor to the established chemoprevention of aliphatic isothiocyanates. PMID:22643862

Abdull Razis, Ahmad F; Hanlon, Natalya; Soltys, Ewa; Krizova, Veronika; Iori, Renato; Plant, Kathryn E; Plant, Nick; Ioannides, Costas



Xanthines as Adenosine Receptor Antagonists  

PubMed Central

The natural plant alkaloids caffeine and theophylline were the first adenosine receptor (AR) antagonists described in the literature. They exhibit micromolar affinities and are non-selective. A large number of derivatives and analogs have subsequently been synthesized and evaluated as AR antagonists. Very potent antagonists have thus been developed with selectivity for each of the four AR subtypes.

Jacobson, Kenneth A.



The selective and competitive N-methyl-D-aspartate receptor antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid, prevents synaptic toxicity induced by amyloid-? in mice.  


The toxicity of amyloid ? (A?) is highly associated with Alzheimer's disease (AD), which has a high incidence in elderly people worldwide. While the current treatment for moderate and severe AD includes blockage of the N-methyl-d-aspartate receptor (NMDAR), the molecular mechanisms of its effect are still poorly understood. Herein, we report that a single i.p. administration of the selective and competitive (NMDAR) antagonist LY235959 reduced A? neurotoxicity by preventing the down-regulation of glial glutamate transporters (glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)), the decrease in glutamate uptake, and the production of reactive oxygen species (ROS) induced by A?(1-40). Importantly, the blockage of NMDAR restored the A?(1-40)-induced synaptic dysfunction and cognitive impairment. However, LY235959 failed to prevent the inflammatory response associated with A?(1-40) treatment. Altogether, our data indicate that the acute administration of A? promotes oxidative stress, a decrease in glutamate transporter expression, and neurotoxicity. Our results reinforce the idea that NMDAR plays a critical regulatory action in A? toxicity and they provide further pre-clinical evidence for the potential role of the selective and competitive NMDAR antagonists in the treatment of AD. PMID:21756976

Bicca, M A; Figueiredo, C P; Piermartiri, T C; Meotti, F C; Bouzon, Z L; Tasca, C I; Medeiros, R; Calixto, J B



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  

SciTech Connect

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{sub 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{sub 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{sub 2}?1??) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC{sub 50} = 0.0005 ?M), indicating a higher affinity of the compound for Torpedo (?1{sub 2}?1??) than for the mouse (?1{sub 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. -- Highlights: ? APS12-2 produces concentration-dependent inhibition of nerve-evoked muscle contraction in vitro. ? APS12-2 blocks MEPPs and EPPs at the neuromuscular junction. APS12-2 blocks ACh-activated current in Xenopus oocytes incorporated with Torpedo nAChRs.

Grandi?, Marjana [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia); Aráoz, Romulo; Molgó, Jordi [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Turk, Tom; Sep?i?, Kristina [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia)] [Department of Biology, Biotechnical Faculty, University of Ljubljana, Ve?na pot 111, SI-1000 Ljubljana (Slovenia); Benoit, Evelyne [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France)] [CNRS, Institut de Neurobiologie Alfred Fessard, FRC 2118, Laboratoire de Neurobiologie et Développement, UPR 3294, F-91198 Gif-sur-Yvette Cedex (France); Frangež, Robert, E-mail: [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)] [Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, University of Ljubljana, Gerbi?eva 60, SI-1000 Ljubljana (Slovenia)



Vitronectin receptor antagonists  

US Patent & Trademark Office Database

Compounds of formula (I) are disclosed, wherein: A is a fibrinogen antagonist template; W is a linking moiety of the form --(CHR.sup.g).sub.a --U--(CHR.sup.g).sub.b --V--; Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 are independently N or C--R.sup.y, provided that no more than one Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 is N; R' is H or C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.0-6 -alkyl or Ar--C.sub.0-6 alkyl; R.sup.g is H or C.sub.1-6 alkyl, Het-C.sub.0-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.0-6 alkyl or Ar--C.sub.0-6 alkyl; R.sup.k is R.sup.g, --C(O)R.sup.g or --C(O)OR.sup.g R.sup.i is H, C.sub.1-6 alkyl, Het-C.sub.0-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.0-6 alkyl, Ar--C.sub.0-6 alkyl, Het-C.sub.0-6 alkyl--U'--C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl-C.sub.0-6 alkyl--U'--C.sub.1-6 alkyl or Ar--C.sub.0-6 alkyl--U'--C.sub.1-6 alkyl; R.sup.y is H, halo, --OR.sup.g, --SR.sup.g, --CN, --NR.sup.g R.sup.k, --NO.sub.2, --CF.sub.3, CF.sub.3 S(O).sub.r, --CO.sub.2 R.sup.g, --COR.sup.g or --CONR.sup.g.sub.2, or C.sub.1-6 alkyl optionally substituted by halo, --OR.sup.g, --SR.sup.g, --CN, --NR.sup.8 R", --NO.sub.2, --CF.sub.3, R'S(O).sub.3 --, --CO.sub.2 R.sup.g, --COR.sup.g or --CONR.sup.g.sub.2 ; U and V are absent or CO, CR.sup.g.sub.2, C(.dbd.CR.sup.g.sub.2), S(O).sub.c, O, NR.sup.g, CR.sup.g OR.sup.g, CR.sup.g (OR.sup.k)CR.sup.g.sub.2, CR.sup.g.sub.7 CR.sup.g (OR.sup.k), C(O)CR.sup.g.sub.2, CR.sup.g.sub.2 C(O), CONR.sup.i, NR.sup.i CO, OC(O), C(O)O, OC(S), C(S)NR.sup.g, NR.sup.8 C(S), S(O.sub..sub.2 NR.sup.g, NR.sup.g S(O).sub.2 N.dbd.N, NR.sup.g NR.sup.g, NR.sup.g CR.sup.g.sub.2, NR.sup.g CR.sup.g.sub.2, CR.sup.g.sub.2 O, OCR.sup.g.sub.2, CR.sup.g .dbd.CR.sup.g, C.ident.C, Ar or Het; a is 0, 1 or 2; c is 0, 1 or 2; r is 0, 1 or 2; and u is 0 or 1; or pharmaceutically acceptable salts thereof, which are vitronectin receptor antagonists useful in the treatment of osteoporosis. ##STR1##



Structure-affinity relationship studies of non-competitive NMDA receptor antagonists derived from dexoxadrol and etoxadrol.  


The synthesis and NMDA receptor affinity of ring and side-chain homologues of etoxadrol and dexoxadrol are described. For the regioselective synthesis of etoxadrol homologues, the regioisomeric 4-azidobutanediols (+/-)-9 and (+/-)-14 were employed. A synthesis of the enantiomerically pure azidobutanediols (S)-, (R)-9 and (S)-, (R)-14 was developed and the homochiral building blocks were used for the synthesis of enantiomerically pure etoxadrol and dexoxadrol homologues. The affinity of the racemic and enantiomerically pure primary amines toward the phencyclidine binding site of the NMDA receptor was investigated in receptor binding studies with tritium labeled [3H]-(+)-MK-801 as radioligand. Benzaldehyde derivatives (+/-)-12a, (+/-)-13a, and (+/-)-16a bearing a proton at the acetalic position do not interact significantly with the NMDA receptor. An enantioselective NMDA receptor binding was observed for the trans-configured 2-(2-ethyl-2-phenyl-1,3-dioxolan-4-yl)ethanamine 13b, the (2-ethyl-2-phenyl-1,3-dioxan-4-yl)methanamine 16b, and the (2,2-diphenyl-1,3-dioxan-4-yl)methanamine 16c. The NMDA receptor affinity of these compounds resides almost exclusively in the (S)-configured enantiomers (2S,4S)-13b, (2S,4S)-16b, and (4S)-16c. The lowest Ki-value in this series was found for the (2S,4S)-configured 1,3-dioxolane (2S,4S)-13b (Ki = 69 nM), which is in the range of the Ki-value of the lead compounds etoxadrol and dexoxadrol, indicating that the 2-aminoethyl and the piperidin-2-yl substituents lead to similar NMDA receptor interactions. PMID:16169732

Aepkers, Marion; Wünsch, Bernhard



Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A-841720, a novel non-competitive mGluR1 receptor antagonist  

PubMed Central

Background and purpose: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. Experimental approach: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. Key results: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC50 values of 10.7±3.9 and 1.0±0.2?nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED50=23??mol?kg?1) and monoiodoacetate-induced joint pain (ED50=43??mol?kg?1). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED50=28 and 27??mol?kg?1, respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. Conclusions and implications. The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.

El-Kouhen, O; Lehto, S G; Pan, J B; Chang, R; Baker, S J; Zhong, C; Hollingsworth, P R; Mikusa, J P; Cronin, E A; Chu, K L; McGaraughty, S P; Uchic, M E; Miller, L N; Rodell, N M; Patel, M; Bhatia, P; Mezler, M; Kolasa, T; Zheng, G Z; Fox, G B; Stewart, A O; Decker, M W; Moreland, R B; Brioni, J D; Honore, P



Aldosterone antagonists destabilize the mineralocorticosteroid receptor.  

PubMed Central

To elucidate the mechanism of action of aldosterone antagonists, we studied the interaction of spironolactone with the chick mineralocorticosteroid receptor (MR). Intestinal cytosol contains specific spironolactone-binding sites (Kd approximately 3 nM; max. no. of binding sites approximately 100 fmol/mg of protein) that have been identified as MRs by competition experiments with steroid ligands and with the monoclonal anti-idiotypic antibody H10E that interacts with aldosterone-binding domain of the MR. Binding studies indicate that aldosterone and spironolactone bind to the MR through a common site that encompasses the epitope recognized by H10E. At 4 degrees C, spironolactone dissociates much more rapidly from the cytosol 8-9 S form of MR (t1/2 38 min) than does aldosterone (t1/2 3240 min). A high dissociation rate was also observed for progesterone, a natural aldosterone antagonist (t1/2 84 min). The covalent linkage of the 90 kDa heat shock protein (hsp90) to the ligand-binding subunit of MR with dimethyl pimelimidate did not notably modify the rate of dissociation of spironolactone from the receptor (t1/2 96 min), excluding the possibility that the rapid dissociation rate of the antagonist was related to hsp90 release. The effects of aldosterone and the two anti-mineralocorticosteroids on the 8-9 S heterooligomeric structure of the MR differed strikingly. Using low-salt density-gradient centrifugation analysis, aldosterone-labelled receptors were recovered as 8-9S complexes, whereas 4 S entities were detected after spironolactone and progesterone binding. This indicated that, under the experimental conditions used, aldosterone antagonists facilitate hsp90 release and thus do not stabilize the non-DNA-binding 8-9S form of MR. We propose that the combination of rapid dissociation of the ligand and a weakened hsp90-receptor interaction is involved in the anti-mineralococorticosteroid activity of aldosterone antagonists.

Couette, B; Lombes, M; Baulieu, E E; Rafestin-Oblin, M E



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



C5a receptor antagonists  

US Patent & Trademark Office Database

The present invention is related to a compound, preferably a C5a receptor antagonist, having the following structure, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21 and R22 are individually and independently selected from the group comprising H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, alkoxyl, substituted alkoxyl, aryloxy, substituted aryloxy, arylalkyloxy, substituted arylalkyloxy, acyloxy, substituted acyloxy, halogen, hydroxyl, nitro, cyano, acyl, substituted acyl, mercapto, alkylthio, substituted alkylthio, amino, substituted amino, alkylamino, substituted alkylamino, bisalkyl amino, substituted bisalkyl amino, cyclic amino, substituted cyclic amino, carbamoyl (--CONH.sub.2), substituted carbamoyl, carboxyl, carbamate, alkoxycarbonyl, substituted alkoxycarbonyl, acylamino, substituted acylamino, sulfamoyl (--SO.sub.2NH.sub.2), substituted sulfamoyl, haloalkyl, haloalkyloxy, --C(O)H, trialkylsilyl and azido. ##STR00001##



The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors.  


We have investigated the mechanism of inhibition and site of action of the novel human metabotropic glutamate receptor 5 (hmGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), which is structurally unrelated to classical metabotropic glutamate receptor (mGluR) ligands. Schild analysis indicated that MPEP acts in a non-competitive manner. MPEP also inhibited to a large extent constitutive receptor activity in cells transiently overexpressing rat mGluR5, suggesting that MPEP acts as an inverse agonist. To investigate the molecular determinants that govern selective ligand binding, a mutagenesis study was performed using chimeras and single amino acid substitutions of hmGluR1 and hmGluR5. The mutants were tested for binding of the novel mGluR5 radioligand [(3)H]2-methyl-6-(3-methoxyphenyl)ethynyl pyridine (M-MPEP), a close analog of MPEP. Replacement of Ala-810 in transmembrane (TM) VII or Pro-655 and Ser-658 in TMIII with the homologous residues of hmGluR1 abolished radioligand binding. In contrast, the reciprocal hmGluR1 mutant bearing these three residues of hmGluR5 showed high affinity for [(3)H]M-MPEP. Radioligand binding to these mutants was also inhibited by 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt), a structurally unrelated non-competitive mGluR1 antagonist previously shown to interact with residues Thr-815 and Ala-818 in TMVII of hmGluR1. These results indicate that MPEP and CPCCOEt bind to overlapping binding pockets in the TM region of group I mGluRs but interact with different non-conserved residues. PMID:10934211

Pagano, A; Ruegg, D; Litschig, S; Stoehr, N; Stierlin, C; Heinrich, M; Floersheim, P; Prezèau, L; Carroll, F; Pin, J P; Cambria, A; Vranesic, I; Flor, P J; Gasparini, F; Kuhn, R



Suramin is a slowly-equilibrating but competitive antagonist at P2x-receptors in the rabbit isolated ear artery.  

PubMed Central

1. The antagonist dynamics of suramin were investigated at P2x-receptors in isolated rings of endothelium-denuded ear artery from New Zealand White (NZW) rabbits. 2. alpha, beta-Methylene adenosine 5'-triphosphate (ATP) concentration-effect curves were constructed cumulatively in a paired curve design in the absence and presence of increasing concentrations of suramin, incubated for 45 min. The slope of the resulting Schild plot was significantly greater than unity (1.50 +/- 0.08). 3. Assuming that slow equilibration by suramin explains the steep Schild plot, further experiments were conducted using short (15 min) and long (3 h) incubation times. The resulting Schild plot slopes were 1.66 +/- 0.36 and 1.06 +/- 0.13 respectively confirming the assumption. However, after 3 h incubation, suramin also caused depression of alpha, beta-methylene ATP curves. 4. In an attempt to minimize the depressant effect of suramin, a kinetic study was designed to calculate the minimum incubation times for each concentration of suramin used in the Schild analysis to achieve effectively complete equilibrium. Theoretically fractional occupancy for the antagonist is given by (r - 1)/r, where r is the dose-ratio. A plot of (r - 1)/r against time allowed the apparent 'on' and 'off' rate constants to be calculated. 5. With the resulting rate constant estimates, an optimised antagonism study was carried out in which incubation times were chosen such that greater than 95% occupancy by suramin could be achieved without agonist curve depression at each concentration of suramin used.(ABSTRACT TRUNCATED AT 250 WORDS)

Leff, P.; Wood, B. E.; O'Connor, S. E.



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



Peripheral 5-HT2-like receptors. Can they be classified with the available antagonists?  

PubMed Central

Interactions between 5-hydroxytryptamine (5-HT) and the so-called 5-HT2 receptor antagonists ketanserin, spiperone, trazodone and methysergide were studied in isolated preparations of the rabbit aorta, rat jugular vein, and rat caudal artery. Trazodone and spiperone were apparently simple competitive antagonists since they produced antagonism that was surmountable over the concentration range studied and, in each tissue, their apparent affinity appeared to be independent of the antagonist concentration. Furthermore, concentration-ratios obtained with the two antagonists in combination suggested that antagonism was additive, implying mutual competition with a single population of 5-HT receptors. Ketanserin was a non-surmountable antagonist of 5-HT in the rat caudal artery and methysergide demonstrated surmountable, competitive antagonism only in the rabbit aorta. Antagonist dissociation constants estimated for apparently competitive interactions showed that ketanserin, spiperone and trazodone expressed affinities which differed according to the tissue used. In the case of trazodone, affinity estimates differed by as much as 12 fold. These discrepancies were independent of the 5-HT receptor agonist used and could not be attributed to an inadequate equilibration of the antagonist. These results can be interpreted in two ways: either the receptors in the different tissues are heterogeneous or the antagonists used here must be considered as unreliable probes for the classification of 5-HT2-like receptors.

Leff, P.; Martin, G. R.



Interaction of competitive antagonists: the anti-curare action of hexamethonium and other antagonists at the skeletal neuromuscular junction.  

PubMed Central

1. In the rat isolated diaphragm preparation hexamethonium and other low potency competitive antagonists of acetylcholine (ACh), including gallamine and hyoscine butylbromide, reverse block by the potent antagonists tubocurarine, pancuronium and alcuronium. 2. In the presence of tubocurarine, hexamethonium increases the amplitude of the end-plate potential without increasing the quantal content. It enhances the response to ACh applied iontophoretically to the end-plate but does not enhance the response to ACh applied in the bath. 3. The anti-curare effect of hexamethonium is abolished in the diaphragm of the rat, guinea-pig and mouse by inhibitors of acetylcholinesterase. The effect is not observed in the indirectly stimulated toad sartorius muscle. 4. The effect is explained if tubocurarine does not dissociate appreciably in the time taken for ACh to achieve high occupancy of receptors, so that a fraction of receptors is completely excluded from occupation by ACh. Equilibration with hexamethonium reduces the fraction excluded by tubocurarine and the transmitter now competes with hexamethonium for more receptors and produces a larger response. 5. On the basis of this explanation the half-time for dissociation of tubocurarine must be about 1 millisecond. It follows that tubocurarine does not act competitively with ACh at synapses when transmitter action is sufficiently brief, and that its binding to the receptor is probably diffusion-limited.

Blackman, J G; Gauldie, R W; Milne, R J



Identification of novel estrogen receptor ? antagonists  

Microsoft Academic Search

We have identified novel estrogen receptor alpha (ER?) antagonists using both cell-based and computer-based virtual screening strategies. A mammalian two-hybrid screen was used to select compounds that disrupt the interaction between the ER? ligand binding domain (LBD) and the coactivator SRC-3. A virtual screen was designed to select compounds that fit onto the LxxLL peptide-binding surface of the receptor, based

Dalei Shao; Thomas J. Berrodin; Eric Manas; Diane Hauze; Robert Powers; Ashok Bapat; Daniel Gonder; Richard C. Winneker; Donald E. Frail



Potent, selective MCH1 receptor antagonists  

Microsoft Academic Search

This paper describes the lead optimization of a new series of potent, selective, orally bioavailable, brain-penetrant MCH-1 receptor antagonists. A major focus of the work was to achieve a selectivity profile appropriate for in vivo efficacy studies and safety.

Shawn D. Erickson; Bruce Banner; Steven Berthel; Karin Conde-Knape; Fiorenza Falcioni; Irina Hakimi; Bernard Hennessy; Robert F. Kester; Kyungjin Kim; Chun Ma; Warren McComas; Francis Mennona; Steven Mischke; Lucy Orzechowski; Yimin Qian; Hamid Salari; John Tengi; Kshitij Thakkar; Rebecca Taub; Jefferson W. Tilley; Hong Wang



Quantitative structure activity relationship (QSAR) of competitive N-methyl-D-aspartate (NMDA) antagonists  

NASA Astrophysics Data System (ADS)

Glutamic acid is an excitatory amino acid neurotransmitter in the mammalian central nervous system and the NMDA molecule binds to NMDA-type glutamic acid receptors as a glutamic acid analogue, in vitro. The NMDA-type glutamic acid receptors are known for their function in many neural processes, such as neural plasticity, learning and memory. In addition, excessive NMDA receptor activity has been shown to be related to neurodegenerative diseases like epilepsy so the design of new NMDA antagonists has extra importance as potent drugs for various neural diseases. Potential antagonist molecules are usually synthesized and their activity is measured by experimental techniques. Here, computational chemistry methods are applied to develop a model, which allows one to predict the activity of potent competitive NMDA antagonists. First, various molecular parameters are calculated for a series of competitive NMDA antagonists with known activity values and those parameters are used to make a regression analysis which provides a model that relates the computationally calculated parameters to experimentally determined activity values. By the quantitative structure activity relationship (QSAR) model developed here, it is possible to predict the activity of a potent drug before its synthesis since only theoretically determined molecular parameters are used for the prediction.

Korkut, Anil; Varnali, Tereza


Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight  

Microsoft Academic Search

OBJECTIVE:This study was conducted to elucidate whether antagonistic targeting of the histamine H3 receptor increases hypothalamic histamine levels, in parallel with decreases in food intake and body weight.METHODS:The competitive antagonist potency of a recently synthesized histamine H3 receptor antagonist, NNC 38-1049, was studied in intact HEK293 cells expressing human or rat histamine H3 receptor, in which NNC 38-1049 was allowed

K Malmlöf; F Zaragoza; V Golozoubova; H H F Refsgaard; T Cremers; K Raun; B S Wulff; P B Johansen; B Westerink; K Rimvall



Development of ?-amino-carbonyl compounds as androgen receptor antagonists.  


Aim:Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel ?-amino-carbonyl-based androgen receptor antagonist.Methods:Different isomers of the ?-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts.Results:Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21-1 and 21-2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S).Conclusion:Compound 6012-4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo. PMID:24786235

Zhang, Zhi-Yun; Zhu, Yan-Hui; Zhou, Cai-Hong; Liu, Qing; Lu, Hui-Li; Ge, Yun-Jun; Wang, Ming-Wei



NMDA Receptor Antagonists for Treatment of Depression  

PubMed Central

Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.

Ates-Alagoz, Zeynep; Adejare, Adeboye



Muscarinic Receptor Antagonists: Effects on Pulmonary Function  

PubMed Central

In healthy lungs, muscarinic receptors control smooth muscle tone, mucus secretion, vasodilation, and inflammation. In chronic obstructive pulmonary disease (COPD) and asthma, cholinergic mechanisms contribute to increased bronchoconstriction and mucus secretion that limit airflow. This chapter reviews neuronal and nonneuronal sources of acetylcholine in the lung and the expression and role of M1, M2, and M3 muscarinic receptor subtypes in lung physiology. It also discusses the evidence for and against the role of parasympathetic nerves in asthma, and the current use and therapeutic potential of muscarinic receptor antagonists in COPD and asthma.

Buels, Kalmia S.



Pharmacological activity of retinoic acid receptor alpha-selective antagonists in vitro and in vivo  

PubMed Central

Oral administration of a retinoic acid receptor (RAR) pan-antagonist reversibly inhibits spermatogenesis. Given the importance of RAR? in regulating spermatogenesis, we identified two RAR?-selective antagonists by transactivation and transactivation competition assays and asked whether they effectively inhibit spermatogenesis. Although these two antagonists were potent in vitro, they displayed poor in vivo activity in mice when administered orally. Testicular weights were normal and morphological analysis revealed normal spermatid alignment and sperm release. In vitro drug property analyses were performed with one of these antagonists and compared with the pan-antagonist. We showed that the discrepancies may be explained by several factors, including high plasma protein binding, faster hepatic metabolism relative to the pan-antagonist, and only moderate permeability. The conclusion of poor oral bioavailability was supported by more pronounced defects in mice when the antagonist was administered intravenously versus intraperitoneally. These results are crucial for designing new RAR?-selective antagonists for pharmaceutical application.

Chung, Sanny S. W.; Cuellar, Rebecca A. D.; Wang, Xiangyuan; Reczek, Peter R.; Georg, Gunda I.; Wolgemuth, Debra J.



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



Continuous intracerebroventricular infusion of the competitive NMDA receptor antagonist, LY235959, facilitates escalation of cocaine self-administration and increases break point for cocaine in Sprague-Dawley rats  

PubMed Central

Although escalation of consumption is an important characteristic of cocaine dependence, the neurobiological mechanisms that mediate this phenomenon have not been fully described. In this study, we used male, Sprague-Dawley rats to measure the effects of acute and continuous intracerebroventricular (ICV) administration of the competitive NMDA receptor antagonist, LY235959, on cocaine self-administration behavior under various schedules of reinforcement and access conditions. Single ICV infusions of LY235959 (0.03 – 0.3 ?g/5 ?l) produced dose-dependent and statistically-significant decreases in the number of cocaine infusions earned under a progressive ratio schedule of reinforcement. In a second experiment, vehicle or LY235959 (0.2 – 0.3 ?g/day) was continuously administered ICV to rats via surgically implanted subcutaneous osmotic minipump/intracranial cannula assemblies. Both vehicle- and LY235959-treated rats significantly escalated cocaine self-administration over the 10 long access sessions; however, rats treated with LY235959 escalated cocaine self-administration faster and to a greater degree than vehicle-treated rats. There was a statistically significant increase in cocaine infusions earned under the PR schedule in LY235959-treated rats, but not vehicle-treated rats, after 10 long access cocaine self-administration sessions. These data support the hypothesis that escalation of cocaine consumption is mediated by hypo-glutamatergic tone in the central nervous system and this facilitation of escalation is associated with an increase in motivation to respond for cocaine.

Allen, Richard M.; Uban, Kristina A.; Atwood, Elizabeth M.; Albeck, David S.; Yamamoto, Dorothy J.



Implementation of a Fluorescence-Based Screening Assay Identifies Histamine H3 Receptor Antagonists Clobenpropit and Iodophenpropit as Subunit-Selective N-Methyl-d-Aspartate Receptor Antagonists  

PubMed Central

N-Methyl-d-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.

Hansen, Kasper B.; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L.; Yuan, Hongjie; Vance, Katie M.; Orr, Anna G.; Kvist, Trine; Ogden, Kevin K.; Le, Phuong; Vellano, Kimberly M.; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T. J.; Snyder, James P.; Brauner-Osborne, Hans



Phenylthiophenecarboxamide antagonists of the olfactory receptor co-receptor subunit from a mosquito.  


Insects detect environmental chemicals using chemosensory receptors, such as the ORs, a family of odorant-gated ion channels. Insect ORs are multimeric complexes of unknown stoichiometry, formed by a common subunit (the odorant receptor co-receptor subunit, Orco) and one of many variable subunits that confer odorant specificity. The recent discovery of Orco directed ligands, including both agonists and antagonists, suggests Orco as a promising target for chemical control of insects. In addition to competitively inhibiting OR activation by Orco agonists, several Orco antagonists have been shown to act through a non-competitive mechanism to inhibit OR activation by odorants. We previously identified a series of Orco antagonists, including N-(4-ethylphenyl)-2-thiophenecarboxamide (OX1a, previously referred to as OLC20). Here, we explore the chemical space around the OX1a structure to identify more potent Orco antagonists. Cqui\\Orco+Cqui\\Or21, an OR from Culex quinquefasciatus (the Southern House Mosquito) that responds to 3-methylindole (skatole) and is thought to mediate oviposition behavior, was expressed in Xenopus oocytes and receptor function assayed by two-electrode voltage clamp electrophysiology. 22 structural analogs of OX1a were screened for antagonism of OR activation by an Orco agonist. By varying the moieties decorating the phenyl and thiophene rings, and altering the distance between the rings, we were able to identify antagonists with improved potency. Detailed examination of three of these compounds (N-mesityl-2-thiophenecarboxamide, N-(4-methylbenzyl)-2-thiophenecarboxamide and N-(2-ethylphenyl)-3-(2-thienyl)-2-propenamide) demonstrated competitive inhibition of receptor activation by an Orco agonist and non-competitive inhibition of receptor activation by an odorant. The ability to inhibit OR activation by odorants may be a general property of this class of Orco antagonist, suggesting that odorant mediated behaviors can be manipulated through Orco antagonism. The high conservation of Orco across insect species and previous demonstrations that various Orco ligands are active at ORs derived from several different insect orders suggests that Orco antagonists may have broad applicability. PMID:24358366

Chen, Sisi; Luetje, Charles W



Cooperative Activation of Gene Expression by Agonists and Antagonists Mediated by Estrogen Receptor Heteroligand Dimer Complexes  

PubMed Central

Estrogen receptor (ER) antagonists are generally thought to inhibit estrogen action through competitive inhibition, resulting in receptor binding to antagonist rather than agonist. However, microarray analyses reveal a group of genes for which ER agonist and antagonist cooperatively regulate expression, suggesting additional models of combined agonist/antagonist action must exist. In conjunction with a chimeric reporter gene and two modified ERs, one [ER?(GSCKV)] with a mutation in the DNA-binding domain and the other (ER?-G521R) with a ligand-binding specificity mutation, we herein demonstrate that ER agonist and antagonist cooperatively activate gene expression through an ER heteroligand dimer complex (ER-HLD) consisting of one subunit of the receptor dimer bound to agonist and another occupied by antagonist. Coimmunoprecipitation experiments confirmed interaction between the agonist-bound and antagonist-bound receptors. This cooperative activation of gene expression was enhanced by steroid receptor coactivator 3 coactivator, and required each ligand-bound subunit of the dimer to bind to DNA, as well as both activation function 1 domains for maximal transcriptional activity. Ligand combinations able to induce ER-HLD transcriptional activity include the agonists 17?-estradiol or conjugated estrogens with the antagonists tamoxifen, raloxifene, bazedoxifene, or fulvestrant. Moreover, ER-HLD can activate transcription in the context of a natural promoter. Taken together, these findings broaden our understanding of the complex relationship between ER agonist and antagonist, and suggest a novel model by which cell and tissue selective effects of antiestrogens may be achieved.

Liu, Shuang; Han, Sang Jun



Ligands of the histamine H3-receptor: new potent antagonists of the 2-thioimidazole type.  


An overview of H3-receptor ligands is presented, with particular attention to antagonists. The protein binding of the classical H3-receptor antagonist thioperamide and its effect on in vivo distribution are discussed. A series of H3-receptor antagonists characterised by the presence of an imidazole ring, a spacer (ethylthio-, ethylamino-, propylthio- or propylamino-chain), a second heterocycle nucleus and a lipophilic group is described. Their H3-receptor antagonist potency has been measured on electrically stimulated guinea-pig intestine, and their affinity for central H3-receptor has been determined by competitive inhibition of [3H]N alpha-methylhistamine binding to rat cortex. Biphasic inhibition curves have been observed in some cases. Compounds endowed with interesting activity belong mostly to the class of 2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazole, having a phenyl or a cyclohexyl group. PMID:9274000

Plazzi, P V; Mor, M; Bordi, F; Silva, C; Rivara, S; Caretta, A; Ballabeni, V; Impicciatore, M; Vitali, T



Agonist Antagonist Interactions at the Rapidly Desensitizing P2X3 Receptor  

PubMed Central

P2X3 receptors (P2XRs), as members of the purine receptor family, are deeply involved in chronic pain sensation and therefore, specific, competitive antagonists are of great interest for perspective pain management. Heretofore, Schild plot analysis has been commonly used for studying the interaction of competitive antagonists and the corresponding receptor. Unfortunately, the steady-state between antagonist and agonist, as a precondition for this kind of analysis, cannot be reached at fast desensitizing receptors like P2X3R making Schild plot analysis inappropriate. The aim of this study was to establish a new method to analyze the interaction of antagonists with their binding sites at the rapidly desensitizing human P2X3R. The patch-clamp technique was used to investigate the structurally divergent, preferential antagonists A317491, TNP-ATP and PPADS. The P2X1,3-selective ?,?-methylene ATP (?,?-meATP) was used as an agonist to induce current responses at the wild-type (wt) P2X3R and several agonist binding site mutants. Afterwards a Markov model combining sequential transitions of the receptor from the closed to the open and desensitized mode in the presence or absence of associated antagonist molecules was developed according to the measured data. The P2X3R-induced currents could be fitted correctly with the help of this Markov model allowing identification of amino acids within the binding site which are important for antagonist binding. In conclusion, Markov models are suitable to simulate agonist antagonist interactions at fast desensitizing receptors such as the P2X3R. Among the antagonists investigated, TNP-ATP and A317491 acted in a competitive manner, while PPADS was identified as a (pseudo)irreversible blocker.

Helms, Nick; Kowalski, Maria; Illes, Peter; Riedel, Thomas



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



Update in TSH Receptor Agonists and Antagonists  

PubMed Central

The physiological role of the TSH receptor (TSHR) as a major regulator of thyroid function is well understood, but TSHRs are also expressed in multiple normal extrathyroidal tissues, and the physiological roles of TSHRs in these tissues are unclear. Moreover, TSHRs play a major role in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Small molecule, “drug-like” TSHR agonists, neutral antagonists, and inverse agonists may be useful as probes of TSHR function in extrathyroidal tissues and as leads to develop drugs for several diseases of the thyroid. In this Update, we review the most recent findings regarding the development and use of these small molecule TSHR ligands.

Neumann, Susanne



Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors.  


Bucindolol is a nonselective beta-adrenergic receptor antagonist that has additional vasodilating properties. Because some beta-adrenergic receptor antagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagonists, we tested the hypothesis that bucindolol can interact with 5-HT receptors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors-and with alpha1-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5-HT1A receptor (Ki, 11 nM), modest affinity for the 5-HT2A receptor (Ki, 382 nM), and no measurable affinity for the 5-HT1D receptor; binding affinity for the 5-HT2B receptor was not studied. Bucindolol also displayed significant binding affinity (Ki, 69 nM) for the alpha1-adrenergic receptors. Alpha1-Adrenergic receptor antagonist activity was confirmed by the ability of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01-30 microg/kg phenylephrine-induced pressor responses in conscious rats. In conscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did not cause bradycardia similar to that elicited by the 5-HT1A-receptor agonist 8-OH-DPAT (3-300 microg/kg, i.v.), nor did bucindolol (1 mg/kg) block the 8-OH-DPAT-induced bradycardia. Bucindolol (10(-9)-10(-5) M) did not cause relaxation in the PGF2alpha-contracted, endothelium-intact porcine coronary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary artery relaxation, indicating that bucindolol does not have significant interactions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta and rat stomach fundus, respectively), but did act as a weak 5-HT2A-receptor antagonist (-log K(B) [M] = 5.4+/-0.1) and 5-HT2B-receptor antagonist (-log K(B) [M] = 7.8+/-0.1). Thus, these data suggest that bucindolol lacks the ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha1-adrenergic receptors and act as a weak 5-HT2A- and 5-HT2B-receptor antagonist. The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown. PMID:10630730

Watts, S W; Fink, G D; Silver, P J; Cushing, D J



Dihydropyridine neuropeptide Y Y(1) receptor antagonists.  


Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip). PMID:11814801

Poindexter, Graham S; Bruce, Marc A; LeBoulluec, Karen L; Monkovic, Ivo; Martin, Scott W; Parker, Eric M; Iben, Larry G; McGovern, Rachel T; Ortiz, Astrid A; Stanley, Jennifer A; Mattson, Gail K; Kozlowski, Michael; Arcuri, Meredith; Antal-Zimanyi, Ildiko



Microscopic kinetics and energetics distinguish GABA(A) receptor agonists from antagonists.  

PubMed Central

Although agonists and competitive antagonists presumably occupy overlapping binding sites on ligand-gated channels, these interactions cannot be identical because agonists cause channel opening whereas antagonists do not. One explanation is that only agonist binding performs enough work on the receptor to cause the conformational changes that lead to gating. This idea is supported by agonist binding rates at GABA(A) and nicotinic acetylcholine receptors that are slower than expected for a diffusion-limited process, suggesting that agonist binding involves an energy-requiring event. This hypothesis predicts that competitive antagonist binding should require less activation energy than agonist binding. To test this idea, we developed a novel deconvolution-based method to compare binding and unbinding kinetics of GABA(A) receptor agonists and antagonists in outside-out patches from rat hippocampal neurons. Agonist and antagonist unbinding rates were steeply correlated with affinity. Unlike the agonists, three of the four antagonists tested had binding rates that were fast, independent of affinity, and could be accounted for by diffusion- and dehydration-limited processes. In contrast, agonist binding involved additional energy-requiring steps, consistent with the idea that channel gating is initiated by agonist-triggered movements within the ligand binding site. Antagonist binding does not appear to produce such movements, and may in fact prevent them.

Jones, M V; Jonas, P; Sahara, Y; Westbrook, G L



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



In Silico Discovery of Androgen Receptor Antagonists with Activity in Castration Resistant Prostate Cancer  

PubMed Central

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.

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



Synthesis of novel histamine H4 receptor antagonists.  


This letter describes the discovery and synthesis of a series of octahydropyrrolo[3,4-c]pyrrole based selective histamine hH4 receptor antagonists. The amidine compound 20 was found to be a potent and selective histamine H4 receptor antagonist with moderate clearance and a high volume of distribution. PMID:22189138

Lane, Charlotte A L; Hay, Duncan; Mowbray, Charles E; Paradowski, Michael; Selby, Matthew D; Swain, Nigel A; Williams, David H



Competitive NMDA receptor blockers reduce striatal glutamate accumulation in ischaemia.  


Our previous studies have shown that kynurenic acid, a broad-spectrum antagonist of excitatory amino acid receptors, depressed the ischaemia-induced accumulation of glutamate and aspartate in rat striatum. In the present experiments we examined the effect of two competitive N-methyl-D-aspartate (NMDA) receptor antagonists on striatal extracellular glutamate concentrations induced by a 30 min '4-vessel occlusion' ischaemia in rats. Local perfusion with 2-amino-5-phosphonovalerate (AP5; 300 microM) and with 2-amino-7-phosphonoheptanoate (AP7; 300 microM), using a microdialysis fibre markedly reduced the ischaemia-induced increase in glutamate concentrations. These results indicate that, during forebrain ischaemia the NMDA receptor type mediates glutamate and aspartate accumulation in rat striatum. PMID:7919176

Ghribi, O; Callebert, J; Plotkine, M; Boulu, R G



[Integrase inhibitors and CCR5 receptor antagonists].  


Integrase inhibitors and CCR5 receptor antagonists, novel class of antiretrovirals, were introduced into clinical practice in late 2000s. Currently available drugs in these classes, raltegravir and maraviroc, show good tolerability and have little impact on lipid or glucose metabolism compared to traditional classes. Disadvantage of these two drugs is the need for twice-daily dosing. The usefulness of raltegravir in both treatment-naïve and treatment-experienced setting has been well established through clinical trials and five years' clinical use, whereas the usefulness of maraviroc in treatment-naïve setting is still unclear. These drugs will be utilized as a key component of NRTI-sparing regimens in the future. PMID:22568139

Tsukada, Kunihisa



Comparison of the effects of pretreatment with competitive or noncompetitive NMDA antagonists on vestibular compensation.  


Unilateral labyrinthectomy (UL) results in a syndrome of ocular motor and postural disorders which abates over time in a process of behavioural recovery known as vestibular compensation. We have previously reported that a single systemic pre-UL injection of the organic Ca2+ channel antagonist verapamil or the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 reduces the behavioural effects of UL in guinea pigs. The present study was conducted to determine if similar effects would be obtained with single injections of the competitive NMDA receptor antagonists 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) or cis-4-(phosphonomethyl)-piperidine-2-carboxylic acid (CGS 19755). Guinea pigs received an IP injection of 5 mg/kg CPP 2.5 h pre-UL, 5 or 10 mg/kg CPP 1 h pre-UL, 10 or 20 mg/kg CGS 19755 1 h pre-UL, or 1 ml/kg vehicle (saline) 1 h pre-UL, and the effects on the compensation of spontaneous nystagmus were measured over the following 52 h post-UL. Pretreatment with CPP had no significant effect on spontaneous nystagmus frequency or its compensation over 52 h post-UL. However, pretreatment with CGS 19755 resulted in a significant decrease in spontaneous nystagmus frequency without any acceleration of the rate of compensation. PMID:8309959

Sansom, A J; Darlington, C L; Smith, P F



Characterization of a putative ?-MSH antagonist 153N-6 at melanocortin receptor subtypes by radioligand binding  

Microsoft Academic Search

This study was conducted to determine the binding properties of recently discovered, putative ?-MSH antagonist 153N-6 peptide at melanocortin receptor subtypes. The results indicated that 153N-6 peptide can competitively inhibit [125I]NDP-MSH binding from all the receptor subtypes investigated. The relative potency order of 153N-6 for inhibiting [125I]NDP-MSH binding was MC1R (Ki 955 ± 35.7 nM) = MC4R (Ki 1151 ±

Vijay Chhajlani



[Novel types of receptor antagonists from the medicinal plant Garcinia mangostana].  


A crude methanolic extract of the fruit hull of Garcinia mangostana L. inhibited the contraction of the isolated rabbit aorta induced by histamine and serotonin. The extract has been fractionated by silica gel chromatography, monitoring the pharmacological activity to give active compounds. On the basis of physicochemical data, the active substances were identified as alpha-mangostin and gamma-mangostin. To define the pharmacological properties of alpha-mangostin, the effect of alpha-mangostin on both histamine H1 and H2 receptors were examined by monitoring the mechanical responses of smooth muscles and measuring the radioligand binding to cultured vascular smooth muscle cells. The results suggest that alpha-mangostin acts as a selective and competitive histamine H1 receptor antagonist. The pharmacological actions of gamma-mangostin on 5-HT receptors were also investigated by using contractile response of vascular smooth muscle, platelet aggregation and radioligand binding studies. The results provide the evidence that gamma-mangostin is a selective and competitive 5-HT2A receptor antagonist. It is of great interest that the structures of alpha-mangostin and gamma-mangostin free from nitrogen atom are not resemble to the common structures of histamine and serotonin receptor antagonists. alpha-Mangostin and gamma-mangostin may become novel types of lead compounds for histamine and serotonin receptor antagonists. PMID:9503424

Furukawa, K; Chairungsrilerd, N; Ohta, T; Nozoe, S; Ohizumi, Y



?1-adrenergic receptor antagonists signal via PDE4 translocation  

PubMed Central

It is generally assumed that antagonists of Gs-coupled receptors do not activate cAMP signalling, because they do not stimulate cAMP production via Gs-protein/adenylyl cyclase activation. Here, we report a new signalling pathway whereby antagonists of ?1-adrenergic receptors (?1ARs) increase cAMP levels locally without stimulating cAMP production directly. Binding of antagonists causes dissociation of a preformed complex between ?1ARs and Type-4 cyclic nucleotide phosphodiesterases (PDE4s). This reduces the local concentration of cAMP-hydrolytic activity, thereby increasing submembrane cAMP and PKA activity. Our study identifies receptor/PDE4 complex dissociation as a novel mechanism of antagonist action that contributes to the pharmacological properties of ?1AR antagonists and might be shared by other receptor subtypes.

Richter, Wito; Mika, Delphine; Blanchard, Elise; Day, Peter; Conti, Marco



Melanocortins and their receptors and antagonists.  


The melanocortins are a group of small protein hormones derived by post-translational cleavage of the proopiomelanocortin (POMC) gene product. The known melanocortin hormones include alpha-melanocyte stimulating hormone (MSH), beta-MSH, gamma-MSH and adrenocorticotropic hormone (ACTH). Five melanocortin receptors (MCIR through to MC5R) have been identified and most of these show tissue-specific expression patterns, as well as different binding affinities for each of the melanocortin hormones. The central melanocortin system consists of alpha-MSH, agouti-related protein (AGRP), MC3R and MC4R. AGRP and alpha-MSH are believed to be the natural antagonist and agonist respectively of MC3R and MC4R. This central melanocortin system is thought to play a fundamental role in the control of feeding and body weight. Knock-out mice models and genetic studies have pointed to the importance of the melanocortins in complex human pathways such as pigmentation, lipolysis, food intake, thermogenesis, sexual behaviour, memory and inflammatory response. Recently the melanocortins and their receptors have been the target for drug-based treatment of human physiological processes. MC3R and MC4R are likely targets for controlling body weight; MCIR may be used in the treatment of inflammation and MC2R for the treatment of glucocortical deficiency. A role for MCSR still remains unclear, but the evidence suggests an exocrine gland function. PMID:14535656

Voisey, J; Carroll, L; van Daal, A



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



Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates  

SciTech Connect

The binding properties of (-)-(/sup 3/H)quinuclidinyl benzilate and (/sup 3/H) N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-(/sup 3/H)quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of (/sup 3/H)N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when (/sup 3/H)N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-(/sup 3/H) quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.

Lee, J.H.; el-Fakahany, E.E.



NMDA Receptor Antagonist Ketamine Impairs Feature Integration in Visual Perception  

PubMed Central

Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.

Meuwese, Julia D. I.; van Loon, Anouk M.; Scholte, H. Steven; Lirk, Philipp B.; Vulink, Nienke C. C.; Hollmann, Markus W.; Lamme, Victor A. F.



Action of agonists and antagonists at muscarinic receptors present on ileum and atria in vitro.  

PubMed Central

The action of 'selective' agonists and antagonists at muscarinic receptors mediating ileal contractions, and the rate and force of atrial contractions has been assessed. The effect of nicotinic receptor stimulation, catecholamine release and acetylcholinesterase (AChE) action on muscarinic activity has also been assessed. The nicotinic actions of carbachol did not affect its agonist potency nor the antagonist affinity data obtained when this agonist was used in atrial and ileal preparations. Antagonist data indicated that muscarinic receptors mediating the rate and force of atrial contractions did not differ. Differences in agonist potencies at these two muscarinic receptors were attributable to either differences in intrinsic efficacy or susceptibility to the action of acetylcholinesterase. The small differences in agonist potency observed between atrial and ileal muscarinic receptors were considered not sufficient to indicate receptor heterogeneity. The pirenzepine affinity data indicated that all three receptors are of the M2 type. Affinity data using secoverine and 4-diphenyl-acetoxy-N-methyl piperidine methiodide indicated that ileal and atrial muscarinic receptors differ. Data obtained using gallamine, pancuronium and stercuronium cannot be regarded as indicative of receptor affinity since the antagonism is not competitive; it did nonetheless corroborate the conclusion that ileal and atrial muscarinic receptors are different.

Clague, R. U.; Eglen, R. M.; Strachan, A. C.; Whiting, R. L.



Prostanoid receptor antagonists: development strategies and therapeutic applications  

PubMed Central

Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage.

Jones, RL; Giembycz, MA; Woodward, DF



Eprosartan mesylate, an angiotensin II receptor antagonist.  


The title compound, eprosartan mesylate {systematic name: 2-butyl-1-(4-carb-oxy-benz-yl)-5-[(E)-2-carb-oxy-3-(thio-phen-2-yl)prop-1-en-yl]-1H-imidazol-3-ium methane-sulfonate}, C(23)H(25)N(2)O(4)S(+)·CH(3)O(3)S(-), one of the angiotensin II-receptor antagonists, is effective in regulating hypertension, induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure and glaucoma. In the eprosartan residue, which appears in this crystal in the cationic imidazolium form, the benzene ring plane is almost orthogonal to that of the imidazole ring, making a dihedral angle of 87.89?(2)°. The thio-phene ring forms dihedral angles of 66.54?(2) and 67.12?(2)° with the benzene and imidazole rings, respectively. The imidazolium NH group and the H atom of the aromatic carboxyl group participate in hydrogen bonds with the the O atoms of the anion, thus forming centrosymmetric aggregates made up of two cations and two anions each. The second carboxyl group further links the above-mentioned aggregates through a conventional centrosymmetric hydrogen-bonding motif into infinite chains along [011]. PMID:21754064

Qian, Jing-Jing; Hu, Xiu-Rong; Gu, Jianming; Wu, Su-Xiang



Eprosartan mesylate, an angiotensin II receptor antagonist  

PubMed Central

The title compound, eprosartan mesylate {systematic name: 2-butyl-1-(4-carb­oxy­benz­yl)-5-[(E)-2-carb­oxy-3-(thio­phen-2-yl)prop-1-en­yl]-1H-imidazol-3-ium methane­sulfonate}, C23H25N2O4S+·CH3O3S?, one of the angiotensin II-receptor antagonists, is effective in regulating hypertension, induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure and glaucoma. In the eprosartan residue, which appears in this crystal in the cationic imidazolium form, the benzene ring plane is almost orthogonal to that of the imidazole ring, making a dihedral angle of 87.89?(2)°. The thio­phene ring forms dihedral angles of 66.54?(2) and 67.12?(2)° with the benzene and imidazole rings, respectively. The imidazolium NH group and the H atom of the aromatic carboxyl group participate in hydrogen bonds with the the O atoms of the anion, thus forming centrosymmetric aggregates made up of two cations and two anions each. The second carboxyl group further links the above-mentioned aggregates through a conventional centrosymmetric hydrogen-bonding motif into infinite chains along [011].

Qian, Jing-Jing; Hu, Xiu-Rong; Gu, Jianming; Wu, Su-Xiang



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



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



Therapeutic potential of histamine H3 receptor agonists and antagonists.  


The histamine H3 receptor was discovered 15 years ago, and many potent and selective H3 receptor agonists and antagonists have since been developed. Currently, much attention is being focused on the therapeutic potential of H3 receptor ligands. In this review, Rob Leurs, Patrizio Blandina, Clark Tedford and Henk Timmerman describe the available H3 receptor agonists and antagonists and their effects in a variety of pharmacological models in vitro and in vivo. The possible therapeutic applications of the various compounds are discussed. PMID:9652190

Leurs, R; Blandina, P; Tedford, C; Timmerman, H



Azaindoles as potent CRTH2 receptor antagonists.  


A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed. PMID:21185722

Simard, Daniel; Leblanc, Yves; Berthelette, Carl; Zaghdane, M Helmi; Molinaro, Carmela; Wang, Zhaoyin; Gallant, Michel; Lau, Stephen; Thao, Trinh; Hamel, Martine; Stocco, Rino; Sawyer, Nicole; Sillaots, Susan; Gervais, Francois; Houle, Robert; Lévesque, Jean-François



Identification of a novel conformationally constrained glucagon receptor antagonist.  


Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences. PMID:24418771

Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel



Preliminary mutational analysis of the human kinin B2 receptor for nonpeptide antagonist ligands recognition.  


FR173657, LF16,0335, and LF16,0687 are nonpeptide antagonists, endowed with high affinity and selectivity for the human kinin B2 receptor. The kinin B2 receptor belongs to the family of G-protein-coupled receptors with seven transmembrane (TM) helices. In the present study, we aimed, through computer-assisted modeling and mutagenesis, to identify residues in the human B2 receptor (hB2R) amino acid sequence that are involved in nonpeptide antagonist binding in order to build up experimental data as a first step towards a molecular model of nonpeptide ligands binding site. Fourteen amino acid residues within the TM segments were mutated to alanine. The wild type and mutant receptors were stably expressed in Chinese hamster ovary (dhfr-) cells and tested for their ability to bind agonist ([3H]bradykinin) and peptide antagonist ([3H]MENI 1270) radioligands. The affinity of nonpeptide ligands was determined by heterologous competition experiments using the above radioligands. We found that some mutations in TM2 (W86A) and TM7 (Y295A, N297A) impair the binding affinity of the three nonpeptide antagonists. On the other hand, some mutated residues in TM3 (S1 17A) and TM6 (W256A) reduce the affinity of LF16,0335 and LF16,0687 only. Results are discussed in order to build up a hypothesis for the likely different interactions of various nonpeptide ligands with the B2 receptor. PMID:12025965

Meini, Stefania; Cucchi, Paola; Zappitelli, Sabrina; Rotondaro, Luigi; Quartara, Laura; Giolitti, Alessandro; Maggi, Carlo Alberto



The Serotonin 5HT2A Receptors Antagonist M100907 Prevents Impairment in Attentional Performance by NMDA Receptor Blockade in the Rat Prefrontal Cortex  

Microsoft Academic Search

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

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



Pharmacology of an original and selective nonpeptide antagonist ligand for the human tachykinin NK 2 receptor  

Microsoft Academic Search

The pharmacological outline of a novel and original antagonist at the human tachykinin NK2 receptor is presented, namely MEN13510 (N-N?-bis-[2-(1H-indol-3-yl)-ethyl]-N,N?-bis-(3-thiomorpholin-4-yl-propyl)-phthalamide). MEN13510 retained nanomolar affinity for the human tachykinin NK2 receptor (Ki 6.4 nM), and micromolar affinity for the human tachykinin NK1 and NK3 receptors. A competitive antagonism is indicated by the Schild analysis (pKB 7.8, slope ?0.94) of concentration–response curves

Stefania Meini; Claudio Catalani; Francesca Bellucci; Paola Cucchi; Sandro Giuliani; Sabrina Zappitelli; Luigi Rotondaro; Franco Pasqui; Antonio Guidi; Maria Altamura; Alessandro Giolitti; Carlo Alberto Maggi



DR4004, a putative 5HT 7 receptor antagonist, also has functional activity at the dopamine D2 receptor  

Microsoft Academic Search

The tetrahydrobenzindole, 2a-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl)-2a,3,4,5-tetrahydrobenzo[cd]indol-2(1H)-one (DR4004) has been described as a highly selective antagonist for the 5-hydroxytryptamine7 (5-HT7) receptor [J. Med. Chem. 42 (1999) 533]. Consistent with original data, DR4004 bound to rat hypothalamic membranes with an affinity of 7.3±0.2 (pKi±S.E.M.) for the 5-HT7 receptor. However, competition binding studies showed that DR4004 had poor receptor selectivity with the following affinity profile; dopamine

Helen A Kogan; Charles A Marsden; Kevin C. F Fone



Biochemical and Pharmacological Profile of a Potent and Selective Nonpeptide Antagonist of the Neurotensin Receptor  

Microsoft Academic Search

We describe the characteristics of SR 48692, a selective, nonpeptide antagonist of the neurotensin receptor. In vitro, this compound competitively inhibits 125I-labeled neurotensin binding to the high-affinity binding site present in brain tissue from various species with IC50 values of 0.99 ± 0.14 nM (guinea pig), 4.0 ± 0.4 nM (rat mesencephalic cells), 7.6 ± 0.6 nM (COS-7 cells transfected

Danielle Gully; Maryse Canton; Robert Boigegrain; Francis Jeanjean; Jean-Charles Molimard; Martine Poncelet; Christiane Gueudet; Michel Heaulme; Roger Leyris; Aline Brouard; Didier Pelaprat; Catherine Labbe-Jullie; Jean Mazella; Philippe Soubrie; Jean-Pierre Maffrand; William Rostene; Patrick Kitabgi; Gerard Le Fur



Highlights of D1 dopamine receptor antagonist research.  


SCH 39166 is now undergoing clinical trials in schizophrenics as a selective D1 dopamine receptor antagonist. It differs from SCH 23390, the prototype D1 receptor antagonist, by having reduced affinity for serotonin receptors and a longer duration of action in primates, as measured in the squirrel monkey conditioned avoidance paradigm. Further studies on this difference in primates indicates that it may be attributable to reduced affinity of SCH 39166 compared to SCH 23390 for the hepatic glucuronosyltransferase system. Their affinities are similar in rats, a species in which both have similar duration of action. These and other studies presented are consistent with the novel profile of SCH 39166. PMID:1365409

Barnett, A; McQuade, R D; Tedford, C



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



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  

PubMed Central

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 (IP1) assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with Kb 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 (ROt1/2) compared to bosentan and ambrisentan (ROt1/2?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 IP1 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 ROt1/2 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.

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



Non-NMDA receptor antagonist-induced drinking in rat  

NASA Technical Reports Server (NTRS)

Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

Xu, Z.; Johnson, A. K.



Adenosine Receptor Antagonists and Retinal Neovascularization in Vivo  

Microsoft Academic Search

PURPOSE. The role of adenosine receptor (AdoR) antagonists in human retinal endothelial cell function in vitro has previously been determined. In this study, efficacy of AdoR antagonist administration in reducing retinal neovascularization was ex- amined in a mouse pup model of oxygen-induced retinopathy. METHODS. A previously described model of oxygen-induced retinal neovascularization in newborn mouse pups was used to examine

Robert P. Mino; Polyxenie E. Spoerri; Sergio Caballero; Luiz Belardinelli; Italo Biaggioni; Maria B. Grant



5HT 3 receptor antagonists and migraine therapy  

Microsoft Academic Search

Summary Neuronal 5-hydroxytryptamine3 (5-HT3) receptors mediate the excitatory effects of 5-HT. They are located in pain- and nausea-modulating areas in the central nervous system and on C-fibre primary afferents in the peripheral nervous system. Consequently, these receptors mediate the painful and emetic effects of 5-HT. Selective and potent 5-HT3 receptor antagonists have been shown to block inflammatory and 5-HT induced

M. D. Ferrari



Endothelin subtype A receptor antagonist induces osteopenia in growing rats  

Microsoft Academic Search

Previous studies suggested that endothelin (ET) peptides are involved in bone metabolism. We examined the effects of long-term blockade of the ETA receptor, a receptor subtype primarily involved in the anabolic actions of ET, on bone mineral status in growing rats. Eight-week-old rats injected intraperitoneally with FR139317 50 mg\\/kg body weight, a specific ETA receptor antagonist, for 2 or 4

Hirokazu Tsukahara; Chikahide Hori; Masahiro Hiraoka; Kazutaka Yamamoto; Yasushi Ishii; Mitsufumi Mayumi



Biarylcarboxybenzamide derivatives as potent vanilloid receptor (VR1) antagonistic ligands  

Microsoft Academic Search

Seventeen biarylcarboxybenzamide derivatives were prepared for the study of their agonistic\\/antagonistic activities to the vanilloid receptor (VR1) in rat DRG neurons. The replacement of the piperazine moiety of the lead compound 1 with phenyl ring showed quite enhanced antagonistic activity. Among the prepared derivatives, N-(4-tert-butylphenyl)-4-pyridine-2-yl-benzamide (2, IC50=31nM) and N-(4-tert-butylphenyl)-4-(3-methylpyridine-2-yl)benzamide (3g, IC50=31nM), showed 5-fold higher antagonistic activity than 1 in 45Ca2+-influx

Hyeung-geun Park; Ji-yeon Choi; Mi-hyun Kim; Sea-hoon Choi; Mi-kyung Park; Jihye Lee; Young-Ger Suh; Hawon Cho; Uhtaek Oh; Hee-Doo Kim; Yung Hyup Joo; Song Seok Shin; Jin Kwan Kim; Yeon Su Jeong; Hyun-Ju Koh; Young-Ho Park; Sang-sup Jew



SRA880, in vitro characterization of the first non-peptide somatostatin sst(1) receptor antagonist.  


This report describes the in vitro features of the first somatostatin sst(1) receptor selective non-peptide antagonist, SRA880 ([3R,4aR,10aR]-1,2,3,4,4a,5,10,10a-Octahydro-6-methoxy-1-methyl-benz[g] quinoline-3-carboxylic-acid-4-(4-nitro-phenyl)-piperazine-amide, hydrogen malonate). SRA was evaluated in a number of in vitro systems of various species, both at native and recombinant receptors, using radioligand binding and second messenger/transduction studies. SRA880 has high affinity for native rat, mouse, monkey and human cerebral cortex somatostatin sst(1) receptors (pK(d) = 7.8-8.6) and for human recombinant sst(1) receptors (pK(d) = 8.0-8.1). SRA880 displayed significantly lower affinity for the other human recombinant somatostatin receptors ( pK(d) < or = 6.0) or a wide range of neurotransmitter receptors, except for the human dopamine D4 receptors. SRA880 was characterized in various transduction assays: somatotropin release inhibiting factor (SRIF) induced inhibition of forskolin-stimulated cAMP accumulation, SRIF stimulated-GTPgammaS binding, and SRIF stimulated luciferase gene expression; in all tests, SRA880 was devoid of intrinsic activity and acted as an apparently surmountable antagonist with pK(B) values of 7.5-7.7. Combined with the data from binding studies, these results suggest that SRA880 acts as a competitive antagonist. Thus, SRA880 is the first non-peptide somatostatin sst(1) receptor antagonist to be reported; SRA880 will be a useful tool for the characterization of somatostatin sst(1) receptor-mediated effects both in vitro and in vivo. PMID:15135911

Hoyer, D; Nunn, C; Hannon, J; Schoeffter, P; Feuerbach, D; Schuepbach, E; Langenegger, D; Bouhelal, R; Hurth, K; Neumann, P; Troxler, T; Pfaeffli, P



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



Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain  

PubMed Central

Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.

Bendix, Ivo; Serdar, Meray; Herz, Josephine; von Haefen, Clarissa; Nasser, Fatme; Rohrer, Benjamin; Endesfelder, Stefanie; Felderhoff-Mueser, Ursula; Spies, Claudia D.; Sifringer, Marco



Diffusion-limited reactions in G-protein activation: Unexpected Consequences of Antagonist and Agonist Competition  

PubMed Central

In this work, we ask whether the simultaneous movement of agonist and antagonist among surface receptors (i.e. continually associating and dissociating from individual receptors according to specified kinetics) has any unexpected consequences for G-protein activation and receptor desensitization. A Monte Carlo model framework is used to track the diffusion and reaction of individual receptors, allowing the requirement for receptors and G-proteins or receptors and kinases to find each other by diffusion (collision coupling) to be implemented explicitly. We find that at constant agonist occupancy the effect of an antagonist on both G-protein activation and the ratio of G-protein activation to receptor desensitization can be modulated by varying the antagonist dissociation kinetics. The explanation for this effect is that antagonist dissociation kinetics influence the ability of agonists to access particular receptors and thus reach G-proteins and kinases near those receptors. Relevant parameter ranges for observation of these effects are identified. These results are useful for understanding experimental and therapeutic situations when both agonist and antagonist are present, and in addition may offer new insights into insurmountable antagonism.

Brinkerhoff, Christopher J.; Choi, Ji Sun



Triterpenes from Alisma orientalis act as androgen receptor agonists, progesterone receptor antagonists, and glucocorticoid receptor antagonists.  


Alisma orientalis, a well-known traditional medicine, exerts numerous pharmacological effects including anti-diabetes, anti-hepatitis, and anti-diuretics but its bioactivity is not fully clear. Androgen receptor (AR), progesterone receptor (PR), and glucocorticoid receptor (GR) are three members of nuclear receptor superfamily that has been widely targeted for developing treatments for essential diseases including prostate cancer and breast cancer. In this study, two triterpenes, alisol M 23-acetate and alisol A 23-acetate from Alisma orientalis were determined whether they may act as androgen receptor (AR), progesterone receptor (PR), or glucocorticoid receptor (GR) modulators. Indeed, in the transient transfection reporter assays, alisol M 23-acetate and alisol A 23-acetate transactivated AR in dose-dependent manner, while they transrepressed the transactivation effects exerted by agonist-activated PR and GR. Through molecular modeling docking studies, they were shown to respectively interact with AR, PR, or GR ligand binding pocket fairly well. All these results indicate that alisol M 23-acetate and alisol A 23-acetate from Alisma orientalis might possess therapeutic effects through their modulation of AR, PR, and GR pathways. PMID:24915879

Lin, Hsiang-Ru



Medicinal chemistry of A2A adenosine receptor antagonists.  


Due to the clearly demonstrated receptor-receptor interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, the discovery and development of potent and selective A(2A)adenosine receptor antagonists became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Different compounds have been deeply investigated as A(2A) adenosine receptor antagonists, which could be classified in two great families: xanthine derivatives and nitrogen poliheterocyclic systems. These studies led to the discovery of some highly potent and selective A(2A) adenosine receptor antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002), which have been used as pharmacological tools for studying this receptor subtype. However, those compounds showed some problems that do not permit their use in clinical studies, such as poor water solubility (SCH58261, and xanthine derivatives) or good affinity for A(2B) adenosine receptor subtype (ZM241385). In the last few years great efforts have been made to overcome these problems, trying to optimize not only the pharmacological profile but also the pharmacokinetic character of this class of compounds. The aim of this report is to briefly summarize the recent progress made in this attractive field of research. PMID:12570758

Cacciari, Barbara; Pastorin, Giorgia; Spalluto, Giampiero



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



Fluorescent Human EP3 Receptor Antagonists  

PubMed Central

Exchange of the lipophilc part of ortho-substituted cinnamic acid lead structures with different small molecule fluorophoric moieties via a dimethylene spacer resulted in hEP3R ligands with affinities in the nanomolar concentration range. Synthesized compounds emit fluorescence in the blue, green, and red range of light and have been tested concerning their potential as a pharmacological tool. hEP3Rs were visualized by confocal laser scanning microscopy on HT-29 cells, on murine kidney tissues, and on human brain tissues and functionally were characterized as antagonists on human platelets. Inhibition of PGE2 and collagen-induced platelet aggregation was measured after preincubation with novel hEP3R ligands. The pyryllium-labeled ligand 8 has been shown as one of the most promising structures, displaying a useful fluorescence and highly affine hEP3R antagonists.



Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists.  


The purpose of the present studies was to compare a novel series of alkoxy-oxazolyl-tetrahydropyridines (A-OXTPs) as muscarinic receptor antagonists. The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2 receptors in brainstem, and [3H]oxotremorine-M to high affinity muscarinic agonist binding sites in cortex. All of the compounds had higher affinity for [3H]pirenzepine than for [3H]QNB or [3H]oxotremorine-M labeled receptors, consistent with an interpretation that they are relatively selective M1 receptor antagonists, although none were as selective as pirenzepine. In addition, dose-response curves were determined for antagonism of oxotremorine-induced salivation (mediated by M3 receptors) and tremor (mediated by non-M1 receptors) in mice. In general, the A-OXTPs were equipotent and equieffective in antagonizing both salivation and tremor, although there were modest differences for some compounds. Dose-response curves also were determined on behavior maintained under a spatial-alternation schedule of food presentation in rats as a measure of effects on working memory. The A-OXTPs produced dose-related decreases in percent correct responding at doses three- to ten-fold lower than those which decreased rates of responding. However, only one compound, MB-OXTP, produced effects on percent correct responding consistent with a selective effect on memory as opposed to non-memory variables. The present results provide evidence that these alkoxy-oxazolyl-tetrahydropyridines are a novel series of modestly M1-selective muscarinic receptor antagonists, and that one member of the series, MB-OXTP, appears to be more selective in its effects on memory than previously studies muscarinic antagonists. PMID:7753969

Shannon, H E; Bymaster, F P; Hendrix, J C; Quimby, S J; Mitch, C H



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



Pharmacological characterization of EK112, a new combined angiotensin II and thromboxane A(2) receptor antagonist.  


The pharmacological characterization of EK112, a new combined angiotensin II and thromboxane A(2) receptor blocking agent, was examined in this study. EK112 was found to be a angiotensin II receptor antagonist, as revealed by its competitive antagonism of angiotensin II-induced smooth muscle contraction (pA(2) value of 7. 63 +/- 0.14) in rabbit aorta. It also had an angiotensin II blocking action in guinea pig ileum (pA(2) value of 7.87 +/- 0.67). Additionally, EK112 also possessed thromboxane A(2) receptor blocking activity, since it competitively antagonized aortic contractile responses elicited by U46619 and PGF(2alpha)(pK(B) values of 6.67 +/- 0.09 and 6.24 +/- 0.09, respectively) in rat. In contrast, EK112 did not affect the contractile responses to many other receptor agonists. EK112 did not mimic that of the angiotensin-converting enzyme (ACE) inhibitor, captopril, to enhance the muscle contraction elicited by bradykinin in guinea pig ileum, suggesting that EK112 did not inhibit ACE. Neither cyclic AMP nor cyclic GMP content in rat aortic rings was changed by EK112. These data demonstrate that EK112 is a selective antagonist of angiotensin II > thromboxane A(2) thromboxane A(2) receptor. PMID:10793265

Hwang, T L; Yeh, Y A; Chern, J W; Teng, C M



Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure  

PubMed Central

Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses. Methods We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex (PFC) neurons. Results The results demonstrate that acute treatment with the non-competitive NMDA channel blocker ketamine or the selective NR2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonia and anxiogenic behaviors. We also find that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (EPSCs) in layer V pyramidal neurons in the PFC, and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin (mTOR) protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in an mTOR-dependent manner.

Li, Nanxin; Liu, Rong-Jian; Dwyer, Jason M.; Banasr, Mounira; Lee, Boyoung; Son, Hyeon; Li, Xiao-Yuan; Aghajanian, George; Duman, Ronald S.



Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y13 receptor  

PubMed Central

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 synthesized and tested. A 6-benzyl-5?-methyl phosphonate analogue was prepared to examine the effect of stable replacement of the azo linkage. The highest antagonistic potency was observed for 6-(3-nitrophenylazo) derivatives of pyridoxal-5?-phosphate. The 2-chloro-5-nitro analogue (MRS 2211) and 4-chloro-3-nitro analogue (MRS 2603) inhibited ADP (100 nM)-induced inositol trisphosphate (IP3) formation with pIC50 values of 5.97 and 6.18, respectively, being 45- and 74-fold more potent than PPADS. The antagonism of MRS 2211 was competitive with a pA2 value of 6.3. MRS2211 and MRS2603 inhibited phospholipase C (PLC) responses to 30 nM 2-methylthio-ADP in human P2Y1 receptor-mediated 1321N1 astrocytoma cells with IC50 values of >10 and 0.245 ?M, respectively. Both analogues were inactive (IC50 > 10 ?M) as antagonists of human P2Y12 receptor-mediated PLC responses in 1321N1 astrocytoma cells. Thus, MRS2211 displayed >20-fold selectivity as antagonist of the P2Y13 receptor in comparison to P2Y1 and P2Y12 receptors, while MRS2603 antagonized both P2Y1 and P2Y13 receptors.

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



Antidiuretic effects of the endothelin receptor antagonist avosentan.  


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 ET(A) receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ET(B) receptors may occur. Incremental doses of the predominant ET(A) 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 ET(B) 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 ET(B) receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with predominant ET(A) receptor blockers. PMID:22529820

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



Novel benzopolycyclic amines with NMDA receptor antagonist activity.  


A new series of benzopolycyclic amines active as NMDA receptor antagonists were synthesized. Most of them exhibited increased activity compared with related analogues previously published. All the tested compounds were more potent than clinically approved amantadine and one of them displayed a lower IC50 value than memantine, an anti-Alzheimer's approved drug. PMID:24698811

Valverde, Elena; Sureda, Francesc X; Vázquez, Santiago



The effects of NMDA receptor antagonists at anticonvulsive doses on the performance of rats in the water maze task.  


In the present study we investigated the effects of two competitive NMDA receptor antagonists, CGP 37849 (DL-(E)-2-amino-4-methyl-phosphono-3-pentonoic acid) and CGP 39551 (carboxyethyl ester of CGP 37849) as well as MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenz(a,d)cycloheptene-5,10-imine hydrogen maleate), a non-competitive antagonist, administered systemically before training, on the acquisition of a water maze task used to assess spatial learning and memory in rats. The competitive NMDA receptor antagonists dose dependently impaired water maze acquisition (increased escape distance), but did not significantly affect swimming speed in rats. MK-801 induced clear behavioral effects and impaired the acquisition of the water maze task. However, as training advanced drug-treated rats did show a decrease in distance swam per trial before encountering the platform in the water pool. This suggests that drug treatments did not abolish learning. When the anticonvulsive properties of the drugs were determined, MK-801 did not show any protection in the maximal electroshock (MES) test at doses already impairing the acquisition of the water maze task while the two competitive NMDA receptor antagonists protected the rats against seizures at doses not impairing acquisition. This result suggests a wider therapeutic range for CGP 39551 and especially for CGP 37849 than for MK-801 in the treatment of epilepsy. PMID:7768268

Ylinen, A; Pitkänen, M; Sirviö, J; Hartikainen, T; Sivenius, J; Koivisto, E; Riekkinen, P J



The cardio-selectivity of himbacine: a muscarine receptor antagonist  

Microsoft Academic Search

The antimuscarinic actions of himbacine were compared with those of atropine and\\/or homatropine on atria, ileum and trachea from guinea-pigs and rat uterus preparations.1.The antagonism of acetylcholine or carbachol by all the antagonists was competitive on the preparations studied. The pA2 values of himbacine in all smooth muscle preparations were similar )around 7.2) whereas in atria it exhibited about 10-fold

S. Anwar-ul; H. Gilani; L. B. Cobbin



Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats  

Microsoft Academic Search

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly “forgetting” curve

B. J. Cole; M. Klewer; G. H. Jones; D. N. Stephens



Nociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs.  


Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) were identified in the mid 90s as a novel peptidergic system structurally related to opioids. A growing body of preclinical evidence suggests that blockade of NOP receptors evokes antidepressant-like actions. These have been explored using a range of compounds (peptide and non peptide antagonists), across different species (rat and mouse) and assays (behavioral despair and chronic mild stress) suggesting a robust and consistent antidepressant-like effect. Moreover, rats and mice knockout for the NOP receptor gene display an antidepressant-like phenotype in behavioral despair assays. Electrophysiological, immunohistochemical and neurochemical studies point to an important role played by monoaminergic systems, particularly 5-HTergic, in mediating the antidepressant-like properties of NOP antagonists. However other putative mechanisms of action, including modulation of the CRF system, circadian rhythm and a possible neuroendocrine-immune control might be involved. A close relationship between the N/OFQ-NOP receptor system and stress responses is well described in the literature. Stressful situations also alter endocrine, behavioral and neurochemical parameters in rats and chronic administration of a NOP antagonist restored these alterations. Interestingly, clinical findings showed that plasma N/OFQ levels were significantly altered in major and post-partum depression, and bipolar disease patients. Collectively, data in the literature support the notion that blockade of NOP receptor signaling could be a novel and interesting strategy for the development of innovative antidepressants. PMID:23711793

Gavioli, Elaine Cristina; Calo', Girolamo



Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists.  


Intracellular calcium ([Ca(2+)]i) influx through N-methyl-d-aspartic acid (NMDA) receptors in cortical neurons is central to NMDA receptor-mediated excitotoxicity. Drugs that uncompetitively modulate NMDA receptor-mediated [Ca(2+)]i influx are potential leads for development to treat NMDA receptor-mediated neuronal damage since these drugs spare NMDA receptor normal functions. Ligands to alpha(2)-adrenoceptors and imidazoline I(2) receptors confer neuroprotection possibility through modulating NMDA receptor-mediated [Ca(2+)]i influx. Here, we investigated the characteristics of several ligands to alpha(2)-adrenoceptors and imidazoline I(2) receptor, in inhibiting NMDA receptor-mediated [Ca(2+)]i influx in cultured cortical neurons using a ratiometric calcium imaging technique. In contrast to MK801, which non-reversibly blocks NMDA receptor-mediated [Ca(2+)]i influx, imidazoline I(2) receptor antagonists, Idazoxan, and 2-(2-benzofuranyl)-2-imidazoline (2-BFI)-mediated inhibition of [Ca(2+)]i influx can be rapidly reversed when removed, in a manner similar to that of memantine, an uncompetitive antagonist to NMDA receptors. Interestingly, ligands to alpha(2)-adrenoceptors, including agmatine sulfate and yohimbine, and a ligand to the nicotinic receptor, levamisol, neither inhibited NMDA receptor-mediated [Ca(2+)]i influx, nor provided neuroprotection against glutamate toxicity, suggesting selective inhibition of NMDA receptor activities. The inhibition of NMDA receptor by Idazoxan and 2-BFI also led to the suppression of NMDA receptor-mediated calpain activity as a result of blocking NMDA receptor activity, rather than through direct inhibition of calpain activity. Collectively, these studies demonstrated that imidazoline I(2) receptor antagonists transiently and reversibly block NMDA receptor-mediated [Ca(2+)]i influx. These compounds are leads for further development as uncompetitive antagonists to NMDA receptor-mediated excitotoxicity. PMID:19958763

Jiang, Susan X; Zheng, Rong-Yuan; Zeng, Jin-Qi; Li, Xiao-Li; Han, Zhao; Hou, Sheng T



MEN15596, a novel nonpeptide tachykinin NK 2 receptor antagonist  

Microsoft Academic Search

The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies

Cecilia Cialdai; Manuela Tramontana; Riccardo Patacchini; Alessandro Lecci; Claudio Catalani; Rose-Marie Catalioto; Stefania Meini; Claudio Valenti; Maria Altamura; Sandro Giuliani; Carlo Alberto Maggi



Thermodynamic analysis of antagonist and agonist interactions with dopamine receptors.  


The binding of [3H]spiperone to dopamine D-2 receptors and its inhibition by antagonists and agonists were examined in microsomes derived from the sheep caudate nucleus, at temperatures between 37 and 1 degree C, and the thermodynamic parameters of the binding were evaluated. The affinity of the receptor for the antagonists, spiperone and (+)-butaclamol, decreased as the incubation temperature decreased; the affinity for haloperidol did not further decrease at temperatures below 15 degrees C. The binding of the antagonists was associated with very large increases in entropy, as expected for hydrophobic interactions. The enthalpy and entropy changes associated with haloperidol binding were dependent on temperature, in contrast to those associated with spiperone and (+)-butaclamol. The magnitude of the entropy increase associated with the specific binding of the antagonists did not correlate with the degree of lipophilicity of these drugs. The data suggest that, in addition to hydrophobic forces, other forces are also involved in the antagonist-dopamine receptor interactions, and that a conformational change of the receptor could occur when the antagonist binds. Agonist binding data are consistent with a two-state model of the receptor, a high-affinity state (RH) and a low-affinity state (RL). The affinity of dopamine binding to the RH decreased with decreasing temperatures below 20 degrees C, whereas the affinity for the RL increased at low temperatures. In contrast, the affinity of apomorphine for both states of receptor decreased as the temperature decreased from 30 to 8 degrees C. A clear distinction between the energetics of high-affinity and low-affinity agonist binding was observed. The formation of the high-affinity complex was associated with larger increases in enthalpy and entropy than the interaction with the low-affinity state was. The results suggest that the interaction of the receptor with the G-proteins, induced or stabilized by the binding of agonist, leads to an increase in entropy and to negative heat capacity changes in the system. PMID:2452751

Duarte, E P; Oliveira, C R; Carvalho, A P



O R I G I N A L A R T I C L E NMDA receptor antagonists reduce restraint-induced release of prolactin in male rats  

Microsoft Academic Search

OBJECTIVE: To investigate the effects of N-methyl-D-aspartate (NMDA) recep- tor antagonists on restraint-induced release of prolactin (PRL) in male Wistar rats of different ages. DESIGN: Rats were implanted with a brain ventricular for icv injection, and with a jugular vein cannula for iv injection. Competitive NMDA receptor antagonist AP-5 and noncompetitive NMDA receptor blocker MK-801 was injected via brain cannula

Jian-Xiang Liu; Ji-Zeng Du; Sayaka Asai; Zhan-Quan Shi; Gen Watanabe; Kazuyoshi Taya


Antagonist-induced intracellular sequestration of rabbit bradykinin B(2) receptor.  


In a contractility assay based on the rabbit jugular vein, the structurally related drugs NPC 17731 or icatibant (1 to 3 nmol/L) were insurmountable antagonists of bradykinin (BK) B(2) receptors (B(2)Rs). After ample washing (3 hours), the antagonism exerted by these peptides was not reversible. By contrast, the antagonist LF 16. 0687 (30 to 100 nmol/L) was competitive and reversible. A rabbit B(2)R-green fluorescent protein (B(2)R-GFP) conjugate was expressed in mammalian cells. In COS-1 cells, it exhibited an affinity for [3H]BK (K(D)=1.61 nmol/L) similar to that of the wild-type rabbit B(2)R. The stably expressed construction in HEK-293 cells was functionally active (phospholipase A(2) assay), and the antagonists mentioned above retained their respective surmountable or insurmountable behavior. Competition of [(3)H]BK binding to B(2)R-GFP by the antagonists or BK was largely reversible after a 3-hour washout period at 0 degrees C; at 37 degrees C, icatibant or NPC 17731 effects were not reversible. B(2)R-GFP was visualized in the plasma membranes of HEK-293 cells and rapidly internalized in response to BK. NPC 17731 or icatibant slowly translocated B(2)R-GFP into cells over 24 hours, whereas LF 16.0687 had no effect on the subcellular distribution of B(2)R-GFP. Cell extract immunoblotting with anti-GFP antibodies revealed a 101- to 105-kDa protein that was not significantly degraded on 24 hours of cell treatment with any of the ligands but was translocated in part to the 15 000-g pellet of the extract on treatment with BK or the noncompetitive antagonists. NPC 17731 and icatibant are noncompetitive, nonequilibrium antagonists that promote the cellular sequestration of rabbit B(2)R expressed in an heterologous system. PMID:10856284

Houle, S; Larrivée, J F; Bachvarova, M; Bouthillier, J; Bachvarov, D R; Marceau, F



Androgen Receptor Antagonists in Castration-Resistant Prostate Cancer  

PubMed Central

Persistent androgen receptor signaling despite low levels of serum androgens has been identified as a critical target for drug discovery in castration-resistant prostate cancer. As proof of principle that the androgen receptor remains relevant in castration-resistant prostate cancer, two recently FDA-approved androgen receptor–targeted agents—abiraterone and enzalutamide—have increased overall survival for patients with castration-resistant prostate cancer in the setting of prior chemotherapy. This review focuses on the androgen receptor and two direct antagonists, enzalutamide and ARN-509. These next-generation androgen receptor antagonists offer great promise for patients with advanced disease. Relative to conventional antiandrogens such as bicalutamide, they bind to the receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity in preclinical models. The success of these androgen receptor–targeted agents in the clinic has changed the landscape of therapy for patients with castration-resistant prostate cancer, and further therapeutic options building on this platform are currently in development.

Rathkopf, Dana; Scher, Howard I.



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



Common and uncommon behavioural effects of antagonists for different modulatory sites in the NMDA receptor/channel complex.  


The behavioural significance of the N-methyl-D-aspartate (NMDA) receptor/channel complex was investigated in rats, using different types of antagonists including D-2-amino-phosphonovaleric acid, (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid, 7-Cl kynurenate, ifenprodil, phencyclidine (PCP), MK-801, ketamine, (+/-)-N-allylnormetazocine, dextromethorphan, ZnCl2, and MgCl2. All antagonists produced an impairment of learning and muscle relaxation when administered i.c.v. Frequent circling was characteristically produced by ligands for PCP binding sites and was unaffected by concomitant administration of a competitive NMDA receptor antagonist. These results suggest that the NMDA receptor/channel plays an important role in regulating learning/memory processes and muscle tone, whereas PCP binding sites unassociated with the NMDA channel are involved in the production of characteristic circling behaviour. PMID:8223917

Murata, S; Kawasaki, K



Competitive antagonism at thromboxane receptors in human platelets.  

PubMed Central

The inhibitory effects of three prostanoid analogues, EP 045, EP 092 and pinane thromboxane A2 (PTA2), on the aggregation of human platelets in vitro have been investigated. In diluted platelet-rich plasma (PRP), EP 045 (20 microM) and EP 092 (1 microM) completely inhibited irreversible aggregation responses to thromboxane A2 (TXA2), prostaglandin H2 (PGH2) and five chemically stable thromboxane mimetics, including 11,9-epoxymethano-PGH2 and 9,11-azo-PGH2. Reversible aggregation produced by the prostanoid analogue, CTA2, was also inhibited. The block of the stable agonist action was surmountable. In plasma-free platelet suspensions EP 045 and EP 092 were more potent antagonists. Schild analysis indicated a competitive type of antagonism for EP 045 (affinity constant of 1.1 X 10(7) M-1); the nature of the EP 092 block is not clear. Primary aggregation waves induced by ADP, platelet activating factor (Paf) and adrenaline were unaffected by EP 045 and EP 092, whereas the corresponding second phases of aggregation were suppressed. Aggregation and 5-hydroxytryptamine (5-HT) release induced by either PGH2 or 11,9-epoxymethano-PGH2 were inhibited in a parallel manner by EP 045. Inhibition of thromboxane biosynthesis is not involved in these effects. EP 045 and EP 092 did not raise adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in the platelet suspensions. In plasma-free platelet suspensions PTA2 produced a shape change response which could be blocked by EP 045. PTA2, therefore, has a thromboxane-like agonist action. The block of the aggregatory action of 11,9-epoxymethano-PGH2 by PTA2 appears to be mainly due to competition at the thromboxane receptor. However, PTA2 produced a slight rise in cyclic AMP levels; this could be due to a very weak stimulant action on either PGI2 or PGD2 receptors present in the human platelet. Functional antagonism by PTA2 may therefore augment its thromboxane receptor blocking activity. The results are discussed in terms of (a) the specificity of antagonism produced by EP 045, EP 092 and PTA2, (b) the validity of affinity constant determinations for receptor antagonists when aggregation is the biological response, and (c) the characteristics of the human platelet thromboxane receptor in comparison with those of thromboxane receptors in smooth muscle.

Armstrong, R. A.; Jones, R. L.; Peesapati, V.; Will, S. G.; Wilson, N. H.



Decorin is a novel antagonistic ligand of the Met receptor  

PubMed Central

Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (Kd = ?1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life = ?6 min). Decorin suppresses intracellular levels of ?-catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, decorin contributes to reduction in primary tumor growth and metastastic spreading.

Goldoni, Silvia; Humphries, Ashley; Nystrom, Alexander; Sattar, Sampurna; Owens, Rick T.; McQuillan, David J.; Ireton, Keith



Nicotinic receptor antagonists as treatments for nicotine abuse.  


Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the ?4?2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at ?3?2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While ?-conotoxin MII (?-CtxMII)-insensitive nAChRs (e.g., ?4?2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, ?-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at ?-CtxMII-sensitive nAChR subtypes that contain ?6 and ?2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, nonquaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1nM) nicotine-evoked DA release in vitro by acting as antagonists at ?-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats. PMID:24484986

Crooks, Peter A; Bardo, Michael T; Dwoskin, Linda P



Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine.  


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. PMID:24133375

Funder, John W



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



Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.  


The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function. PMID:24039134

Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah



N-methyl-D-aspartate receptor antagonists potentiate the antinociceptive effects of morphine in squirrel monkeys.  


Data from rodent antinociception models indicate that N-methyl-D-aspartate (NMDA) receptor antagonists do not produce antinociception alone or potentiate morphine antinociception, but do attenuate the development of morphine tolerance. This study examined the antinociceptive effects of the noncompetitive NMDA receptor antagonist dizocilpine, the competitive NMDA receptor antagonist (-)-6-phosphonomethyl-decahydroisoquinoline-3-carboxylic acid (LY235959), and the glycine-site antagonist (+)-(1-hydroxy-3-aminopyrrolidine-2-one) [(+)-HA-966], alone and in combination with morphine in a squirrel monkey titration procedure. In this procedure, shock (delivered to the tail) increased in intensity every 15 s from 0.01 to 2.0 mA in 30 increments. Five lever presses during any given 15-s shock period produced a 15-s shock-free period after which shock resumed at the next lower intensity. Morphine (0.3-3.0 mg/kg i.m.) dose-dependently increased the intensity below which monkeys maintained shock 50% of the time (median shock level; MSL). In contrast, dizocilpine (0.003-0.1 mg/kg i.m.) produced only modest increases in MSL in some monkeys (three of five) at the highest dose tested. Neither LY235959 (0.1-1.0 mg/kg i.m.) or (+)-HA-966 (10-56 mg/kg i.m.) increased MSL in any monkey tested. Dizocilpine, LY235959, and (+)-HA-966, when administered in combination with doses of morphine (1.0 mg/kg, 1.7 mg/kg) that either produced no antinociception or produced very little antinociception, were all found to dose-dependently potentiate the antinociceptive effect of morphine. Importantly, although these NMDA antagonists in combination with morphine produced marked increases in MSL, these combinations did not alter response rate, demonstrating that the potentiation was not due to nonspecific motor effects. PMID:11408554

Allen, R M; Dykstra, L A



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.



Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist.  


We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol - 5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AII) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT1 receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contraction of rabbit aortic rings by AII was antagonized by SC-52458 in a competitive and reversible manner (pA2 of 8.18). SC-52458 had no effect on the activity of angiotensin converting enzyme (ACE) or renin in vitro. In normotensive rats, administration of SC-52458, either intravenously (i.v.) or by gavage, inhibited the pressor response to AII. Daily treatment with SC-52458 at 20, 30, and 50 mg/kg by gavage for 4 days decreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-deficient dogs demonstrated that oral administration of SC-52458 decreased BP and that this activity was correlated with significant plasma levels of the compound. SC-52458 is an orally active, competitive AT1-receptor antagonist with antihypertensive properties. PMID:7505365

Olins, G M; Corpus, V M; Chen, S T; McMahon, E G; Palomo, M A; McGraw, D E; Smits, G J; Null, C L; Brown, M A; Bittner, S E



Pharmacology of an original and selective nonpeptide antagonist ligand for the human tachykinin NK2 receptor.  


The pharmacological outline of a novel and original antagonist at the human tachykinin NK2 receptor is presented, namely MEN13510 (N-N'-bis-[2-(1H-indol-3-yl)-ethyl]-N,N'-bis-(3-thiomorpholin-4-yl-propyl)-phthalamide). MEN13510 retained nanomolar affinity for the human tachykinin NK2 receptor (Ki 6.4 nM), and micromolar affinity for the human tachykinin NK1 and NK3 receptors. A competitive antagonism is indicated by the Schild analysis (pK(B) 7.8, slope -0.94) of concentration-response curves of NKA induced inositolphosphates accumulation in Chinese hamster ovary (CHO) cells expressing the human NK2 receptor in the presence of MEN13510 (30-300 nM concentration range). The MEN13510 interaction with the human NK2 receptor was evaluated by means of heterologous inhibition binding experiments, by using agonist and antagonist radioligands ([125I]NKA, [3H]nepadutant, [3H]saredutant) at a series of mutant receptors having single aminoacidic substitutions of residues located in transmembrane (TM) segments 3, 4, 5, 6, and 7. MEN13510 affinity was not affected by the mutations in TM 3 and 4 (Q109A, F112A, T171A, C167G), and it was reduced by 10-fold at the I202F mutant, but not at the Y206A (TM4). Amongst the investigated mutants bearing the mutated residues in TM6 (F270A, Y266F, W263A) only F270A decreased the MEN13510 affinity by 7-fold. Even mutations in TM7 did reduce MEN13510 affinity by 32-fold (Y289T, but not Y289F) and 13-fold (F293A). Studied mutations represent the human tachykinin NK2 receptor discriminants involved in the binding of previously reported peptidic and nonpeptidic antagonists, against which results obtained with MEN13510 are compared. Results indicate that the binding site of this antagonist is, at least in part, overlapping to that described for NKA or saredutant. Finally we show that MEN13510 retains nanomolar affinity for the recently discovered splice variant of the human tachykinin NK2 receptor, namely beta isoform, as it has been described for the nonpeptide antagonist saredutant. PMID:15925360

Meini, Stefania; Catalani, Claudio; Bellucci, Francesca; Cucchi, Paola; Giuliani, Sandro; Zappitelli, Sabrina; Rotondaro, Luigi; Pasqui, Franco; Guidi, Antonio; Altamura, Maria; Giolitti, Alessandro; Maggi, Carlo Alberto



Therapeutic brain concentration of the NMDA receptor antagonist amantadine  

Microsoft Academic Search

Amantadine (1-amino-adamantane) is clinically used for the management of Parkinson's disease and drug-induced extrapyramidal symptoms. It has previously been shown that amantadine is a low-affinity uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with rapid blocking and unblocking channel kinetics (Ki-value at the PCP binding site = 10 ?M). The aim of the present studies was to estimate concentrations of amantadine in the

J. Kornhuber; G. Quack; W. Danysz; K. Jellinger; W. Danielczyk; W. Gsell; P. Riederer



Menetrier's disease: evolution of disease under histamine-2 receptor antagonists.  


A 33-yr-old man, with known peptic disease, developed giant thickening of the gastric mucosa and hypoproteinemia. Serial endoscopic and x-ray examinations of the upper gastrointestinal tract were available before and after the development of Menetrier's disease. In a 1-yr interval, erosive gastritis developed in a normal gastric mucosa, which was followed a few months later by hypoproteinemia. The patient developed the disease while being treated with histamine-2 receptor antagonists. PMID:1595656

Geist, M; Fich, A; Mogle, P



Energy Restriction Negates NMDA Receptor Antagonist Efficacy in Ischemic Stroke  

Microsoft Academic Search

Preclinical evaluation of drugs for neurological disorders is usually performed on overfed rodents, without consideration\\u000a of how metabolic state might affect drug efficacy. Using a widely employed mouse model of focal ischemic stroke, we found\\u000a that that the NMDA receptor antagonist dizocilpine (MK-801) reduces brain damage and improves functional outcome in mice on\\u000a the usual ad libitum diet, but exhibits

Jeong Seon Yoon; Mohamed R. Mughal; Mark P. Mattson


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 potential of endothelin receptors agonists and antagonists.  


Endothelins are potent predominantly vasoconstricting agents that act as local autocrine and paracrine mediators. Endothelin-1 is the most potent and sustained vasoconstrictor and pressor substance yet identified. Abnormalities of the endothelin system occur in a range of diseases associated with vasoconstriction, vasospasm, and vascular hypertrophy. ET receptor antagonists were until recently regarded as drugs of great promise in patients with congestive heart failure, pulmonary hypertension and others. The aim of this article is a survey of compounds that affect the endothelin receptors and clinical trials with these agents. PMID:16259315

Patocka, Jirí; Merka, Vladimír; Hrdina, Vratislav; Hrdina, Radomír



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)



Vasopressin antagonists block peripheral as well as central vasopressin receptors.  


The aim of the present study was to differentiate between the postulated central behavioral effects of vasopressin and its pressor response, which is mainly mediated by peripheral vascular receptors. Thus, the interaction between the vasopressor antagonists dPTyr(Me)AVP (AAVPa) and d(CH2)5Tyr(Me)AVP (AAVPb) with the effects of [Arg8]vasopressin (AVP-(1-9)) and [pGlu4,Cyt6]AVP-(4-8) (referred to as AVP-(4-8)) was examined using passive avoidance behavior and the pressor response as parameters. AVP-(4-8) was approximately 4 and 200 times more potent than AVP-(1-9) in facilitating passive avoidance behavior after subcutaneous (SC) or intracerebroventricular (ICV) administration respectively. This effect of SC injected AVP-(1-9) and AVP-(4-8) could be prevented by both vasopressor antagonists following SC treatment. A similar antagonistic action was found when AVP-(1-9) or AVP-(4-8) and the antagonist AAVPb were administered ICV. SC injection of AAVPb prevented the behavioral effect of ICV administered AVP-(1-9) while ICV treatment with the antagonist blocked the behavioral action of systemically injected AVP-(1-9) and AVP-(4-8). In contrast to SC injected AVP-(1-9) which dose-dependently increased blood pressure and decreased heart rate, AVP-(4-8) injected SC in identical doses did not affect blood pressure and heart rate, neither did AVP-(1-9) and AVP-(4-8) when injected ICV in behaviorally active doses. A SC, but not an ICV injection of the antagonist AAVPb could prevent the blood pressure increase and bradycardia induced by SC AVP-(1-9).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6093152

De Wied, D; Gaffori, O; Van Ree, J M; De Jong, W



Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine  

PubMed Central

The clinical effectiveness of antagonizing the calcitonin gene-related peptide (CGRP) receptor for relief of migraine pain has been clearly demonstrated, but the road to the development of these small molecule antagonists has been daunting. The key hurdle that needed to be overcome was the CGRP receptor itself. The vast majority of the current antagonists recognize similar epitopes on the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). RAMP1 is a relatively small, single, transmembrane-spanning protein and along with the G-protein-coupled receptor CLR comprise a functional CGRP receptor. The tri-helical extracellular domain of RAMP1 plays a key role in the high affinity binding of CGRP receptor antagonists and drives their species-selective pharmacology. Over the years, a significant amount of mutagenesis data has been generated to identify specific amino acids or regions within CLR and RAMP1 that are critical to antagonist binding and has directed attention to the CLR/RAMP1 extracellular domain (ECD) complex. Recently, the crystal structure of the CGRP receptor ECD has been elucidated and not only reinforces the early mutagenesis data, but provides critical insight into the molecular mechanism of CGRP receptor antagonism. This review will highlight the drug design hurdles that must be overcome to meet the desired potency, selectivity and pharmacokinetic profile while retaining drug-like properties. Although the development of these antagonists has proved challenging, blocking the CGRP receptor may one day represent a new way to manage migraine and offer hope to migraine sufferers. LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein-Coupled Receptors. To view the other articles in this section visit

Moore, Eric L; Salvatore, Christopher A



Muscarinic Receptor Agonists and Antagonists: Effects on Cancer  

PubMed Central

Many epithelial and endothelial cells express a cholinergic autocrine loop in which acetylcholine acts as a growth factor to stimulate cell growth. Cancers derived from these tissues similarly express a cholinergic autocrine loop and ACh secreted by the cancer or neighboring cells interacts with M3 muscarinic receptors expressed on the cancer cells to stimulate tumor growth. Primary proliferative pathways involve MAPK and Akt activation. The ability of muscarinic agonists to stimulate, and M3 antagonists to inhibit tumor growth has clearly been demonstrated for lung and colon cancer. The ability of muscarinic agonists to stimulate growth has been shown for melanoma, pancreatic, breast, ovarian, prostate and brain cancers, suggesting that M3 antagonists will also inhibit growth of these tumors as well. As yet no clinical trials have proven the efficacy of M3 antagonists as cancer therapeutics, though the widespread clinical use and low toxicity of M3 antagonists support the potential role of these drugs as adjuvants to current cancer therapies.



An antagonist peptide–EPO receptor complex suggests that receptor dimerization is not sufficient for activation  

Microsoft Academic Search

Dimerization of the erythropoietin (EPO) receptor (EPOR), in the presence of either natural (EPO) or synthetic (EPO-mimetic peptides, EMPs) ligands is the principal extracellular event that leads to receptor activation. The crystal structure of the extracellular domain of EPOR bound to an inactive (antagonist) peptide at 2.7 Å resolution has unexpectedly revealed that dimerization still occurs, but the orientation between

Oded Livnah; Dana L. Johnson; Enrico A. Stura; Francis X. Farrell; Francis P. Barbone; Yun You; Kathleen D. Liu; Mark A. Goldsmith; Wen He; Christopher D. Krause; Sidney Pestka; Linda K. Jolliffe; Ian A. Wilson



Bombesin receptor antagonists [corrected]. 1. Analogues with deleted, inverted or substituted amino acid residues.  


Bombesin is a 14-residue peptide hormone which serves a variety of biological functions, including cell growth control in Swiss 3T3 cultured fibroblasts. It has been also involved in an autocrine system regulating the growth of small cell lung carcinoma. A series of bombesin analogues were developed by amino acid deletion, inversion or substitution in the carboxy-terminal region, identified by the target cell receptor. Their properties were examined for: i) competitive binding assays; ii) mitogenic induction and inhibition assays; iii) effects on early cellular events (inositol phosphates production and protein tyrosine phosphorylation). Inversion of the Trp residue, or deletion of the C-terminal tripeptide amide, induced complete loss of receptor affinity and biological effects. Deletion of the His residue, or its derivatization as His (Dnp) in conjunction with Met deletion or modification, gave rise to compounds with reduced receptor affinity and weak antagonistic properties. Other modifications in the C-terminal tripeptide affected the potency but not the biological profile of the parent peptide. These results indicate the basis for the eventual design of improved, specific bombesin receptor antagonists and stimulate further studies on their possible application in the therapy of human small cell lung cancer. PMID:1965286

De Castiglione, R; Gozzini, L; Mena, R; Brugnolotti, M; Ciomei, M; Molinari, I; Comoglio, P M; Gaudino, G



Lactam Constraints Provide Insights into the Receptor-Bound Conformation of Secretin and Stabilize a Receptor Antagonist  

PubMed Central

The natural ligands for family B G protein-coupled receptors are moderate length linear peptides having diffuse pharmacophores. The amino-terminal regions of these ligands are critical for biological activity, with their amino-terminal truncation leading to production of orthosteric antagonists. The carboxyl-terminal regions of these peptides are thought to occupy a ligand-binding cleft within the disulfide-bonded amino-terminal domains of these receptors, with the peptides in amphipathic helical conformations. In the current work, we have characterized the binding and activity of a series of 11 truncated and lactam-constrained secretin(5-27) analogues at the prototypic member of this family, the secretin receptor. One peptide in this series with lactam connecting residues 16 and 20 (c[E16,K20][Y10]sec(5-27)) improved the binding affinity of its unconstrained parental peptide 22-fold, while retaining absence of endogenous biological activity and competitive antagonist characteristics. Homology modeling with molecular mechanics and molecular dynamics simulations established that this constrained peptide occupies the ligand-binding cleft in orientation similar to natural full-length secretin, and provided insights into why this peptide was more effective than other truncated conformationally-constrained peptides in the series. This lactam bridge is believed to stabilize an extended ?-helical conformation of this peptide while in solution and to not interfere with critical residue-residue approximations while docked to the receptor.

Dong, Maoqing; Te, Jerez A.; Xu, Xiequn; Wang, Jinhui; Pinon, Delia I.; Storjohann, Laura; Bordner, Andrew J.; Miller, Laurence J.



Comparative antagonist pharmacology at the native mouse bradykinin B2 receptor: radioligand binding and smooth muscle contractility studies  

PubMed Central

Background and purpose: The aim was to characterize the recently discovered non-peptide antagonist MEN16132 at the mouse B2 receptor, relative to other antagonists. Experimental approach: [3H]-BK binding experiments used mouse lung and ileum tissue membranes and antagonist potency was measured in the isolated ileum contractility assay. Key results: Two BK binding sites resulted from saturation and homologous competition experiments. A role for the B1 receptor was excluded because of the poor affinity of B1 receptor ligands (pIC50 <5). MEN16132, and the other reference antagonists, inhibited only one portion of BK specific binding, and the rank order of potency was (pIC50): Icatibant (lung 10.7; ileum 10.2)=MEN11270 (lung 10.4; ileum 9.9)=MEN16132 (lung 10.5; ileum 9.9). > LF16-0687 (lung 8.9; ileum 8.8) > FR173657 (lung 8.6; ileum 8.2). BK homologous curves performed with lung membranes after treatment with the antagonist MEN16132 or Icatibant (10 nM) displayed only the low affinity site. The functional antagonism by MEN16132 (pA2 9.4) and Icatibant (pA2 9.1), towards BK (control EC50 6.1 nM) induced ileum contractions, was concentration-dependent and surmountable, but the Schild plot slope was less than unity. Conclusions and Implications: In mouse tissue, radiolabelled BK recognizes two binding sites and B2 receptor antagonists can compete only for the higher affinity one. The pharmacological profile of the novel non-peptide antagonist MEN16132 indicates that it exhibits subnanomolar affinity and potency for the mouse B2 receptor and is suitable for further characterization in in vivo pathophysiological models.

Meini, S; Cucchi, P; Bellucci, F; Catalani, C; Giuliani, S; Santicioli, P; Maggi, C A



Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat  

PubMed Central

BACKGROUND AND PURPOSE Neurocognitive disorders afflict approximately 20% of HIV-infected patients. HIV-1-infected cells in the brain shed viral proteins such as transactivator of transcription (Tat). Tat elicits cell death and synapse loss via processes initiated by NMDA receptor activation but mediated by separate downstream signalling pathways. Subunit selective NMDA receptor antagonists may differentially modulate survival relative to synaptic changes. EXPERIMENTAL APPROACH Tat-evoked cell death was quantified by measuring propidium iodide uptake into rat hippocampal neurons in culture. The effects of Tat on synaptic changes were measured using an imaging-based assay that quantified clusters of the scaffolding protein postsynaptic density 95 fused to green fluorescent protein. KEY RESULTS Dizocilpine, a non-competitive NMDA receptor antagonist, inhibited Tat-induced synapse loss, subsequent synapse recovery and Tat-induced cell death with comparable potencies. Memantine (10 µM) and ifenprodil (10 µM), which preferentially inhibit GluN2B-containing NMDA receptors, protected from Tat-induced cell death with no effect on synapse loss. Surprisingly, memantine and ifenprodil induced synapse recovery in the presence of Tat. In contrast, the GluN2A-prefering antagonist TCN201 prevented synapse loss and recovery with no effect on cell death. CONCLUSIONS AND IMPLICATIONS Synapse loss is a protective mechanism that enables the cell to cope with excess excitatory input. Thus, memantine and ifenprodil are promising neuroprotective drugs because they spare synaptic changes and promote survival. These GluN2B-preferring drugs induced recovery from Tat-evoked synapse loss, suggesting that synaptic pharmacology changed during the neurotoxic process. NMDA receptor subtypes differentially participate in the adaptation and death induced by excitotoxic insult.

Shin, AH; Kim, HJ; Thayer, SA



Design and synthesis of N-alkylated saccharins as selective ?-1a adrenergic receptor antagonists  

Microsoft Academic Search

Benign prostatic hyperplasia can be managed pharmacologically with ?-1 adrenergic receptor antagonists. Agents that demonstrate selectivity for the ?-1 a receptor subtype may offer advantages in clinical applications with respect to hypotensive side effects. The N-alkylated saccharins reported here represent a new class of subtype selective ?-1 a adrenergic receptor antagonists which demonstrate potent effects on prostate function in vivo

Jennie B. Nerenberg; Jill M. Erb; Wayne J. Thompson; Hee-Yoon Lee; James P. Guare; Peter M. Munson; Jeffrey M. Bergman; Joel R. Huff; Theodore P. Broten; Raymond S. L. Chang; Tsing B. Chen; Stacey O'Malley; Terry W. Schorn; Ann L. Scott



Substituted Tetrahydroisoquinolines as Selective Antagonists for the Orexin 1 Receptor  

PubMed Central

Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats.

Perrey, David A.; German, Nadezhda A.; Gilmour, Brian P.; Li, Jun-Xu; Harris, Danni L.; Thomas, Brian F.; Zhang, Yanan



Characterization of putative GRP and NMB-receptor antagonist's interaction with human receptors  

PubMed Central

The mammalian Bombesin (Bn) peptides neuromedin B (NMB) and gastrin-releasing peptide (GRP) actions are mediated by two receptors (NMB-receptor, GRP-receptor) which are widely distributed in the GI tract and CNS. From primarily animal studies NMB/GRP-receptor activation has physiological/pathophysiological effects in the CNS and GI tract including stimulating of growth of cancers and normal tissues. Whereas these Bn receptor's effects have been extensively studied in nonhuman cells and animals, little is known of the physiological/pathological role(s) in humans, largely due of lack of potent antagonists. To address this issue we compared NMB-receptor/GRP-receptor affinity/potency of 10 chemical classes of putative antagonists (35 compounds) for human Bn-receptors by performing binding studies or assessing abilities to activate hGRP/hNMB-receptor[assessing phospholipase C activation] in 4 different cells containing native Bn receptors or transfected receptors. From binding studies 23 were GRP-receptor-preferring, 4 were NMB-receptor, and 8-nonselective. For the hGRP-receptor-preferring analogues none showed hGRP-receptor agonist activity, but 13 were full or-partial hNMB-receptor agonists at hNMB-receptors. For hNMB-receptor-preferring analogues none were agonists. Analogue #24([(3-Ph-Pr6),His7,D-Ala11,D-Pro13,?(13-14), Phe14]Bn(6-14)NH2) and analogue #7[D-Phe6,Leu13,?(CH2NH),Cpa14]Bn(6-14) were the most potent (0.2-1.4 nM) and selective ((>10, 000-fold) for the hGRP-receptor with analogue #7.5[D-Tpi6,Leu13, ?(CH2NH),Leu14]Bn(6-14) [RC-3095] (0.2-1.4 nM) slightly less selective. Analogue #34(PD168368) had the highest affinity for hNMB-receptor (1.32-1.58 nM) and the greatest selectivity (2298-6952-fold) for the hNMB-receptor. These results demonstrate numerous putative hGRP/hNMB-receptor antagonists identified in nonhuman cells and/or animals have agonist activity at the hNMB-receptor, limiting their potential usefulness. However, a number were identified which were potent/selective for human Bn receptors and should be useful for investigating their roles in human physiological/pathophysiological conditions.

Gonzalez, Nieves; Mantey, Samuel A.; Pradhan, Tapas K.; Sancho, Veronica; Moody, Terry W.; Coy, David H.; Jensen, Robert T.



Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor  

PubMed Central

BACKGROUND AND PURPOSE Understanding the role of the EP2 receptor has been hampered by the lack of a selective antagonist. Recently, a selective EP2 receptor antagonist, PF-04418948, has been discovered. The aim of this study was to demonstrate the selectivity profile of PF-04418948 for the EP2 receptor over other EP receptors using a range of isolated tissue systems. EXPERIMENTAL APPROACH PF-04418948 was profiled on a range of isolated tissues to assess its EP receptor potency and selectivity: ONO-DI-004-induced contraction of guinea pig trachea (EP1); ONO-AE1-259 and PGE2- induced relaxation of mouse and guinea pig trachea (EP2); PGE2-induced depolarization of guinea pig isolated vagus (EP3); PGE2-induced relaxation of human and rat trachea (EP4). PF-04418948 was also profiled in functional murine TP, IP, DP and FP receptor assays. KEY RESULTS In bioassay systems, where assessment of potency/selectivity is made against the ‘native’ receptor, PF-04418948 only acted as an antagonist of EP2 receptor-mediated events. PF-04418948 competitively inhibited relaxations of murine and guinea pig trachea induced by ONO-AE1-259 and PGE2 respectively. However, the affinity of PF-04418948 was not equal in the two preparations. CONCLUSIONS AND IMPLICATIONS Using a wide range of bioassay systems, we have demonstrated that PF-04418948 is a selective EP2-receptor antagonist. Interestingly, an atypically low affinity was found on the guinea pig trachea, questioning its utility as an EP2 receptor assay system. Nevertheless, this compound should be an invaluable tool for investigating the biological activity of PGE2 and the role of EP2 receptors in health and disease.

Birrell, Mark A; Maher, Sarah A; Buckley, James; Dale, Nicole; Bonvini, Sara; Raemdonck, Kristof; Pullen, Nick; Giembycz, Mark A; Belvisi, Maria G



[Vasopressin V2 receptor antagonists: pharmacological properties and clinical implications].  


Vasopressin, or anti-diuretic hormone, is a peptide hormone that plays an important role in the regulation of extracellular volume and its osmolarity. Increased plasma osmolarity and hypovolemia are the principal physiological stimuli for vasopressin release. The biological effects of vasopressin on its target organs are mediated by two receptors: V1 and V2. V2 is localized to renal tissue and its activation leads to upregulation of aquaporin-2 in the collecting duct allowing the reabsorption of large volumes of water. In contrast, V1 is expressed mainly in blood vessel walls, and its activation results in vascoconstriction. Besides the physiological importance of the vasopressin system, it also plays a crucial role in the pathogenesis of various diseases, including congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion. These clinical syndromes are characterized by enhanced plasma levels of vasopressin, which correlate with the severity of the disease and largely contribute to the development of edema and hyponatremia. Great efforts have been invested in attempting to develop selective and long lasting vasopressin antagonists. However, general medicine and particularly nephrology, suffered from the absence of non-peptide vasopressin blockers that could be taken orally. The last few years have witnessed the development of numerous selective vasopressin antagonists with high bioavailability and long half-lives. Administration of these antagonists to patients with congestive heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion substantially enhanced free water excretion and moderately increased serum sodium concentrations. No side effects, except for mild increased thirst sensation, were observed. The present review focuses on the recent developments in vasopressin research, with special emphasize on the development of selective non-peptide antagonists and their clinical use. PMID:16400790

Abassi, Zaid; Bishara, Bishara; Yaccob, Afif; Hoffman, Aaron



The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates.  


Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease. PMID:7907775

Lange, K W; Löschmann, P A; Sofic, E; Burg, M; Horowski, R; Kalveram, K T; Wachtel, H; Riederer, P



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.



Novel antagonists for proteinase-activated receptor 2: inhibition of cellular and vascular responses in vitro and in vivo  

PubMed Central

Background and purpose: Proteinase-activated receptor 2 (PAR2) is a G-protein coupled receptor associated with many pathophysiological functions. To date, the development of PAR2 antagonists has been limited. Here, we identify a number of novel peptide-mimetic PAR2 antagonists and demonstrate inhibitory effects on PAR2-mediated intracellular signalling pathways and vascular responses. Experimental approach: The peptide-mimetic compound library based on the structures of PAR2 agonist peptides were screened for inhibition of PAR2-induced calcium mobilisation in human keratinocytes. Representative compounds were further evaluated by radioligand binding and inhibition of NF?B transcriptional activity and IL-8 production. The vascular effects of the antagonists were assessed using in vitro and in vivo models. Key results: Two compounds, K-12940 and K-14585, significantly reduced SLIGKV-induced Ca2+ mobilisation in primary human keratinocytes. Both K-12940 and K-14585 exhibited competitive inhibition for the binding of a high-affinity radiolabelled PAR2-ligand, [3H]-2-furoyl-LIGRL-NH2, to human PAR2 with Ki values of 1.94 and 0.627 µM respectively. NF?B reporter activity and IL-8 production were also significantly reduced. Furthermore, relaxation of rat-isolated aorta induced by SLIGRL-NH2 was inhibited competitively by K-14585. K-14585 also significantly lowered plasma extravasation in the dorsal skin of guinea pigs and reduced salivation in mice. Conclusions and implications: K-12940 and K-14585 antagonized PAR2 competitively, resulting in inhibition of PAR2-mediated signalling and physiological responses both in vitro and in vivo. These peptide-mimetic PAR2 antagonists could be useful in evaluating PAR2-mediated biological events and might lead to a new generation of therapeutically useful antagonists.

Kanke, T; Kabeya, M; Kubo, S; Kondo, S; Yasuoka, K; Tagashira, J; Ishiwata, H; Saka, M; Furuyama, T; Nishiyama, T; Doi, T; Hattori, Y; Kawabata, A; Cunningham, MR; Plevin, R



Antipsychotic agents antagonize non-competitive N -methyl- d -aspartate antagonist-induced behaviors  

Microsoft Academic Search

Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitiveN-methyl-d-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA\\/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and

R. Corbett; F. Camacho; A. T. Woods; L. L. Kerman; R. J. Fishkin; K. Brooks; R. W. Dunn



Angiotensin II type 2 receptor antagonist reduces bleomycin-induced pulmonary fibrosis in mice  

Microsoft Academic Search

BACKGROUND: The role of angiotensin II type 2 receptor (AT2) in pulmonary fibrosis is unknown. To evaluate the influence of angiotensin II type 1 receptor (AT1) and AT2 antagonists in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. METHODS: We examined effects of the AT1 antagonist (AT1A) olmesartan medoxomil (olmesartan) and the AT2 antagonist (AT2A) PD-123319 on BLM-induced pulmonary fibrosis,

Yuko Waseda; Masahide Yasui; Yoriko Nishizawa; Kanako Inuzuka; Hazuki Takato; Yukari Ichikawa; Atsuro Tagami; Masaki Fujimura; Shinji Nakao



Evidence That Orexigenic Effects of Melanocortin 4 Receptor Antagonist HS014 Are Mediated by Neuropeptide Y  

Microsoft Academic Search

Recent studies using melanocortin-4 receptor (MC4R) knockout mice and MC4R antagonists have shown that weakening of MC4R-ergic tone increases food intake and causes obesity. In this study, we used the newly discovered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y1receptor antagonist 1229U91 and the selective serotonin uptake inhibitor fluoxetine

Ants Kask; Lembit Rägo; Paul Korrovits; Jarl E. S. Wikberg; Helgi B. Schiöth



Novel small molecule bradykinin B1 receptor antagonists. Part 3: hydroxyurea derivatives.  


Hydroxy urea moieties are introduced as a new class of bradykinin B(1) receptor antagonists. First, the SAR of the lead compound was systematically explored. Subsequent optimization resulted in the identification of several biaryl-based hydroxyurea bradykinin B(1) receptor antagonists with low-nanomolar activity and very high oral bioavailability in the rat. PMID:20036120

Schnatbaum, Karsten; Schaudt, Marco; Stragies, Roland; Pfeifer, Jochen R; Gibson, Christoph; Locardi, Elsa; Scharn, Dirk; Richter, Uwe; Kalkhof, Holger; Dinkel, Klaus; Zischinsky, Gunther



[Mineralocorticoid receptor antagonists and therapeutic strategies of cardiovascular damage].  


In recent years, much attention has focused on the role of aldosterone and mineralocorticoid receptors (MRs) in the pathophysiology of hypertension and cardiovascular disease. Patients with primary aldosteronism, in whom angiotensin II levels are low, have a higher incidence of cardiovascular complications than patients with essential hypertension. The Randomized Aldactone Evaluation Study (RALES) demonstrated that adding a non-specific MR antagonist, spironolactone, to a standard therapy that included angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and digoxin, significantly reduced morbidity and mortality in patients with moderate to severe heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed that the addition of a selective MR antagonist (ARM), eplerenone, to an optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These data suggest that aldosterone induces cardiac injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent cardiac injury, through mechanisms that cannot be simply explained by hemodynamic changes. Although, MRA are highly effective in patients with heart failure, the risk of hyperkalemia should not be overlooked. Serious hyperkalemia events were reported in some MRA clinical trials; however these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. PMID:24861116

Verdugo, Fernando J; Montellano, Felipe A; Carreño, Juan E; Marusic, Elisa T



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



Preliminary investigations into triazole derived androgen receptor antagonists.  


A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40?M, the most promising three compounds were found to display IC50 values of 40-50?M against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue. PMID:24726305

Altimari, Jarrad M; Niranjan, Birunthi; Risbridger, Gail P; Schweiker, Stephanie S; Lohning, Anna E; Henderson, Luke C



Bovine pancreatic polypeptide as an antagonist of muscarinic cholinergic receptors  

SciTech Connect

In dispersed acini from rat pancreas, it was found that bovine pancreatic polypeptide (BPP) and its C-fragment hexapeptide amide (PP-6), at concentrations of 0.1 and 30, respectively, could significantly inhibit amylase secretion stimulated by carbachol, and this inhibition by BPP was dose dependent. /sup 45/Ca outflux induced by carbachol was also inhibited by BPP or PP-6, but they had no effect on cholecystokinin octapeptide- (CCK-8) or A23187-stimulated /sup 45/Ca outflux. BPP was also capable of displacing the specific binding of (/sup 3/H)-quinuclidinyl benzilate to its receptors, and it possessed a higher affinity (K/sub i/35nM) than carbachol (K/sub i/ 1.8 in binding with M-receptors. It is concluded from this study that BPP acts as an antagonist of muscarinic cholinergic receptors in rat pancreatic acini. In addition, BPP inhibited the potentiation of amylase secretion caused by the combination of carbachol plus secretin or vasoactive intestinal peptide. This may be a possible explanation of the inhibitory effect of BPP on secretin-induced pancreatic enzyme secretion shown in vivo, since pancreatic enzyme secretion stimulated by secretin under experimental conditions may be the result of potentiation of enzyme release produced by the peptide in combination with a cholinergic stimulant.

Pan, G.Z.; Lu, L.; Qian, J.; Xue, B.G.



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

PubMed Central

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.

Kitanaka, Junichi; Kitanaka, Nobue; Hall, F. Scott; Uhl, George R.; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Takemuraa, Motohiko



Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise  

PubMed Central

We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (?-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml·min?1·100 mmHg?1) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (?FVC; change from normoxic baseline) during hypoxic exercise with saline was 172 ± 29 and 314 ± 34 ml·min?1·100 mmHg?1 (10% and 20%, respectively). Aminophylline administration did not affect ?FVC during hypoxic exercise at 10% (190 ± 29 ml·min?1·100 mmHg?1, P = 0.4) or 20% (287 ± 48 ml·min?1·100 mmHg?1, P = 0.3). In protocol 2, ?FVC due to hypoxic exercise with phentolamine infusion was 313 ± 30 and 453 ± 41 ml·min?1·100 mmHg?1 (10% and 20% respectively). ?FVC was similar at 10% (352 ± 39 ml·min?1·100 mmHg?1, P = 0.8) and 20% (528 ± 45 ml·min?1·100 mmHg?1, P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, ?FVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

Madery, Brandon D.; Pike, Tasha L.; Eisenach, John H.; Dietz, Niki M.; Joyner, Michael J.; Wilkins, Brad W.



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



Selection for biocontrol bacteria antagonistic toward Rosellinia necatrix by enrichment of competitive avocado root tip colonizers.  


Biological control of soil-borne pathogens is frequently based on the application of antagonistic microorganisms selected solely for their ability to produce in vitro antifungal factors. The aim of this work was to select bacteria that efficiently colonize the roots of avocado plants and display antagonism towards Rosellinia necatrix, the causal agent of avocado white root rot. A high frequency of antagonistic strains (ten isolates, 24.4%) was obtained using a novel procedure based on the selection of competitive avocado root tip colonizers. Amplification and sequencing of the 16S rRNA gene, in combination with biochemical characterization, showed that eight and two of the selected isolates belonged to the genera Pseudomonas and Stenotrophomonas, respectively. Characterization of antifungal compounds produced by the antagonistic strains showed variable production of exoenzymes and HCN. Only one of these strains, Pseudomonas sp. AVO94, produced a compound that could be related to antifungal antibiotics. All of the ten selected strains showed twitching motility, a cell movement involved in competitive colonization of root tips. Production of N-acyl-homoserine lactones and indole-3-acetic acid was also reported for some of these isolates. Resistance to several bacterial antibiotics was tested, and three strains showing resistance to only one of them were selected for biocontrol assays. The three selected strains persisted in the rhizosphere of avocado plants at levels considered crucial for efficient biocontrol, 10(5)-10(6) colony forming units/g of root; two of them, Pseudomonas putida AVO102 and Pseudomonas pseudoalcaligenes AVO110, demonstrated significant protection of avocado plants against white root rot. PMID:17467245

Pliego, Clara; Cazorla, Francisco Manuel; González-Sánchez, María Angeles; Pérez-Jiménez, Rosa María; de Vicente, Antonio; Ramos, Cayo



Antiabsence seizure activity of specific GABAB and gamma-Hydroxybutyric acid receptor antagonists.  


Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures possibly by GABAB-receptor-mediated mechanisms. The object of these experiments was to examine the effectiveness of a range of specific GABAB-receptor agonists and antagonists of varying specificity, as well as the specific GHB-receptor antagonist NCS 382, in two experimental animal models of generalized absence seizures: one in which the seizures are induced by GHB and the other in which the seizures are induced by administration of low-dose (20-mg/kg) pentylenetetrazole. All specific GABAB-receptor antagonists as well as the specific GHB-receptor antagonist produced blockade of experimental absence seizures in both models; pretreatment with GABAB-receptor agonists resulted in generalized absence status epilepticus lasting for hours. These data confirm the concept that specific GABAB-receptor antagonist activity confers antiabsence seizure activity, suggest that the same holds for specific GHB-receptor antagonists, and raise the possibility that both GHB- and GABAB-antagonist drugs have the potential to be useful therapeutic agents in generalized absence seizures. PMID:8848463

Snead, O C



Vasopressin receptor antagonists and their role in clinical medicine  

PubMed Central

Hyponatremia is the most common electrolyte abnormality in hospitalized patients. Its treatment is based not only on extracellular fluid volume status of patients but also on its pathogenetic mechanisms. Conventional treatment of hyponatremia like fluid restriction, which is useful in euvolemic and hypervolemic hyponatremia, has very poor patient compliance over long term. Vasopressin receptor antagonists (Vaptans) are a new group of nonpeptide drugs which have been used in various clinical conditions with limited success. Whereas conivaptan is to be administered intravenously, the other vaptans like tolvaptan, lixivaptan, and satavaptan are effective as oral medication. They produce aquaresis by their action on vasopressin type 2 (V2R) receptors in the collecting duct and thus increase solute free water excretion. Vaptans are being used as an alternative to fluid restriction in euvolemic and hypervolemic hyponatremic patients. Efficacy of vaptans is now well accepted for management of correction of hyponatremia over a short period. However, its efficacy in improving the long-term morbidity and mortality in patients with chronic hyponatremia due to cirrhosis and heart failure is yet to be established. Vaptans have not become the mainstay treatment of hyponatremia yet.

Narayen, Girish; Mandal, Surya Narayan



Use of Enterally Delivered Angiotensin II Type Ia Receptor Antagonists to Reduce the Severity of Colitis  

Microsoft Academic Search

Background  Renin-angiotensin system blockade reduces inflammation in several organ systems. Having found a fourfold increase in angiotensin\\u000a II type Ia receptor expression in a dextran sodium sulfate colitis model, we targeted blockade with angiotensin II type Ia\\u000a receptor antagonists to prevent colitis development. Because hypotension is a major complication of angiotensin II type Ia\\u000a receptor antagonists use, we hypothesized that use

Manabu Okawada; Hiroyuki Koga; Scott D. Larsen; Hollis D. Showalter; Anjanette J. Turbiak; Xiaohong Jin; Peter C. Lucas; Elke Lipka; John Hillfinger; Jae Seung Kim; Daniel H. Teitelbaum


The NK1 receptor antagonist aprepitant as a broad spectrum antitumor drug  

Microsoft Academic Search

Summary  Aprepitant is a selective high-affinity antagonist of human substance P (SP)\\/Neurokinin-1 (NK-1) receptors. Until now this\\u000a drug has been used as anxiolytic, antidepressant and antiemetic. It has been demonstrated that SP induces cell proliferation\\u000a and NK-1 receptor antagonists different to aprepitant inhibit growth in several human cancer cell lines, where NK-1 receptors\\u000a are overexpressed. The purpose of this study is

Miguel Muñoz; Marisa Rosso



Design and microwave-assisted synthesis of novel macrocyclic peptides active at melanocortin receptors: discovery of potent and selective hMC5R receptor antagonists.  


Differentiation of the physiological role of the melanocortin receptor 5 MC5R from that of other melanocortin receptors will require development of high affinity and selective antagonists. To date, a few synthetic antagonist ligands active at hMC5 receptor are available, but most do not have appreciable selectivity. With the aim to gain more potent and selective antagonists for the MC5R ligands, we have designed, synthesized, and pharmacologically characterized a series of alkylthioaryl-bridged macrocyclic peptide analogues derived from MT-II and SHU9119. These 20-membered macrocycles were synthesized by a tandem combination using solid phase peptide synthesis and microwave-assisted reactions. Biological assays for binding affinities and adenylate cyclase activities for the hMC1R, hMC3R, hMC4R, and hMC5R showed that three analogues, compounds, 9, 4, and 7, are selective antagonists at the hMC5 receptor. In particular, compound 9(PG-20N) is a selective and competitive hMC5R antagonist, with IC 50 of 130 +/- 11 nM, and a pA 2 value of 8.3, and represents an important tool for further biological investigations of the hMC5R. Compounds 4 and 7 (PG14N, PG17N) show potent and selective allosteric inhibition at hMC5R with IC 50 values of 38 +/- 3 nM and 58 +/- 6 nM, respectively. Compound 9 will be used to further investigate and more clearly understand the physiological roles played by the MC5 receptor in humans and other animals. PMID:18412316

Grieco, Paolo; Cai, Minying; Liu, Lu; Mayorov, Alexander; Chandler, Kevin; Trivedi, Dev; Lin, Guangxin; Campiglia, Pietro; Novellino, Ettore; Hruby, Victor J



Allosteric modulation of muscarinic receptor signaling: alcuronium-induced conversion of pilocarpine from an agonist into an antagonist.  


Previous studies on allosteric interactions at muscarinic receptors have often focused on ligand-receptor binding interactions, because ligand binding seemed to reflect functional consequences. The prototypal allosteric agent alcuronium is known to bind with similar affinity to the M(2) subtype of muscarinic acetylcholine receptors whether or not the receptors are occupied by the agonist pilocarpine. To determine allosteric modulation of receptor signaling by alcuronium, the effects of pilocarpine were measured in contracting guinea pig left atria and on G-protein coupling in M(2)-transfected Chinese hamster ovary (CHO) cell membranes. Alcuronium dose-dependently suppressed pilocarpine-induced reduction of isometric contraction force in atria (pIC(50, Alc) = 5.63) without any effect on the EC(50) of pilocarpine, consistent with an allosteric mechanism. In contrast, alcuronium shifted the concentration-effect curve of the agonist oxotremorine M to the right without affecting the maximal effect, in a formally competitive manner (pK(A, Alc) = 5.54). If pilocarpine remained receptor bound in the presence of alcuronium, this indicates that pilocarpine can no longer act as an agonist. In support of this hypothesis, pilocarpine acted as a competitive antagonist against oxotremorine M in the presence of 10 microM alcuronium. Measuring guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in CHO-M(2) membranes yielded similar results. Alcuronium suppressed pilocarpine-induced stimulation of [(35)S]GTPgammaS binding (pIC(50, Alc) = 5.47) without shift in EC(50), whereas it competitively shifted the response to oxotremorine M (pK(A, Alc) = 5.97). [(3)H]Oxotremorine M binding data corresponded with the functional findings. In conclusion, alcuronium converted the agonist pilocarpine into an antagonist-a novel type of functional allosteric interaction. PMID:11961078

Zahn, Katrin; Eckstein, Niels; Tränkle, Christian; Sadée, Wolfgang; Mohr, Klaus



Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.  


To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics. PMID:24776492

Sadek, Bassem; Kuder, Kamil; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Stark, Holger; La?ewska, Dorota; Adem, Abdu; Kie?-Kononowicz, Katarzyna



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



The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement  

PubMed Central

Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1?h: ShA) or long (12?h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

Barbier, Estelle; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Juergens, Nathan; Park, Paula E; Misra, Kaushik K; Cheng, Kejun; Rice, Kenner C; Schank, Jesse; Schulteis, Gery; Koob, George F; Heilig, Markus



An antagonistic monoclonal antibody (B-N6) specific for the human neurotensin receptor-1.  


The neuropeptide neurotensin (NT) interacts with two types of human receptors (hNTR) termed hNTR-1 and hNTR-2. This study describes a monoclonal antibody (MAb) specific for hNTR-1, B-N6. This MAb binds specifically to hNTR-1, but not to hNTR-2 transfected CHO cells. B-N6 and NT display a reciprocal competition and react in a similar way to trypsin, suggesting that the B-N6 epitope is at or close to the NT binding site on the third extracellular loop. Unlike B-N6, NT induces hNTR-1 internalization. Although neither NT-FITC nor B-N6 binding was detected by flow cytometry on different human cells, specific mRNA expression for hNTR-1 was detected in these cells. In CHO cells expressing hNTR-1 and a luciferase gene coupled to the krox24 reporter, B-N6 and the antagonist SR 48692 inhibited NT-induced intracellular activation of krox24 in a dose-dependent manner. From these results it is concluded that B-N6 is an antagonistic anti-hNTR-1 MAb. PMID:10189059

Ovigne, J M; Vermot-Desroches, C; Lecron, J C; Portier, M; Lupker, J; Pecceu, F; Wijdenes, J



Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide  

PubMed Central

We report the crystal structure of a soluble form of human urokinase-type plasminogen activator receptor (uPAR/CD87), which is expressed at the invasive areas of the tumor-stromal microenvironment in many human cancers. The structure was solved at 2.7 Å in association with a competitive peptide inhibitor of the urokinase-type plasminogen activator (uPA)–uPAR interaction. uPAR is composed of three consecutive three-finger domains organized in an almost circular manner, which generates both a deep internal cavity where the peptide binds in a helical conformation, and a large external surface. This knowledge combined with the discovery of a convergent binding motif shared by the antagonist peptide and uPA allowed us to build a model of the human uPA–uPAR complex. This model reveals that the receptor-binding module of uPA engages the uPAR central cavity, thus leaving the external receptor surface accessible for other protein interactions (vitronectin and integrins). By this unique structural assembly, uPAR can orchestrate the fine interplay with the partners that are required to guide uPA-focalized proteolysis on the cell surface and control cell adhesion and migration.

Llinas, Paola; Helene Le Du, Marie; Gardsvoll, Henrik; Dan?, Keld; Ploug, Michael; Gilquin, Bernard; Stura, Enrico A; Menez, Andre



Structural insights into competitive antagonism in NMDA receptors.  


There has been a great level of enthusiasm to downregulate overactive N-methyl-D-aspartate (NMDA) receptors to protect neurons from excitotoxicity. NMDA receptors play pivotal roles in basic brain development and functions as well as in neurological disorders and diseases. However, mechanistic understanding of antagonism in NMDA receptors is limited due to complete lack of antagonist-bound structures for the L-glutamate-binding GluN2 subunits. Here, we report the crystal structures of GluN1/GluN2A NMDA receptor ligand-binding domain (LBD) heterodimers in complex with GluN1- and GluN2-targeting antagonists. The crystal structures reveal that the antagonists, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and 1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA), have discrete binding modes and mechanisms for opening of the bilobed architecture of GluN2A LBD compared to the agonist-bound form. The current study shows distinct ways by which the conformations of NMDA receptor LBDs may be controlled and coupled to receptor inhibition and provides possible strategies to develop therapeutic compounds with higher subtype-specificity. PMID:24462099

Jespersen, Annie; Tajima, Nami; Fernandez-Cuervo, Gabriela; Garnier-Amblard, Ethel C; Furukawa, Hiro



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



Binding site and ligand flexibility revealed by high resolution crystal structures of GluK1 competitive antagonists  

PubMed Central

The availability of crystal structures for the ligand binding domains of ionotropic glutamate receptors, combined with their key role in synaptic function in the normal and diseased brain, offers a unique selection of targets for pharmaceutical research compared to other drug targets for which the atomic structure of the ligand binding sites is not known. Currently only a few antagonist structures have been solved, and these reveal ligand specific conformational changes that hinder rational drug design. Here we report high resolution crystal structures for three kainate receptor GluK1 antagonist complexes which reveal new and unexpected modes of binding, highlighting the continued need for experimentally determined receptor-ligand complexes.

Alushin, Gregory M.; Jane, David; Mayer, Mark L.



Neuroprotective doses of N-methyl-D-aspartate receptor antagonists profoundly reduce the minimum alveolar anesthetic concentration (MAC) for isoflurane in rats.  


N-methyl-D-aspartate (NMDA) receptor antagonists, which block one of the glutamate receptors, have provided evidence of cerebral protection in animal models of focal cerebral ischemia. We examined the effect of neuroprotective doses of one noncompetitive (dizocilpine) and two competitive (D-CPP-ene, CGS 19755) NMDA antagonists on the minimum alveolar anesthetic concentration (MAC) of isoflurane in rats. A single bolus injection of any of the three NMDA antagonists produced a significant (P < 0.01) and sustained (> 3 h) decrease in the MAC of isoflurane. Dizocilpine decreased MAC by 33%-38% at a dose of 0.15 mg/kg and 48%-54% at a dose of 0.5 mg/kg. D-CPP-ene decreased MAC by 32%-37% at a dose of 1.5 mg/kg and 39%-45% at a dose of 4.5 mg/kg. CGS 19755 decreased MAC by 19%-24% at a dose of 3 mg/kg and 49%-58% at a dose of 10 mg/kg. Dizocilpine, but not the competitive antagonists, produced a small transient decrease in mean arterial blood pressure. The sustained anesthetic potency of neuroprotective doses of NMDA antagonists supports the idea that glutaminergic receptor activity is involved in determining the anesthetic state. PMID:8214668

Kuroda, Y; Strebel, S; Rafferty, C; Bullock, R



Non-competitive pharmacological antagonism at the rabbit B(1) receptor.  


The B(1) receptor for kinins, stimulated by kinin metabolites without the C-terminal Arg residue (e.g., des-Arg(9)-bradykinin (BK) and Lys-des-Arg(9)-BK), is an increasingly recognized molecular target for the development of analgesic and anti-inflammatory drugs. Recently developed antagonists of this receptor were compared to a conventional antagonist, Ac-Lys-[Leu(8)]-des-Arg(9)-BK, in pharmacological assays based on the rabbit B(1) receptor. B-9858 (Lys-Lys-[Hyp(3), Igl(5), D-Igl(7), Oic(8)]des-Arg(9)-BK) and three other analogues possessing the alpha-2-indanylglycine(5) (Igl(5)) residue (order of potency B-9858 approximately B-10146>B-10148>B-10050) were partially insurmountable antagonists of des-Arg(9)-BK in the contractility assay based on rabbit aortic rings. B-9858-induced depression of the maximal effect was more pronounced in tissues treated with the protein synthesis inhibitor cycloheximide to block the spontaneous increase of response attributed to the post-isolation formation of B(1) receptors, and only partly reversible on washing. By comparison, Ac-Lys-[Leu(8)]des-Arg(9)-BK was a surmountable antagonist (pA(2) 7. 5), even in cycloheximide-treated tissues. B-9958 (Lys-[Hyp(3), CpG(5), D-Tic(7), CpG(8)]des-Arg(9)-BK) was also surmountable (pA(2) 8.5). The binding of [(3)H]-Lys-des-Arg(9)-BK to recombinant rabbit B(1) receptors expressed in COS-1 cells was influenced by two of the antagonists: while Ac-Lys-[Leu(8)]des-Arg(9)-BK competed for the radioligand binding without affecting the B(max), B-9858 decreased the B(max) in a time-dependent and washout-resistant manner. B-9858 and analogues possessing Igl(5) are the first reported non-competitive, non-equilibrium antagonists of the kinin B(1) receptor. PMID:11053207

Larrivée, J F; Gera, L; Houle, S; Bouthillier, J; Bachvarov, D R; Stewart, J M; Marceau, F



Non-competitive pharmacological antagonism at the rabbit B1 receptor  

PubMed Central

The B1 receptor for kinins, stimulated by kinin metabolites without the C-terminal Arg residue (e.g., des-Arg9-bradykinin (BK) and Lys-des-Arg9-BK), is an increasingly recognized molecular target for the development of analgesic and anti-inflammatory drugs. Recently developed antagonists of this receptor were compared to a conventional antagonist, Ac-Lys-[Leu8]-des-Arg9-BK, in pharmacological assays based on the rabbit B1 receptor. B-9858 (Lys-Lys-[Hyp3, Igl5, D-Igl7, Oic8]des-Arg9-BK) and three other analogues possessing the ?-2-indanylglycine5 (Igl5) residue (order of potency B-9858 ? B-10146>B-10148>B-10050) were partially insurmountable antagonists of des-Arg9-BK in the contractility assay based on rabbit aortic rings. B-9858-induced depression of the maximal effect was more pronounced in tissues treated with the protein synthesis inhibitor cycloheximide to block the spontaneous increase of response attributed to the post-isolation formation of B1 receptors, and only partly reversible on washing. By comparison, Ac-Lys-[Leu8]des-Arg9-BK was a surmountable antagonist (pA2 7.5), even in cycloheximide-treated tissues. B-9958 (Lys-[Hyp3, CpG5, D-Tic7, CpG8]des-Arg9-BK) was also surmountable (pA2 8.5). The binding of [3H]-Lys-des-Arg9-BK to recombinant rabbit B1 receptors expressed in COS-1 cells was influenced by two of the antagonists: while Ac-Lys-[Leu8]des-Arg9-BK competed for the radioligand binding without affecting the Bmax, B-9858 decreased the Bmax in a time-dependent and washout-resistant manner. B-9858 and analogues possessing Igl5 are the first reported non-competitive, non-equilibrium antagonists of the kinin B1 receptor.

Larrivee, Jean-Francois; Gera, Lajos; Houle, Steeve; Bouthillier, Johanne; Bachvarov, Dimcho R; Stewart, John M; Marceau, Francois



Applicability of DPI formulations for novel neurokinin receptor antagonist.  


A novel triple neurokinin receptor antagonist (TNRA) could have pharmaceutical efficacy for asthma and/or chronic obstructive pulmonary disease. TNRA is potentially developed as inhalation medicine. The aim of this investigation was to evaluate the applicability of dry powder inhaler (DPI) formulation for TNRA. DPI formulation containing lactose was used for this feasibility study. Mechanofusion process for surface modification was applied on lactose particles to prepare four different DPI formulations. The mixture of TNRA and lactose was administered to rats intratracheally using an insufflator. The deposition pattern and blood concentration profile of TNRA were evaluated. Although there was no significant difference in deposition on deep lungs between the four formulations, DPI formulations containing mechanofusion-processed lactose showed longer T(max) and t(1/2) and higher AUC(0-infinity) and MRT compared to that containing intact lactose. On the other hand, the contact angle measurement showed that the mechanofusion process decreased the polar part of the surface energy of the lactose. Therefore, the prolongation of the wetting of the formulated powder mixture seemed to delay the dissolution of TNRA deposited in respiratory tract. It was concluded that DPI formulation containing mechanofusion-processed lactose could be suitable for inhalation of TNRA. PMID:18294787

Kumon, M; Yabe, Y; Kasuya, Y; Suzuki, M; Kusai, A; Yonemochi, E; Terada, K



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



Leukotriene receptor antagonists for chronic urticaria: a systematic review  

PubMed Central

A significant proportion of patients with chronic urticaria respond inadequately to first line treatment with antihistamines. Leukotreine receptor antagonists (LTRA) are also used for chronic urticaria, although firm recommendations on their use are lacking. We performed a systematic review of randomised trials to determine the role of LTRA in treatment of chronic urticaria. A search of PUBMED, EMBASE, SCOPUS, LILACS, the Cochrane Central Register of Controlled Trials, and the Web of Science for relevant randomized control trials or cross over studies yielded 10 eligible studies. The heterogeneity of trials were high, preventing valid meta-analysis of data. Most trials indicated that LTRA are not superior to placebo or antihistamine therapy, while combination therapy of LTRA and antihistamines appear to be more efficacious compared to antihistamine alone. The side effect profile and tolerability of this group of drugs is acceptable. The use of LTRA as monotherapy cannot be recommended. LTRA are effective add-on therapy to anti-histamines, and their use in patients responding poorly to antihistamines is justifiable. Further well designed randomized controlled trials with clear and standardized outcome measures are needed to determine the role of LTRA in chronic urticaria.



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



A role for the androgen receptor in the endometrial antiproliferative effects of progesterone antagonists  

Microsoft Academic Search

In women and nonhuman primates, treatment with progesterone antagonists suppresses estrogen-dependent mitotic activity in the endometrial glands. This antiproliferative effect is paradoxical, because progesterone antagonists do not bind to the estrogen receptor (ER). While this phenomenon has been termed a “functional noncompetitive antiestrogenic effect,” it does not occur in all species or in all regions of the primate reproductive tract,

Robert M Brenner; Ov D Slayden; Nihar R Nayak; David T Baird; Hilary O. D Critchley



Neuroprotection is associated with ?-adrenergic receptor antagonists during cardiac surgery: Evidence from 2,575 patients  

Microsoft Academic Search

Objective: To determine the impact of perioperative ?-adrenergic receptor (?AR) antagonist administration on neurologic complications. Design: Observational database analysis. Setting: A clinical investigation at a single tertiary academic medical center. Participants: Elective coronary artery bypass graft surgical patients operated on in the period 1994-1996. Interventions: Patients were divided into 2 groups: (1) patients given ?AR antagonist–blocking drugs in the perioperative

David W. Amory; Alina Grigore; John K. Amory; Mark A. Gerhardt; William D. White; Peter K. Smith; Debra A. Schwinn; J. G. Reves; Mark F. Newman



3-Urea-1-(phenylmethyl)-pyridones as novel, potent, and selective EP3 receptor antagonists.  


A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described. PMID:20926294

Li, Yue H; Tseng, Pei-San; Evans, Karen A; Jaworski, Jon-Paul; Morrow, Dwight M; Fries, Harvey E; Wu, Charlene W; Edwards, Richard M; Jin, Jian



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


High-throughput screening of 3.87 million 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. PMID:21129964

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



Quantifying the association and dissociation rates of unlabelled antagonists at the muscarinic M3 receptor  

PubMed Central

Slow receptor dissociation kinetics has been implicated in the long clinical duration of action of the muscarinic receptor antagonist tiotropium. However, despite the potential benefits of new drugs with slow dissociation kinetics, the rate parameters of new compounds are seldom measured due to technical difficulties and financial implications associated with radiolabeling multiple ligands. Here we describe the development and optimisation of a medium throughput assay which is capable of measuring the kinetic parameters of novel, unlabelled compounds. Radioligand binding studies were performed with membranes derived from CHO cells recombinantly expressing the human M3 muscarinic receptor. Initial characterisation of the radioligand [3H]-NMS yielded on and off rates of 4.1±0.2 × 108?M?1?min?1 and 0.015±0.0005?min?1, respectively. The specific binding of [3H]-NMS was measured over time in the presence and absence of several concentrations of unlabelled competitor compounds. These data were analysed using a competition kinetic model to provide on and off rates for the unlabelled competitor. Comparison of the kinetically derived Kd (koff/kon) with Ki values generated at equilibrium showed an excellent correlation (r2=0.99), providing good validation of the method. The on and off rates were also used in theoretical computer simulations to successfully predict the effect of incubation time on apparent IC50 values. This study demonstrates that a medium-throughput competition kinetic binding assay can be used to determine accurate on and off rates of unlabelled compounds, providing the opportunity to optimise for kinetic parameters early in the drug discovery process.

Dowling, Mark R; Charlton, Steven J



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.



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



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 neurotensin receptor 1 (NTR1) with a specific antagonist, SR48692, could sensitize prostate cancer to ionizing radiation, thus improving outcomes of radiotherapy. We demonstrated that SR48692 selectively sen...

J. Dziegielewski



No Effect of Nutritional Adenosine Receptor Antagonists on Exercise Performance in the Heat.  

National Technical Information Service (NTIS)

Nutritional adenosine receptor antagonists can enhance endurance exercise performance in temperate environments, but their efficacy during heat stress is not well understood. This double-blinded, placebo-controlled study compared the effects of an acute d...

B. B. Michniak-Kohn B. R. Ely J. C. Rood R. W. Kenefick S. N. Cheuvront



Effects of Urotensin II Receptor Antagonist, GSK1440115, in Asthma.  


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. PMID:23641215

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



From virtual to clinical: The discovery of PGN-1531, a novel antagonist of the prostanoid EP4 receptor.  


In this Letter, we present the results of a hit-finding and lead optimization programme against the EP4 receptor (EP4R). In a short time period, we were able to discover five structurally diverse series of hit compounds using a combination of virtual screening methods. The most favoured hit, compound 6, was demonstrated to be a competitive antagonist of the EP4R. Compound 73 was identified following several rounds of optimization, which centred on improving both the primary EP4R affinity and selectivity against the related EP2R as well as the aqueous solubility. This work culminated in the preparation of PGN-1531, the sodium salt of 73, which showed a marked improvement in solubility (>10mg/mL). PGN-1531 is a potent and selective antagonist at EP4Rs in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. PMID:24703233

Sutton, Jon; Clark, David E; Higgs, Christopher; de Groot, Marcel J; Harris, Neil V; Taylor, Andrea; Lockey, Peter M; Maubach, Karen; Woodrooffe, Amanda; Davis, Richard J; Coleman, Robert A; Clark, Kenneth L



The discovery of the benzazepine class of histamine H3 receptor antagonists.  


This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties. PMID:24161834

Wilson, David M; Apps, James; Bailey, Nicholas; Bamford, Mark J; Beresford, Isabel J; Briggs, Michael A; Calver, Andrew R; Crook, Barry; Davis, Robert P; Davis, Susannah; Dean, David K; Harris, Leanne; Heightman, Tom D; Panchal, Terry; Parr, Christopher A; Quashie, Nigel; Steadman, Jon G A; Schogger, Joanne; Sehmi, Sanjeet S; Stean, Tania O; Takle, Andrew K; Trail, Brenda K; White, Trevor; Witherington, Jason; Worby, Angela; Medhurst, Andrew D



In vitro production of interleukin-1 receptor antagonist in chronic renal failure, CAPD and HD  

Microsoft Academic Search

In vitro production of interleukin-1 receptor antagonist in chronic renal failure, CAPD and HD. Dialysis-related symptoms are believed to be mediated, at least in part, by monocyte\\/macrophage-derived pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor (TNF). Measuring the production of interleukin-1 receptor antagonist (IL-Ra), a naturally occurring inhibitor of IL-1, opens avenues to study the balance between these two

Brian J G Pereira; Debra D Poutsiaka; Andrew J King; James A Strom; Geetha Narayan; Andrew S Levey; Charles A Dinarello



Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists  

Microsoft Academic Search

Current research on angiotensin II AT1-receptor antagonists (AIIRAs) and selected studies presented at the recent symposium held in Amsterdam, The Netherlands, on 6 June 1998, titled ‘Angiotensin II Receptor Antagonists are NOT all the Same’ are reviewed. AIIRAs offer a number of potential advantages over alternative antihypertensive agents acting via the renin-angiotensin-aldosterone system. They combine blood pressure-lowering effects at least

PS Sever



Dopaminergic basis for the facilitation of brain stimulation reward by the NMDA receptor antagonist, MK-801  

Microsoft Academic Search

MK-801 (dizocilpine maleate), an antagonist of the NMDA receptor, was given alone or in combination with dopamine D1 and D2 receptor antagonists to rats self-stimulating in lateral hypothalamus to determine whether the dopamine neurons play a role in mediating the effects of MK-801. MK-801 given at a dose of 0.1 mg\\/kg i.p. to self-stimulators induced a prolonged facilitation of lever-pressing,

Marianne E. Olds



Therapeutic Potential of Tachykinin Receptor Antagonists in Depression and Anxiety Disorders  

Microsoft Academic Search

\\u000a Neuropeptides, including the tachykinins substance P, neurokinin A and neurokinin B, are potentially important new targets\\u000a for the development of psychotropic drugs. NK1, NK2 and NK3 tachykinin receptor antagonists are currently undergoing clinical trials to investigate their therapeutic applications in\\u000a central nervous system (CNS) disorders. Substance P (NK1) receptor antagonists (NK1RAs) have been clinically valid ated as a novel approach

N. M. J. Rupniak


Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone  

Microsoft Academic Search

Background: Aprepitant is a neurokinin1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids

Jacqueline B. McCrea; Anup K. Majumdar; Michael R. Goldberg; Marian Iwamoto; Cynthia Gargano; Deborah L. Panebianco; Michael Hesney; Christopher R. Lines; Kevin J. Petty; Paul J. Deutsch; M. Gail Murphy; Keith M. Gottesdiener; D. Ronald Goldwater; Robert A. Blum



Novel NK(3) receptor antagonists for the treatment of schizophrenia and other CNS indications.  


The cloning of the three tachykinin receptors in the late 1980s formed the basis of intense preclinical research efforts into the systems relating to the tachykinin receptors, as well as compound screening campaigns. Remarkably, orally active non-peptide antagonists were successfully identified for all three of the tachykinin receptors, providing tools for further evaluation of the pharmacology of these receptor systems. The NK3 receptor (mammalian tachykinin receptor 3), which exhibited a discrete expression pattern and the modulatory regulation of various transmitter systems in the CNS, has attracted significant interest. Preclinical studies demonstrated that the NK3 receptor might be a promising target for CNS disorders, and clinical trials with non-peptide NK3 receptor antagonists have been performed for indications such as schizophrenia, major depressive disorder, panic attacks and Parkinson's disease. In particular, the positive results of the schizophrenia meta-trial with osanetant increased the focus on the NK3 receptor system and its clinical potential. Consequently, a significant number of patents covering non-peptide antagonists for the NK3 receptor have been published during the past decade. This review describes the most recent NK3 receptor antagonists (published from 2004 to 2009), which are classified into seven unique templates. PMID:20597024

Simonsen, Klaus B; Juhl, Karsten; Steiniger-Brach, Björn; Nielsen, Søren Møller



Gamma-mangostin, a novel type of 5-hydroxytryptamine 2A receptor antagonist.  


Gamma-mangostin, purified from the fruit hull of the medicinal plant Garcinia mangostana caused a parallel rightwards shift of the concentration/response curve for the contraction elicited by 5-hydroxytryptamine (5-HT) in the rabbit aorta (pA2 = 8.2) without affecting the contractile responses to KCl, phenylephrine (alpha1) or histamine (H1). The perfusion pressure response of rat coronary artery to 5-HT (5-HT2A) was reduced concentration dependently by gamma-mangostin (IC50 = 0.32 microM). 5-HT amplified, ADP-induced aggregation of rabbit platelets (5-HT2A) was inhibited by gamma-mangostin (IC50 = 0.29 microM), whereas that induced by thrombin was not affected, nor did gamma-mangostin affect 5-HT-induced contraction of the guinea-pig ileum (5-HT3)in the presence of 5-HT1, 5-HT2 and 5-HT4 receptor antagonists. Furthermore, 5-HT-induced contraction of the rat fundus (5-HT2B) and 5-HT-induced relaxation of the rabbit aorta in the presence of ketanserin (5-HT1) and carbachol-induced contraction of the guinea-pig ileum (muscarinic M3) were not affected by gamma-mangostin (5 microM). Gamma-mangostin inhibited [3H]spiperone binding to cultured rat aortic myocytes (IC50 = 3.5 nM). The Kd for [3H]spiperone binding was increased by gamma-mangostin (3 nM) from 11.7 to 27.4 nM without affecting Bmax. These results suggest that gamma-mangostin is a novel competitive antagonist, free from a nitrogen atom, for the 5-HT2A receptors in vascular smooth muscles and platelets. PMID:9459569

Chairungsrilerd, N; Furukawa, K I; Ohta, T; Nozoe, S; Ohizumi, Y



The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats  

PubMed Central

Rationale Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice. Objectives Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice. Methods Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755. Results Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition. Conclusions NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low-impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used.

Iemolo, Attilio; Narayan, Aditi R.; Kwak, Jina; Momaney, Duncan



(?)-Nantenine analogs as antagonists at human 5-HT2A receptors: C1 and flexible congeners  

PubMed Central

C1 and flexible analogs of (±)-nantenine were synthesized and evaluated for antagonist activity at human 5-HT2A receptors in a calcium mobilization assay. This work has resulted in the identification of the most potent 5-HT2A antagonist known based on an aporphine. Our results also suggest that the C1 position may be a key site for increasing 5-HT2A antagonist activity in this compound series. In addition, the structural rigidity of the aporphine core appears to be required for nantenine to function as a 5-HT2A antagonist.

Chaudhary, Sandeep; Pecic, Stevan; LeGendre, Onica; Navarro, Hernan A.; Harding, Wayne W.



The in vitro pharmacological profile of TD-1211, a neutral opioid receptor antagonist.  


The clinical efficacy of opioid receptor antagonists for the treatment of opioid-induced constipation (OIC) is established. Peripherally selective antagonists are intended to provide OIC symptom relief without compromising the analgesic effects of centrally penetrant opioid agonists. We describe the in vitro profile of a novel opioid receptor antagonist, TD-1211, at recombinant (human ? and ?, and guinea pig ?) and rodent native opioid receptors. TD-1211 bound with high affinity to human recombinant ? and ?, and guinea pig ? receptors expressed in CHO-K1 cells (pK d?=?9.7, 8.6, and 9.9, respectively). The in vitro receptor selectivity of TD-1211 (??????>??) is similar to that for the peripherally-selective opioid receptor antagonist methylnaltrexone, but contrasts with the ? selectivity of alvimopan. Functionally, TD-1211 behaved as an antagonist at all three receptor types in both recombinant expression systems (pK b?=?9.6, 8.8 and 9.5, at ?, ?, and ?, respectively) and rodent native tissue preparations (? and ? pA2s?=?10.1 and 8.8, respectively (guinea pig ileum), and ? pK b?=?8.4 (hamster vas deferens)). TD-1211 displayed a high degree of selectivity for opioid receptors over a broad panel of cellular targets. These in vitro data justified investigation of the preclinical in vivo activity of TD-1211 (Armstrong et al., Naunyn-Schmiedeberg's Arch Pharm, 2013). PMID:23549670

Tsuruda, Pamela R; Vickery, Ross G; Long, Daniel D; Armstrong, Scott R; Beattie, David T



5-HT6 receptor antagonists as potential therapeutics for cognitive impairment.  


Cognitive impairment (CI) has been recognized as a core feature of Alzheimer's disease (AD) and schizophrenia. The 5-HT(6) receptor is an attractive target for the development of cognitive enhancers due to its unique localization and pharmacology. 5-HT(6) receptor antagonists have been shown to modulate multiple neurotransmitter systems and therefore enhance cognition in preclinical studies. This premise translated into the clinical efficacy of the 5-HT(6) receptor antagonist SB-742457 in mild-to-moderate AD patients. Advances in the understanding of the structure-activity-relationship, the design of novel 5-HT(6) receptor ligands and their potential application for the treatment of CI are reviewed. PMID:20166958

Rossé, Gérard; Schaffhauser, Hervé



Development of selective agonists and antagonists of P2Y receptors  

Microsoft Academic Search

Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of\\u000a many other members of group A G protein-coupled receptors, detailed qualitative and quantitative structure–activity relationships\\u000a (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

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



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



Solution structure of a unique C5a semi-synthetic antagonist: implications in receptor binding.  

PubMed Central

The tertiary structure of a unique C5a receptor antagonist was determined by two-dimensional NMR spectroscopy. The core domain of this 8-kDa antagonist exists as an antiparallel helical bundle, similar to recombinant human (rh)-C5a. However, unlike C5a, the antagonist's C terminus was found to be conformationally restricted along a groove between helices one and four in the core domain. This conformational restriction situates C-terminal D-Arg 75 in a wedge between core residues Arg 46 and His 15. Correlation of the antagonist's tertiary structure with point mutation analysis revealed the formation of a positively charged contiguous contact surface comprised of D-Arg 75, Arg 46, Lys 49, and His 15. The significance of this surface in generating antagonist properties implies a single binding site with the C5a receptor and provides a structural template for drug design.

Zhang, X.; Boyar, W.; Galakatos, N.; Gonnella, N. C.



Agonist- and antagonist-induced conformational changes of loop F and their contributions to the rho1 GABA receptor function.  


Binding of gamma-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 rho1 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. PMID:19015197

Zhang, Jianliang; Xue, Fenqin; Chang, Yongchang



Update on leukotriene receptor antagonists in preschool children wheezing disorders.  


Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS), is the cornerstone of asthma management. Since Leukotrienes (LTs) are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs) are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy. PMID:22734451

Montella, Silvia; Maglione, Marco; De Stefano, Sara; Manna, Angelo; Di Giorgio, Angela; Santamaria, Francesca



Interleukin-1 receptor antagonist in normal and psoriatic epidermis.  

PubMed Central

The objective of these studies was to characterize the IL-1 inhibitory activity present in normal and psoriatic epidermis from clinically stable lesions. Fractionation of normal epidermal cytosol on a molecular sizing column failed to reveal the presence of IL-1 inhibitory bioactivity. However, specific ELISAs indicated that both the IL-1 receptor antagonist (IL-1ra) and IL-1 alpha were present in overlapping peaks. Further fractionation of the normal epidermal cytosol by anion exchange chromatography separated these two molecules, revealing the IL-1 inhibitory bioactivity of the IL-1ra molecule. Similar studies on psoriatic epidermal cytosol indicated the presence of IL-1 inhibitory bioactivity and IL-1ra protein. The IL-1 inhibitory bioactivity of both normal and psoriatic cytosol was neutralized by a mAb specific for IL-1ra. The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin. By Western blot analysis this IL-1ra was approximately 20 kD, slightly larger than monocyte-derived IL-1ra and equivalent to an intracellular variant of IL-1ra expressed by keratinocytes. Polymerase chain reaction indicated the presence of mRNA for both forms of IL-1ra in normal epidermis, with both forms increased in psoriatic-involved skin. Immunofluorescence studies revealed the IL-1ra protein to be concentrated in the stratum granulosum of normal skin and in the basal-midbasal layers of psoriatic epidermis. These results suggest that the balance between intracellular IL-1ra and IL-1 alpha may be an important influence on keratinocyte growth and/or differentiation, as well as on the inflammatory potential of IL-1 in injured skin. Images

Hammerberg, C; Arend, W P; Fisher, G J; Chan, L S; Berger, A E; Haskill, J S; Voorhees, J J; Cooper, K D



The competition between endogenous dopamine and radioligands for specific binding to dopamine receptors.  


The ternary complex model of G-protein-linkage to receptors holds that agonists increase the affinity of the receptors for the G protein. Consequently, an agonist can exert the greatest inhibition of the binding of radioligands which are also agonists. We hypothesized that competition from endogenous dopamine in striatum of living mice should thus have a greater effect on the binding of the D(2,3) agonist N-[(3)H]propylnorapomorphine ([(3)H]NPA), than on the binding of the D(2,3) antagonist [(11)C]raclopride in living brain. The binding potential (p(B(0))), defined as the ratio of bound-to-unbound ligand after reserpine treatment, was measured in mouse striatum for [(11)C]raclopride (p(B(0))(RAC)(C)) = 8.5, and for [(3)H]NPA(p(B(0))(NPA)) = 5.3. Relative to these baseline values after dopamine depletion, saline-treatment decreased the p(B) of [(3)H]NPA by one-half, while the p(B) of [(11)C]raclopride declined by only one-third. Amphetamine decreased the p(B) of [(3)H]NPA to a greater extent than that of [(11)C]raclopride. The apparent inhibition constant of endogenous dopamine depended on the dopamine occupancy and declined to a value 1.66 times greater for [(3)H]NPA than for [(11)C]raclopride at its highest occupancies. Thus, the agonist binding was more sensitive than antagonist binding to competition from endogenous dopamine. Dopamine agonist ligands may be especially useful for PET studies of dopamine receptor occupancy by endogenous synaptic dopamine. Analysis of the effect of dopamine occupancy on the inhibition of agonist indicated a limited supply of G protein, with a maximum ternary complex fraction of 40% of maximum antagonist binding capacity. PMID:12105119

Cumming, Paul; Wong, Dean F; Dannals, Robert F; Gillings, Nic; Hilton, John; Scheffel, Ursula; Gjedde, Albert



Comparison of CGS 15943, ZM 241385 and SCH 58261 as antagonists at human adenosine receptors  

Microsoft Academic Search

Three structurally related non-xanthine compounds, CGS 15943, ZM 241385 and SCH 58261, are potent A2A adenosine receptor antagonists and have been used as tools in many pharmacological studies. We have now characterized their\\u000a affinity and selectivity profile on human adenosine receptors stably transfected into either CHO cells (A1 and A2B receptors) or HEK-293 cells (A2A and A3 receptors). In binding

E. Ongini; Silvio Dionisotti; Stefania Gessi; E. Irenius; Bertil B. Fredholm



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



2-Naphthalenesulphonyl L-aspartyl-(2-phenethyl)amide (2-NAP)--a selective cholecystokinin CCKA-receptor antagonist.  

PubMed Central

1. The in vitro pharmacological characterization of the sodium salt of 2-naphthalenesulphonyl 1-aspartyl-(2-phenethyl)amide [2-NAP], a hydrophilic compound derived from the C-terminal aspartate-phenylalanine dipeptide of cholecystokinin (CCK), is described. 2. 2-NAP behaved as a competitive antagonist of sulphated cholecystokinin octapeptide (CCK-8) at CCKA-receptors in both intact tissue bioassays (guinea-pig gall bladder, pancreas and ileum, human and rabbit gall bladder) and a radioligand displacement assay (guinea-pig pancreatic cells). The mean pKB, over assays, was 6.5. 3. Compared to the other assays, the rabbit gall bladder assay gave a significantly higher pKB estimate [7.0] for 2-NAP and a significantly lower estimate [8.9] for devazepide (formerly L-364,718 and MK-329), a well-characterized CCKA-receptor antagonist; these anomalous results suggest that a different class of CCKA-receptors may be involved. 4. 2-NAP, was found to be highly selective, having at least 300 fold greater affinity for CCKA-receptors than for 50 other pharmacological loci, including gastrin/CCKB, as estimated by bioassay or radioligand displacement.

Hull, R. A.; Shankley, N. P.; Harper, E. A.; Gerkowitch, V. P.; Black, J. W.



Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis.  


Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT3 receptor antagonists in the 1990s was a major advance in the prevention of acute emesis, and highlighted the critical role of serotonin in the emetic response. The next major advance in the treatment of chemotherapy induced nausea and vomiting (CINV) occurred in 2003 with the introduction of aprepitant, a tachykinin 1 (NK1) receptor antagonist. Aprepitant not only reduced acute emesis but also helped in the reduction of delayed emesis. Also in 2003, palonosetron, a second generation 5-HT3 receptor antagonist became available. Unlike the first generation 5-HT3 receptor antagonists, palonosetron demonstrated efficacy in preventing both acute and delayed emesis. This review focuses on the mechanism of action of 5-HT3 and NK1 receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between palonosetron and other 5-HT3 receptor antagonists in the clinic. In vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT3 receptor. The crossroads of acute and delayed emesis seem to include interactions among the 5-HT3 and NK1 receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV. PMID:24184669

Rojas, Camilo; Raje, Mithun; Tsukamoto, Takashi; Slusher, Barbara S



Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.  


Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF) receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC) model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2) protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients. PMID:24637403

Morita, Katsuya; Shiraishi, Seiji; Motoyama, Naoyo; Kitayama, Tomoya; Kanematsu, Takashi; Uezono, Yasuhito; Dohi, Toshihiro



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



NOP receptor mediates anti-analgesia induced by agonist-antagonist opioids.  


Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ?90min after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J-113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia. PMID:24188792

Gear, R W; Bogen, O; Ferrari, L F; Green, P G; Levine, J D



MEN16132, a novel potent and selective nonpeptide antagonist for the human bradykinin B 2 receptor. In vitro pharmacology and molecular characterization  

Microsoft Academic Search

The pharmacological characterization of the novel nonpeptide antagonist for the B2 receptor, namely MEN16132 (4-(S)-Amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride) is presented.The affinity of MEN16132 for the bradykinin B2 receptor has been investigated by means of competition studies at [3H]bradykinin binding to membranes prepared from Chinese Hamster Ovary (CHO) cells expressing the human bradykinin B2 receptor (pKi 10.5), human lung fibroblasts (pKi 10.5),

Paola Cucchi; Stefania Meini; Alessandro Bressan; Claudio Catalani; Francesca Bellucci; Paolo Santicioli; Alessandro Lecci; Angela Faiella; Luigi Rotondaro; Sandro Giuliani; Alessandro Giolitti; Laura Quartara; Carlo Alberto Maggi



The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents  

PubMed Central

Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3) is the main pathway via which it exerts its action in the myometrium. Changes in receptor levels, receptor desensitization, and locally produced oxytocin are factors that influence the effect of oxytocin on uterine contractility in labor. Activation of oxytocin receptor causes myometrial contractions by increasing intracellular Ca+2 and production of prostaglandins. Since oxytocin induces contractions, the inhibition of its action has been a target in the management of preterm labor. Atosiban is today the only oxytocin receptor antagonist that is available as a tocolytic. However, the quest for oxytocin receptor antagonists with a better pharmacological profile has led to the synthesis of peptide and nonpeptide molecules such as barusiban, retosiban, L-368,899, and SSR-126768A. Many of these oxytocin receptor antagonists are used only as pharmacological tools, while others have tocolytic action. In this paper, we summarize the action of oxytocin and its receptor and we present an overview of the clinical and experimental data of oxytocin antagonists and their tocolytic action.

Vrachnis, Nikolaos; Malamas, Fotodotis M.; Sifakis, Stavros; Deligeoroglou, Efthymios; Iliodromiti, Zoe



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



Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system  

Microsoft Academic Search

A novel non-competitive NMDA receptor antagonist MRZ 2\\/576 is a potent but rather short-acting (5–15 min) anticonvulsant following intravenous administration to mice as estimated by the prevention of maximal electroshock induced convulsions. This is most probably due to a rapid elimination of the drug from the central nervous system by transport processes that are sensitive to probenecid. Intravenous administration of

Andreas Friese; Erhard Seiller; Günter Quack; Bianka Lorenz; Jörg Kreuter



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.



Antagonistic Rgg Regulators Mediate Quorum Sensing via Competitive DNA Binding in Streptococcus pyogenes  

PubMed Central

ABSTRACT Recent studies have established the fact that multiple members of the Rgg family of transcriptional regulators serve as key components of quorum sensing (QS) pathways that utilize peptides as intercellular signaling molecules. We previously described a novel QS system in Streptococcus pyogenes which utilizes two Rgg-family regulators (Rgg2 and Rgg3) that respond to neighboring signaling peptides (SHP2 and SHP3) to control gene expression and biofilm formation. We have shown that Rgg2 is a transcriptional activator of target genes, whereas Rgg3 represses expression of these genes, and that SHPs function to activate the QS system. The mechanisms by which Rgg proteins regulate both QS-dependent and QS-independent processes remain poorly defined; thus, we sought to further elucidate how Rgg2 and Rgg3 mediate gene regulation. Here we provide evidence that S. pyogenes employs a unique mechanism of direct competition between the antagonistic, peptide-responsive proteins Rgg2 and Rgg3 for binding at target promoters. The highly conserved, shared binding sites for Rgg2 and Rgg3 are located proximal to the ?35 nucleotide in the target promoters, and the direct competition between the two regulators results in concentration-dependent, exclusive occupation of the target promoters that can be skewed in favor of Rgg2 in vitro by the presence of SHP. These results suggest that exclusionary binding of target promoters by Rgg3 may prevent Rgg2 binding under SHP-limiting conditions, thereby preventing premature induction of the quorum sensing circuit.

LaSarre, Breah; Aggarwal, Chaitanya; Federle, Michael J.



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


The cannabinoid 1 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 with vehicle. High-dose rimonabant also increased DRD2 availability in the ventral striatum (12%) and reduced weight gain. Thus, up-regulation of striatal DRD2 by chronic rimonabant administration may be an underlying mechanism of action and confirms the interactions of the endocannabinoid and dopaminergic systems. PMID:21955259

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



Molecular activation of PPAR? by angiotensin II type 1-receptor antagonists  

Microsoft Academic Search

Objective and designElevated blood pressure and insulin resistance are strongly associated in patients. We explored the potential for the anti-hypertensive angiotensin II type 1-receptor (ATR1) antagonists to improve insulin sensitivity through modulation of the nuclear receptor PPAR?, in vitro and in vivo compared to the potent insulin sensitizer, rosiglitazone.

David V. Erbe; Katherine Gartrell; Yan-Ling Zhang; Vipin Suri; Steven J. Kirincich; Sarah Will; Mylene Perreault; Suyue Wang; James F. Tobin



N-Arylalkylpiperidine urea derivatives as CC chemokine receptor-3 (CCR3) antagonists.  


The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils. PMID:15664858

Batt, Douglas G; Houghton, Gregory C; Roderick, John; Santella, Joseph B; Wacker, Dean A; Welch, Patricia K; Orlovsky, Yevgeniya I; Wadman, Eric A; Trzaskos, James M; Davies, Paul; Decicco, Carl P; Carter, Percy H



Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series.  


Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure-activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles. PMID:24630411

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



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



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



Tryptophanol-derived oxazolopiperidone lactams: Identification of a hit compound as NMDA receptor antagonist.  


N-Methyl-d-aspartate receptors (NMDAR) exacerbated activation leads to neuron death through a phenomenon called excitotoxicity. These receptors are implicated in several neurological diseases (e.g., Alzheimer and Parkinson) and thus represent an important therapeutic target. We herein describe the study of enantiopure tryptophanol-derived oxazolopiperidone lactams as NMDA receptor antagonists. The most active hit exhibited an IC50 of 63.4?M in cultured rat cerebellar granule neurons thus being 1.5 fold more active than clinically approved NMDA antagonist amantadine (IC50=92?M). PMID:24974339

Pereira, Nuno A L; Sureda, Francesc X; Esplugas, Roser; Pérez, Maria; Amat, Mercedes; Santos, Maria M M



Pharmacological characterization of GSK1004723, a novel, long-acting antagonist at histamine H1 and H3 receptors  

PubMed Central

BACKGROUND AND PURPOSE Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H1 and H3 receptor antagonist. EXPERIMENTAL APPROACH GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTP?S binding, superfused human bronchus and guinea pig whole body plethysmography. KEY RESULTS In cell membranes over-expressing human recombinant H1 and H3 receptors, GSK1004723 displayed high affinity, competitive binding (H1 pKi = 10.2; H3 pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t1/2 of 1.2 and 1.5 h for H1 and H3 respectively. GSK1004723 specifically antagonized H1 receptor mediated increases in intracellular calcium and H3 receptor mediated increases in GTP?S binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H1 and H3 receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L?1) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL?1 intranasal) antagonized the histamine-induced response with a duration of up to 72 h. CONCLUSIONS AND IMPLICATIONS GSK1004723 is a potent and selective histamine H1 and H3 receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis.

Slack, RJ; Russell, LJ; Hall, DA; Luttmann, MA; Ford, AJ; Saunders, KA; Hodgson, ST; Connor, HE; Browning, C; Clark, KL



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



The pharmacological properties of a novel MCH1 receptor antagonist isolated from combinatorial libraries.  


Melanin-concentrating hormone (MCH) is a neuropeptide that exhibits potent orexigenic activity. In rodents, it exerts its actions by interacting with one receptor, MCH(1) receptor which is expressed in many parts of the central nervous system (CNS). To study the physiological implications of the MCH system, we need to be able to block it locally and acutely. This necessitates the use of MCH(1) receptor antagonists. While MCH(1) receptor antagonists have been previously reported, they are mainly not accessible to academic research. We apply here a strategy that leads to the isolation of a high affinity and selective MCH(1) receptor antagonist amenable to in vivo analyses without further chemical modifications. This antagonist, TPI 1361-17, was identified through the screening of multiple non-peptide positional scanning synthetic combinatorial libraries (PS-SCL) totaling more than eight hundred thousand compounds in conditions that allow for the identification of only high-affinity compounds. TPI 1361-17 exhibited an IC(50) value of 6.1 nM for inhibition of 1 nM MCH-induced Ca(2+) mobilization and completely displaced the binding of [(125)I] MCH to rat MCH(1) receptor. TPI 1361-17 was found specific, having no affinity for a variety of other G-protein coupled receptors and channels. TPI 1361-17 was found active in vivo since it blocked MCH-induced food intake by 75%. Our results indicate that TPI 1361-17 is a novel and selective MCH(1) receptor antagonist and is an effective tool to study the physiological functions of the MCH system. These results also illustrate the successful application of combinatorial library screening to identify specific surrogate antagonists in an academic setting. PMID:19041642

Nagasaki, Hiroshi; Chung, Shinjae; Dooley, Colette T; Wang, Zhiwei; Li, Chunying; Saito, Yumiko; Clark, Stewart D; Houghten, Richard A; Civelli, Olivier



Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism  

PubMed Central

Background Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence.

Zorrilla, Eric P.; Heilig, Markus; de Wit, Harriet; Shaham, Yavin



The kinetics of competitive antagonism of nicotinic acetylcholine receptors at physiological temperature  

PubMed Central

Detailed information about the ligand-binding site of nicotinic acetylcholine receptors has emerged from structural and mutagenesis experiments. However, these approaches provide only static images of ligand–receptor interactions. Kinetic measurements of changes in protein function are needed to develop a more dynamic picture. Previously, we measured association and dissociation rate constants for competitive inhibition of current through embryonic muscle acetylcholine receptor channels at 25°C. Little is known about competitive antagonism at physiological temperatures. Here, we performed measurements at 37°C and used thermodynamics to estimate the energetics of antagonism. We used rapid solution exchange protocols to determine equilibrium and kinetics of inhibition of acetylcholine-activated currents in outside-out patches by (+)-tubocurarine, pancuronium and cisatracurium. Kinetic rates as high as 600 s?1 were resolved by this technique. Binding was primarily enthalpy driven. The 12°C increase in temperature decreased equilibrium antagonist binding by 1.7- to 1.9-fold. In contrast, association and dissociation rate constants increased 1.9- to 6.0-fold. Activation energies for dissociation were 90 ± 6, 106 ± 8 and 116 ± 10 kJ mol?1 for cisatracurium, (+)-tubocurarine and pancuronium, respectively. The corresponding apparent activation energies for association were 38 ± 6, 85 ± 6 and 107 ± 13 kJ mol?1. The higher activation energy for association of (+)-tubocurarine and pancuronium compared with cisatracurium is notable. This may arise from either a more superficial binding site for the large antagonist cisatracurium compared to the other ligands, or from a change in receptor conformation upon binding of (+)-tubocurarine and pancuronium but not cisatracurium. Differences in ligand desolvation and ligand conformation are not likely to be important.

Demazumder, Deeptankar; Dilger, James P



Anti free radical action of calcium antagonists and H1 and H2 receptors antagonists in neoplastic disease.  


The blood of the subjects suffering from Neoplastic Disease (ND) shows phenomena of membrane peroxidation due to the presence of Free Radicals (FRs), in a quantity much greater than the one observed in the blood of healthy subjects. This can be detected either by calculating the time necessary for the formation of "Heinz bodies" (Hbs), (p < 0.00001) after oxidative stress of the blood in vitro with acetylphenylidrazine (APH), or by calculating the methemoglobin (metHb) quantity that forms after the same treatment (P < 0.00001). The statistical analyses we carried out showed that metHb formation was not affected by age, sex, smoking habits, red blood cell number, Hb, Ht or tumor staging. In this study, by using equal parameters of investigation, we noted that the blood of the subjects with ND who were previously treated with calcium-antagonists drugs and with antagonists of H1 and H2 receptors, gave results completely superimposable on the results obtained from healthy subjects, implying that the treatment had avoided the increase of FRs. Therefore we concluded that calcium-antagonists and the antagonists of the H1 and H2 receptors behave as antioxidant substances, having decreased the FRs damaging activity on the cellular membranes, thus controlling, although to a limited degree, the pejorative evolution of the disease. It is also important to remember that investigations into the ND, even possible screenings, must take into account the above said data, submitting the subjects under investigation to a pharmacological wash out, particularly with those substances which, are considered to be scavengers of FRs. Some of these substances are investigated in this work. PMID:8712695

della Rovere, F; Broccio, M; Granata, A; Zirilli, A; Brugnano, L; Artemisia, A; Broccio, G



Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome  

PubMed Central

Tachykinin NK2 receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 receptor-mediated increase in intestinal motility. Accordingly, selective NK2 receptor antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 receptors located on peripheral branches of primary afferent neurones. NK2 receptor antagonists reduce the hyper-responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 receptor antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.

Lecci, Alessandro; Capriati, Angela; Maggi, Carlo Alberto



H 1 -receptor antagonists: Comparative pharmacology and clinical use  

Microsoft Academic Search

Summary H1-antihistamines have been used in treatment of allergic disorders for more than 30 years. However, many of them have been employed in a less than systematic fashion. Most of the antihistamines show an apparent dual mechanism of action on isolated organs, consisting of a competitive and a non-competitive component. To induce non-competitive antagonism, higher concentrations are usually required, but

D. Reinhardt; U. Borchard



Evidence for distinct antagonist-revealed functional states of 5-hydroxytryptamine(2A) receptor homodimers.  


The serotonin (5-hydroxytryptamine; 5-HT) 2A receptor is a cell surface class A G protein-coupled receptor that regulates a multitude of physiological functions of the body and is a target for antipsychotic drugs. Here we found by means of fluorescence resonance energy transfer and immunoprecipitation studies that the 5-HT(2A)-receptor homodimerized in live cells, which we linked with its antagonist-dependent fingerprint in both binding and receptor signaling. Some antagonists, like the atypical antipsychotics clozapine and risperidone, differentiate themselves from others, like the typical antipsychotic haloperidol, antagonizing these 5-HT(2A) receptor-mediated functions in a pathway-specific manner, explained here by a new model of multiple active interconvertible conformations at dimeric receptors. PMID:19279328

Brea, José; Castro, Marián; Giraldo, Jesús; López-Giménez, Juan F; Padín, Juan Fernando; Quintián, Fátima; Cadavid, Maria Isabel; Vilaró, Maria Teresa; Mengod, Guadalupe; Berg, Kelly A; Clarke, William P; Vilardaga, Jean-Pierre; Milligan, Graeme; Loza, Maria Isabel



Computational insights into the binding mechanism of antagonists with neuropeptide B/W receptor 1.  


Neuropeptide B/W receptor 1 (NPBWR1), previously known as G-protein coupled receptor 7 (GPR7), is a class A G-protein coupled receptor implicated in the modulation of several neuroendocrine functions such as feeding behavior, energy homeostasis, epilepsy, and analgesia. In recent years, a few antagonists have been designed that bind to NPBWR1 with high affinity. However, the exact binding modes between the antagonists and the receptor are still unknown. Unraveling the key pharmacophoric features of the receptor will guide the development of novel compounds with increased potency for therapeutic use. Here, we studied the structural organization of NPBWR1 receptor and its antagonist binding modes through computational approaches. Based on the dynamics and energetic features of receptor-ligand interactions, we categorized the binding affinities of the antagonists for NPBWR1 and identified key residues responsible for ligand recognition by NPBWR1. Binding free energy calculations revealed that the residues Trp102(ECL1), Val113(3.29), Gln281(ECL3), and Ala274(6.58) were crucial for ligand interaction. The results of our study will be useful to understand the structure-function relationship of NPBWR1 that may assist future drug discovery initiatives. PMID:24938207

Patra, Mahesh Chandra; Maharana, Jitendra; Dehury, Budheswar; De, Sachinandan



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



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.



Comparison of the water diuretic activity of kappa receptor agonists and a vasopressin receptor antagonist in dogs.  


Strategies for developing selective water diuretic agents have involved development of kappa opioid receptor agonists and vasopressin V2 receptor antagonists; however, these two classes of compounds have not been compared directly. We have investigated the activity of three kappa receptor agonists and one nonpeptide vasopressin receptor antagonist in conscious dogs. SB 215520, SB 215519 and niravoline are selective kappa agonists with variable abilities to cause a water diuresis and ataxia in rats. When administered to conscious hydropenic dogs, the kappa agonists resulted in an increase in free water clearance; however, these effects were associated with an antinatriuresis, an increase in heart rate and, at the higher doses, central nervous system side effects. Conversely, the vasopressin receptor antagonist, OPC 31260, resulted in a significant water diuresis without any accompanying changes in sodium excretion and heart rate, and with no apparent central nervous system effects. These studies suggest that, at least in dogs, a vasopressin receptor antagonist is a more selective water diuretic than a kappa receptor agonist. PMID:9067301

Brooks, D P; Valente, M; Petrone, G; Depalma, P D; Sbacchi, M; Clarke, G D



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



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 A(2A) 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



A novel class of 5HT 2a receptor antagonists: Aryl aminoguanidines  

Microsoft Academic Search

Local delivery of serotonin (5-HT) produces a rapid edematous response in soft tissues via increased fluid extravasation which is prevented by 5-HT2 antagonists such as ketanserin or mianserin. Here we report the effects of a new class of aminoguanidine 5-HT2 antagonists, with relative selectivity for 5-HT2A receptors which are potent inhibitors of 5-HT-induced paw edema in the rat. Radioligand binding

Henry U. Bryant; David L. Nelson; Donald Button; Harlan W. Cole; Melvyn B. Baez; Virginia L. Lucaites; David B. Wainscott; Cecilia Whitesitt; Jon Reel; Richard Simon; Gary A. Koppel



Interaction of astemizole, an H 1 receptor antagonist, with conventional antiepileptic drugs in mice  

Microsoft Academic Search

Histamine is one of the aminergic neurotransmitters, playing an important role in the regulation of a number of physiological processes. There are several subtypes of histamine receptors—H1, H2, H3 and the recently discovered H4. H1 receptors exist on mast cells, basophils, enterochromaffin cells and in the central nervous system, being located postsynaptically. H1 receptor antagonists, including classical antiallergy drugs, occasionally

Mariusz ?wi?der; Marian Wielosz; Stanis?aw J. Czuczwar



A study of antagonist affinities for the human histamine H2 receptor  

PubMed Central

Background and purpose: Ligand affinity has been a fundamental concept in the field of pharmacology and has traditionally been considered to be constant for a given receptor–ligand interaction. Recent studies have demonstrated that this is not true for all three members of the Gs-coupled ?-adrenoceptor family. This study evaluated antagonist affinity measurements at a different Gs-coupled receptor, the histamine H2 receptor, to determine whether antagonist affinity measurements made at a different family of GPCRs were constant. Experimental approach: CHO cells stably expressing the human histamine H2 receptor and a CRE-SPAP reporter were used and antagonist affinity was assessed in short-term cAMP assays and longer term CRE gene transcription assays. Key results: Nine agonists and seven antagonists, of sufficient potency at the H2 receptor to examine in detail, were identified. Measurements of antagonist affinity were the same regardless of the efficacy of the competing agonist, time of agonist incubation, cellular response measured or presence of a PDE inhibitor. Conclusions and implications: Antagonist affinity at the Gs-coupled histamine H2 receptor obeys the accepted dogma for antagonism at GPCRs. This study further confirms that something unusual is indeed happening with the ?-adrenoceptors and is not an artefact related to the transfected cell system used. As the human histamine H2 receptor does not behave in a similar manner to any of the human ?-adrenoceptors, it is clear that information gathered from one GPCR cannot be simply extrapolated to predict the behaviour of another GPCR. Each GPCR therefore requires careful and detailed evaluation on its own.

Baker, J G



Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa.  


Recent studies have described muscarinic receptors on the mucosa and the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine, and trospium. Specimens were collected from asymptomatic patients (50-72 years old) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [3H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low-affinity sites in mucosa and 78% low-affinity sites in detrusor, probably representing M(2)/M(4) receptors. There was an excellent correlation (r(2) = 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates ( approximately 20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB. PMID:19029429

Mansfield, Kylie J; Chandran, Jonathan J; Vaux, Kenneth J; Millard, Richard J; Christopoulos, Arthur; Mitchelson, Frederick J; Burcher, Elizabeth



Molecular modeling of histamine H3 receptor and QSAR studies on arylbenzofuran derived H3 antagonists.  


Histamine H3 receptors are presynaptic autoreceptors found in both central and peripheral nervous systems of many species. The central effects of these receptors suggest a potential therapeutic role for their antagonists in treatment of several neurological disorders such as epilepsy, schizophrenia, Alzheimer's and Parkinson's diseases. The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure-activity relationship (QSAR) studies and receptor modeling/docking techniques. A combination of partial least squares (PLS) and genetic algorithm (GA) was used in the QSAR approach to select the structural descriptors relevant to the receptor binding affinity of a series of 58 H3 antagonists. The descriptors were selected out of a pool of >1000 descriptors calculated by DRAGON, Hyperchem and ACD labs suite of programs. The resulting QSAR models for rat and human H3 binding affinities were validated using different strategies. QSAR models generated in the current work suggested the role of charge transfer interactions in the ligand-receptor interaction verified using the molecular modeling of the receptor and docking two antagonists to the binding site. The 3D model of human H3 receptor was built based on bovine rhodopsin structure and evaluated by molecular dynamics (MD) simulation in a mixed water-vacuum-water environment. The results were indicative of the stability of the model relating the observed structural changes during the MD simulation to the suggested ligand-receptor interactions. The results of this investigation are expected to be useful in the process of design and development of new potent H3 receptor antagonists. PMID:17561422

Dastmalchi, Siavoush; Hamzeh-Mivehroud, Maryam; Ghafourian, Taravat; Hamzeiy, Hossain



Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y(1) receptor antagonist.  


Treatment of obesity is still a large unmet medical need. Neuropeptide Y is the most potent orexigenic peptide in the animal kingdom. Its five cloned G-protein couple receptors are all implicated in the regulation of energy homeostasis evidenced by overexpression or deletion of neuropeptide Y or its receptors. Neuropeptide Y most likely exerts its orexigenic activity via the neuropeptide Y(1) and neuropeptide Y(5) receptors, although the involvement of the neuropeptide Y(2) and neuropeptide Y(4) receptors are also gaining importance. The lack of potent, selective, and brain penetrable pharmacologic agents at these receptors made our understanding of the modulation of food intake by neuropeptide Y-ergic agents elusive. BMS-193885 (1,4-dihydro-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino] carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester) is a potent and selective neuropeptide Y(1) receptor antagonist. BMS-193885 has 3.3 nM affinity at the neuropeptide Y(1) receptor, acting competitively at the neuropeptide Y binding site. BMS-193885 increased the K(d) of [(125)I]PeptideYY from 0.35 nM to 0.65 nM without changing the B(max) (0.16 pmol/mg of protein) in SK-N-MC cells that endogenously express the neuropeptide Y(1) receptor. It is also found to be a full antagonist with an apparent K(b) of 4.5 nM measured by reversal of forskolin (FK)-stimulated inhibition of cAMP production by neuropeptide Y. Pharmacological profiling showed that BMS-193885 has no appreciable affinity at the other neuropeptide Y receptors, and is also 200-fold less potent at the alpha(2) adrenergic receptor. Testing the compound in a panel of 70 G-protein coupled receptors and ion channels resulted in at least 200-fold or greater selectivity, with the exception of the sigma(1) receptor, where the selectivity was 100-fold. When administered intracerebroventricularly or directly into the paraventricular nucleus of the hypothalamus, it blocked neuropeptide Y-induced food intake in rats. Intraperitoneal administration of BMS-193885 (10 mg/kg) also reduced one-hour neuropeptide Y-induced food intake in satiated rats, as well as spontaneous overnight food consumption. Chronic administration of BMS-193885 (10 mg/kg) i.p. for 44 days significantly reduced food intake and the rate of body weight gain compared to vehicle treated control without developing tolerance or affecting water intake. These results provide supporting evidence that BMS-193885 reduces food intake and body weight via inhibition of the central neuropeptide Y(1) receptor. BMS-193885 has no significant effect of locomotor activity up to 20 mg/kg dose after 1 h of treatment. It also showed no activity in the elevated plus maze when tested after i.p. and i.c.v. administration, indicating that reduction of food intake is unrelated to anxious behavior. BMS-193885 has good systemic bioavailability and brain penetration, but lacks oral bioavailability. The compound had no serious cardiovascular adverse effect in rats and dogs up to 30 and 10 mg/kg dose, respectively, when dosed intravenously. These data demonstrate that BMS-193885 is a potent, selective, brain penetrant Y(1) receptor antagonist that reduces food intake and body weight in animal models of obesity both after acute and chronic administration. Taken together the data suggest that a potent and selective neuropeptide Y(1) receptor antagonist might be an efficacious treatment for obesity in humans. PMID:18573246

Antal-Zimanyi, Ildiko; Bruce, Marc A; Leboulluec, Karen L; Iben, Lawrence G; Mattson, Gail K; McGovern, Rachel T; Hogan, John B; Leahy, Christina L; Flowers, Sharon C; Stanley, Jennifer A; Ortiz, Astrid A; Poindexter, Graham S



Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists.  


Herein, we describe the synthesis and pharmacological profiles of novel quinuclidinyl heteroarylcarbamate derivatives. Among them, the quinuclidin-4-yl thiazolylcarbamate derivative ASP9133 was identified as a promising long-acting muscarinic antagonist (LAMA) showing more selective inhibition of bronchoconstriction against salivation and more rapid onset of action in a rat model than tiotropium bromide. PMID:24837158

Nagashima, Shinya; Matsushima, Yuji; Hamaguchi, Hisao; Nagata, Hiroshi; Kontani, Toru; Moritomo, Ayako; Koshika, Tadatsura; Takeuchi, Makoto



A potential role of odorant receptor agonists and antagonists in the treatment of infertility and contraception.  


In 1992, the identification of odorant receptor expression in mammalian testicular tissue prepared the ground for an ongoing debate about a potential role for these chemoreceptors in significant sperm behaviors, in particular chemotaxis. The identification of hOR17-4, a human testicular odorant receptor that mediates sperm chemotaxis in various bioassays, revealed the first potential key player in this reproductively relevant scenario. Detailed knowledge of the receptor's molecular receptive field, the discovery of a potent receptor antagonist, as well as specific insight into the receptor-linked signaling cascade(s), could establish a basis for pioneering future applications in fertility treatment and/or contraception. PMID:15898342

Spehr, Marc; Hatt, Hanns



MEN16132, a novel potent and selective nonpeptide antagonist for the human bradykinin B2 receptor. In vitro pharmacology and molecular characterization.  


The pharmacological characterization of the novel nonpeptide antagonist for the B2 receptor, namely MEN16132 (4-(S)-Amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride) is presented. The affinity of MEN16132 for the bradykinin B2 receptor has been investigated by means of competition studies at [3H]bradykinin binding to membranes prepared from Chinese Hamster Ovary (CHO) cells expressing the human bradykinin B2 receptor (pKi 10.5), human lung fibroblasts (pKi 10.5), guinea pig airways (pKi 10.0), guinea pig ileum longitudinal smooth muscle (pKi 10.2), or guinea pig cultured colonic myocytes (pKi 10.3). In all assays MEN16132 was as potent as the peptide antagonist Icatibant, and from 3- to 100-fold more potent than the reference nonpeptide antagonists FR173657 or LF16-0687. The selectivity for the bradykinin B2 receptor was checked at the human bradykinin B1 receptor (pKi<5), and at a panel of 26 different receptors and channels. The antagonist potency was measured in functional assays, i.e., in blocking the bradykinin induced inositolphosphates (IP) accumulation at the human (CHO: pKB 10.3) and guinea pig (colonic myocytes: pKB 10.3) B2 receptor, or in antagonizing the bradykinin induced contractile responses in human (detrusor smooth muscle: pKB 9.9) and guinea pig (ileum longitudinal smooth muscle: pKB 10.1) tissues. In both functional assay types MEN16132 exerted a different antagonist pattern, i.e., surmountable at the human and insurmountable at the guinea pig bradykinin B2 receptors. Moreover, the receptor determinants important for the high affinity interaction of MEN16132 with the human bradykinin B2 receptor were investigated by means of radioligand binding studies performed at 24 point-mutated receptors. The results obtained revealed that residues in transmembrane segment 2 (W86A), 3 (I110A), 6 (W256A), and 7 (Y295A, Y295F but not much Y295W), were crucial for the high affinity of MEN16132. In conclusion, MEN16132 is a new, potent, and selective nonpeptide bradykinin B2 receptor antagonist. PMID:16324696

Cucchi, Paola; Meini, Stefania; Bressan, Alessandro; Catalani, Claudio; Bellucci, Francesca; Santicioli, Paolo; Lecci, Alessandro; Faiella, Angela; Rotondaro, Luigi; Giuliani, Sandro; Giolitti, Alessandro; Quartara, Laura; Maggi, Carlo Alberto



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



Novel Cyclic Phosphinic Acids as GABAC ? Receptor Antagonists: Design, Synthesis, and Pharmacology  

PubMed Central

Understanding the role of GABAC receptors in the central nervous system is limited due to a lack of specific ligands. Novel ?-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABAC receptor antagonists. A compound of high potency (19, KB = 10 ?M) and selectivity (greater than 100 times at ?1 GABAC receptors as compared to ?1?2?2L GABAA and GABAB(1b,2) receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead agents for developing into more potent and selective GABAC receptor antagonists with increased lipophilicity for future in vivo studies.



Characterization of a putative alpha-MSH antagonist 153N-6 at melanocortin receptor subtypes by radioligand binding.  


This study was conducted to determine the binding properties of recently discovered, putative alpha-MSH antagonist 153N-6 peptide at melanocortin receptor subtypes. The results indicated that 153N-6 peptide can competitively inhibit [125I]NDP-MSH binding from all the receptor subtypes investigated. The relative potency order of 153N-6 for inhibiting [125I]NDP-MSH binding was MC1R (Ki 955 +/- 35.7 nM) = MC4R (Ki 1151 +/- 106 nM) > MC3R (Ki 3229 +/- 637 nM) > MC5R (Ki 6286 +/- 462 nM), which is different than the potency order of either NDP-MSH or alpha-MSH. Substitution of aspartic acid117 and histidine260 by alanine in melanocortin 1 receptor resulted in a 4.75-fold decrease (Ki 4541 +/- 644 nM) and an 11-fold increase (Ki 84.29 +/- 4.53 nM), respectively, in the relative potency of 153N-6 for competitively inhibiting [125I]NDP-MSH binding. PMID:8801544

Chhajlani, V



Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist.  


The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels. PMID:24900298

Eastwood, Paul; Esteve, Cristina; González, Jacob; Fonquerna, Silvia; Aiguadé, Josep; Carranco, Inés; Doménech, Teresa; Aparici, Mònica; Miralpeix, Montserrat; Albertí, Joan; Córdoba, Mónica; Fernández, Raquel; Pont, Mercè; Godessart, Núria; Prats, Neus; Loza, María Isabel; Cadavid, María Isabel; Nueda, Arsenio; Vidal, Bernat



Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist  

PubMed Central

The structure?activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.



Discovery of novel orally active ureido NPY Y5 receptor antagonists.  


We have derived a novel series of neuropeptide Y (NPY) Y5 receptor antagonists from the biphenylurea 3. Cyclohexylurea 21c, a member of the series, is a potent NPY Y5 receptor antagonist that exhibits excellent pharmacokinetic parameters in rats and dogs. On chronic oral administration to diet-induced obese rats, 21c displayed an anti-obesity profile, causing a modest reduction in food intake, a significant decrease in body weight gain, a decrease in adipose mass, and an increase in lean tissue mass. PMID:18160282

Li, Guoqing; Stamford, Andrew W; Huang, Ying; Cheng, Kuo-Chi; Cook, John; Farley, Constance; Gao, Jun; Ghibaudi, Lorraine; Greenlee, William J; Guzzi, Mario; van Heek, Margaret; Hwa, Joyce J; Kelly, Joe; Mullins, Deborra; Parker, Eric M; Wainhaus, Sam; Zhang, Xiaoping



Chronic treatment with caffeine blunts the hyperlocomotor but not cognitive effects of the N -methyl- d -aspartate receptor antagonist MK-801 in mice  

Microsoft Academic Search

  \\u000a \\u000a Rationale. Administration of N-methyl-d-aspartate (NMDA) receptor antagonists produce hyperlocomotion and cognitive deficits in rodents. Activation of NMDA receptors\\u000a promotes adenosine release, and adenosine agonists prevent central effects of NMDA receptor antagonists. We hypothesized that\\u000a if NMDA receptor antagonists require adenosine to produce behavioral effects, mice tolerant to the adenosine receptor antagonist\\u000a caffeine would have a diminished response to NMDA

Oscar P. Dall'Igna; Adriana L. da Silva; Marcelo O. Dietrich; Anselmo Hoffmann; Ricardo V. de Oliveira; Diogo O. Souza; Diogo R. Lara



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



On the role of P2X 7 receptors in dopamine nerve cell degeneration in a rat model of Parkinson’s disease: studies with the P2X 7 receptor antagonist A-438079  

Microsoft Academic Search

The role of the ATP-gated receptor, P2X7, has been evaluated in the unilateral 6-OHDA rat model of Parkinson’s disease using the P2X7 competitive antagonist A-438079. Nigral P2X7 immunoreactivity was mainly located in microglia but also in astroglia. A-438079 partially but significantly prevented the\\u000a 6-OHDA-induced depletion of striatal DA stores. However, this was not associated with a reduction of DA cell

Daniel MarcellinoDiana; Diana Suárez-Boomgaard; María Dolores Sánchez-Reina; José A. Aguirre; Takashi Yoshitake; Shimako Yoshitake; Beth Hagman; Jan Kehr; Luigi F. Agnati; Kjell Fuxe; Alicia Rivera



An oral selective M3 cholinergic receptor antagonist in COPD  

Microsoft Academic Search

Cholinergic antagonists have been used since the early 1900s as bronchodilators for chronic obstructive pulmonary disease (COPD). The present study investigated whether an oral muscarinic M3-selective anticholinergic agent (OrM3) would provide an improved therapeutic advantage compared with an inhaled anticholinergic agent in patients with COPD. A 6-week, multicentre, randomised, placebo- and active-controlled, parallel-group study was performed at 56 sites in

S. Lu; D. D. Parekh; O. Kuznetsova; S. A. Green; C. A. Tozzi; T. F. Reiss



The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension.  


Hypertension is a major risk factor for stroke and coronary events in elderly people and clinical trials have shown that treatment of hypertension with various drugs can result in a substantial reduction in cerebrovascular and cardiovascular events. The angiotensin II type 1 (AT1) receptor antagonists are the newest class of antihypertensive agents to be used widely in clinical practice. AT1 receptor antagonists can generally be given once-daily. They are also extremely well tolerated with minimal first-dose hypotension and an incidence of adverse effects similar to that seen with placebo. Adverse event rates are significantly lower than with other classes of antihypertensive drugs including ACE inhibitors. These factors result in improved compliance and increased rates of continuance on therapy. AT1 receptor antagonists show similar efficacy in lowering blood pressure to other classes of antihypertensive agents and their antihypertensive effect is potentiated when they are given concomitantly with low-dose thiazide diuretics. AT1 receptor antagonists are eliminated predominantly by the hepatic route but most are not subject to extensive metabolism and interactions with other drugs are uncommon. This is an advantage in the elderly, who are often receiving multiple medications which increases the risk for adverse drug interactions. Dose adjustments are not usually required in the elderly unless there is plasma volume depletion. Although plasma AT1 receptor antagonist concentrations are generally higher in the elderly than in younger subjects, this pharmacokinetic difference may be balanced by decreased activation of the circulating renin-angiotensin-aldosterone system in the elderly. Recent clinical studies in high-risk hypertensive patients with left ventricular hypertrophy or in patients with diabetic nephropathy or heart failure have demonstrated that AT1 receptor antagonists can improve clinical outcomes to a similar or sometimes greater extent than other antihypertensive agents. Many of these studies have included large numbers of older patients and have confirmed the excellent tolerability profile of these drugs. Thus, AT1 receptor antagonists should be considered as a possible first-line treatment or as a component of combination therapy in patients with type 2 diabetes mellitus and microalbuminuria or nephropathy and as an alternative or additional treatment to ACE inhibitors in patients with heart failure or left ventricular dysfunction. AT1 receptor antagonists also appear to reduce the onset of new diabetes compared with some other antihypertensive drugs. The benefits in terms of organ protection have mainly been seen in studies using higher doses of particular AT1 receptor antagonists and it is not certain at present whether these results can be extrapolated to other members of the class. As the elderly are more likely to have developed organ damage related to hypertension or to have heart failure or diabetes as concomitant conditions, AT1 receptor antagonists represent an appropriate option for many elderly patients. The main disadvantage of these drugs is the cost of the medication but this may be offset by their improved tolerability with fewer adverse reactions and thus increased compliance, resulting in better blood pressure control and fewer clinical events. Overall, AT1 receptor antagonists are well tolerated and efficacious for blood pressure-lowering when given as a single daily dose in elderly patients and have many potential benefits in high-risk hypertensive subjects. PMID:16536636

Thomas, G Neil; Chan, Paul; Tomlinson, Brian



Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system.  


Evidence exists to implicate the monoamine histamine in the control of arousal and cognitive functions. Antagonists of H(3) receptors are postsynaptic and presynaptic modulators of neural transmission in a variety of neuronal circuits relevant to cognition. Accumulating neuroanatomical, neurochemical, pharmacological, and behavioral data support the idea that H(3) receptor antagonists may function to improve cognitive performances in disease states (e.g., Alzheimer's disease and mild cognitive impairment states). Thus, H(3) receptor antagonists have been shown to increase performance in attention and memory tests in nonhuman experiments and prevent the degradation in performances produced by scopolamine, MK-801, or age. In contrast, agonists of the H(3) receptor generally produce cognitive impairing effects in animal models. The role of H(3) receptors in these behavioral effects is substantiated by data indicating a central origin for their effects, the selectivity of some of the H(3) receptor antagonists studied, and the pharmacological modification of effects of H(3) receptor antagonists by selective H(3) receptor agonists. Data and issues that challenge the potential role for H(3) receptor antagonists in cognitive processes are also critically reviewed. H(3) receptor antagonists may also have therapeutic value in the management of obesity, pain, sleep disorders, schizophrenia, and attention deficit hyperactivity disorder. PMID:15251226

Witkin, J M; Nelson, D L



Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801.  


Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose-dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects. PMID:19576911

Okamura, Naoe; Reinscheid, Rainer K; Ohgake, Shintaro; Iyo, Masaomi; Hashimoto, Kenji



Kinetics of in vivo binding of antagonist to muscarinic cholinergic receptor in the human heart studied by Positron Emission Tomography  

SciTech Connect

Positron Emission Tomography (PET) was used to analyze in vivo antagonist binding to human myocardial muscarinic cholinergic receptor. The methiodide salt of the muscarinic antagonist, quinuclidinyl benzilate (MQNB), was labeled with the positron emitter, Carbon-11, and injected intravenously to 8 normal subjects. /sup 11/C-MQNB concentration was determined in vivo in the ventricular septum from 40 cross-sectional images acquired at the same transverse level over a period of 70 minutes. In 4 subjects, various amounts of unlabeled atropine were rapidly injected at 20 minutes to study whether atropine competitively inhibited MQNB. The kinetics of binding of /sup 11/C-MQNB were not the same in vivo and in vitro. The apparent dissociation rate of /sup 11/C-MQNB in vivo was much slower (by 1 to 2 orders of magnitude) than that observed in vitro with /sup 3/H-QNB. After atropine injection, /sup 11/C-MQNB dissociated from its binding sites at a rate that apparently depended on the amount of atropine present. /sup 11/C-MQNB kinetics were analyzed with a mathematical model which assumes the existence of a boundary layer containing free ligand in the vicinity of the binding sites. The dissociation rate of the radioligand depends on the probability of its rebinding to a free receptor site. 11 references, 1 table.

Syrota, A.; Paillotin, G.; Davy, J.M.; Aumont, M.C.



Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor.  


Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure-activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5nM in an FXR binding assay and 468.5nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR. PMID:24775917

Yu, Donna D; Lin, Wenwei; Forman, Barry M; Chen, Taosheng



Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms.  


Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear. In the present study, we characterized the non-competitive NMDAr antagonists-increased GBO (30-80 Hz) power. MK-801 (0.05-0.2 mg/kg) increased the GBO power, exhibiting an inverted U-shape dose-response curve; at higher doses (0.3-1 mg/kg), the increase in GBO was reversed. The GBO power was closely correlated with the high-frequency oscillation (130-180 Hz) power following MK-801 administration, while the GBO power was inversely correlated with the increase in delta oscillation (0.5-4 Hz) power at higher doses. PCP (1.25-10 mg/kg) and ketamine (2.5-30 mg/kg) also exhibited the inverted U-shape dose-responses for the basal GBO power similar to MK-801. Interestingly, memantine (10-30 mg/kg) dose-dependently and potently increased the GBO power without remarkably affecting the other frequency band. In contrast, other psychotomimetics, such as methamphetamine (1-10 mg/kg) and DOI (0.5-2 mg/kg), did not induce noticeable changes in the basal GBO power even at doses that induce abnormal behaviors, indicating that the increase in GBO power induced by NMDAr antagonists is not necessarily attributed to psychotomimetic effects. In conclusion, the basal GBO power increase in response to non-competitive NMDAr antagonists may reflect the cortical hyperglutamatergic state through GABAergic disinhibition. PMID:24907590

Hiyoshi, Tetsuaki; Kambe, Daiji; Karasawa, Jun-Ichi; Chaki, Shigeyuki



Rational Design of Potent Antagonists to the Human Growth Hormone Receptor  

NASA Astrophysics Data System (ADS)

A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.



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



Interaction of linear and cyclic peptide antagonists at the human B 2 kinin receptor  

Microsoft Academic Search

The ligand receptor interactions involving the C-terminal moiety of kinin B2 receptor antagonists Icatibant (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-Dtic-Oic-Arg-OH), MEN 11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-Dtic-Oic-Arg)c(7?-10?)) and a series of analogs modified in position 10 were investigated by radioligand-binding experiments at the wild type (WT) and at the Ser111Ala and Ser111Lys mutant human kinin B2 receptors. Icatibant and [Lys10]-Icatibant maintained the same high affinity towards the three receptors.

Paola Cucchi; Stefania Meini; Laura Quartara; Alessandro Giolitti; Sabrina Zappitelli; Luigi Rotondaro; Carlo Alberto Maggi



Characterization of RO4583298 as a novel potent, dual antagonist with in vivo activity at tachykinin NK1 and NK3 receptors  

PubMed Central

BACKGROUND AND PURPOSE Clinical results of osanetant and talnetant (selective-NK3 antagonists) indicate that blocking the NK3 receptor could be beneficial for the treatment of schizophrenia. The objective of this study was to characterize the in vitro and in vivo properties of a novel dual NK1/NK3 antagonist, RO4583298 (2-phenyl-N-(pyridin-3-yl)-N-methylisobutyramide derivative). EXPERIMENTAL APPROACH RO4583298 in vitro pharmacology was investigated using radioligand binding ([3H]-SP, [3H]-osanetant, [3H]-senktide), [3H]-inositol-phosphate accumulation Schild analysis (SP- or [MePhe7]-NKB-induced) and electrophysiological studies in guinea-pig substantia nigra pars compacta (SNpc). The in vivo activity of RO4583298 was assessed using reversal of GR73632-induced foot tapping in gerbils (GFT; NK1) and senktide-induced tail whips in mice (MTW; NK3). KEY RESULTS RO4583298 has a high-affinity for NK1 (human and gerbil) and NK3 (human, cynomolgus monkey, gerbil and guinea-pig) receptors and behaves as a pseudo-irreversible antagonist. Unusually it binds with high-affinity to mouse and rat NK3, yet with a partial non-competitive mode of antagonism. In guinea-pig SNpc, RO4583298 inhibited the senktide-induced potentiation of spontaneous activity of dopaminergic neurones with an apparent non-competitive mechanism of action. RO4583298 (p.o.) robustly blocked the GFT response, and inhibited the MTW. CONCLUSIONS AND IMPLICATIONS RO4583298 is a high-affinity, non-competitive, long-acting in vivo NK1/NK3 antagonist; hence providing a useful in vitro and in vivo pharmacological tool to investigate the roles of NK1 and NK3 receptors in psychiatric disorders.

Malherbe, P; Knoflach, F; Hernandez, MC; Hoffmann, T; Schnider, P; Porter, RH; Wettstein, JG; Ballard, TM; Spooren, W; Steward, L



Arginine vasopressin receptor antagonists (vaptans): pharmacological tools and potential therapeutic agents.  


Arginine vasopressin (AVP) attracted attention as a potentially important neurohormonal mediator of the heart failure (HF) syndrome and hyponatremic states in humans because AVP influences renal handling of free water, vasoconstriction and myocyte biology through activation of V? and V?(a) receptors. Current research is exploring V?- and dual V?(a)/V? receptor antagonism for the treatment of hyponatremia, as well as for the congestion and edema associated with chronic HF, because vasopressin receptor antagonists might offer benefits in comparison with conventional loop diuretics. The purpose of this review is to update the current status of experimental and clinical studies with available vasopressin receptor antagonists (conivaptan and tolvaptan) and their potential role in the treatment of HF and hyponatremia of multiple causes. PMID:20708094

Veeraveedu, Punniyakoti T; Palaniyandi, Suresh S; Yamaguchi, Ken'ichi; Komai, Yutaka; Thandavarayan, Rajarajan A; Sukumaran, Vijayakumar; Watanabe, Kenichi



Design of a Potent CB1 Receptor Antagonist Series: Potential Scaffold for Peripherally-Targeted Agents  

PubMed Central

Antagonism of cannabinoid-1 (CB1) receptor signaling has been demonstrated to inhibit feeding behaviors in humans, but CB1-mediated central nervous system (CNS) side effects have halted the marketing and further development of the lead drugs against this target. However, peripherally restricted CB1 receptor antagonists may hold potential for providing the desired efficacy with reduced CNS side effect profiles. In this report we detail the discovery and structure–activity-relationship analysis of a novel bicyclic scaffold (3) that exhibits potent CB1 receptor antagonism and oral activity in preclinical feeding models. Optimization of physical properties has led to the identification of analogues which are predicted to have reduced CNS exposure and could serve as a starting point for the design of peripherally targeted CB1 receptor antagonists.



Antagonist binding and induced conformational dynamics of GPCR A2A adenosine receptor.  


The A2A adenosine receptor (A2AAR) is a unique G-protein coupled receptor (GPCR), because besides agonist, its antagonist could also lead to therapeutic relevance. Based on A2AAR-antagonist crystal structure, we have studied the binding mechanism of two distinct antagonists, ZM241385 and KW6002, and dynamic behaviors of A2AAR induced by antagonist binding. Key residues interacting with both antagonists and residues specifically binding to one of them are identified. ZM241385 specifically bound to S67(2.65), M177(5.38), and N253(6.55), while KW6002 binds to F62(2.60), A81(3.29), and H264(7.29). Moreover, interactions with L167(5.28) are found for both antagonists, which were not reported in agonist binding. The dynamic behaviors of antagonist bound holo-A2AARs were found to be different from the apo-A2AAR in three typical functional switches, (i) the "ionic lock" was in equilibrium between formation and breakage in apo-A2AAR, but stayed broken in holo-A2AARs; (ii) the "rotamer toggle switch," T88(3.36)/F242(6.44)/W246(6.48), adopted different rotameric conformations in apo-A2AAR and holo-A2AARs; (iii) apo-A2AAR preferred ?-helical intracellular loop (IC)2 and flexible IC3, while holo-A2AARs had a flexible IC2 and ?-helical IC3. Our results indicated that antagonist binding induced different conformational rearrangements of these characteristic functional switches in apo-A2AAR and holo-A2AARs. PMID:23508898

Pang, Xueqin; Yang, Mingjun; Han, Keli



The turnover of estrogen receptor ? by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy  

PubMed Central

It has become apparent of late that even in tamoxifen and/or aromatase resistant breast cancers, ER? remains a bona fide therapeutic target. Not surprisingly, therefore, there has been considerable interest in developing Selective ER Degraders (SERDs), compounds that target the receptor for degradation. Currently, ICI 182,780 (ICI, fulvestrant) is the only SERD approved for the treatment of breast cancer. However, the poor pharmaceutical properties of this injectable drug and its lack of superiority over second line aromatase inhibitors in late stage breast cancer have negatively impacted its clinical use. These findings have provided the impetus to develop second generation, orally bioavailable SERDs with which quantitative turnover of ER? in tumors can be achieved. Interestingly however, the contribution of SERD activity to fulvestrant efficacy is unclear, making it difficult to define the characteristics desired of the next generation of ER antagonists. It is of significance therefore, that we have determined that the antagonist activity of ICI and its ability to induce ER? degradation are not coupled processes. Specifically, our results indicate that it is the ability of ICI to interact with ER? and to (a) competitively displace estradiol and (b) induce a conformational change in ER incompatible with transcriptional activation that are likely to be the most important pharmacological characteristics of this drug. Collectively, these data argue for a renewed emphasis on the development of high affinity, orally bioavailable pure antagonists and suggest that SERD activity though proven effective may not be required for ER? antagonism in breast cancer.

Wardell, Suzanne E.; Marks, Jeffrey R.; McDonnell, Donald P.



Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor.  


The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36?, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1. PMID:24935927

Günther, Sebastian; Sundberg, Eric J



SAR of the arylpiperazine moiety of obeline somatostatin sst 1 receptor antagonists  

Microsoft Academic Search

The SAR of over 50 derivatives of octahydrobenzo[g]quinoline (obeline)-type somatostatin sst1 receptor antagonist 1 is presented, focusing on the modification of its arylpiperazine moiety. Sst1 affinities in this series cover a range of five orders of magnitude with the best derivatives displaying subnanomolar sst1 affinities and >10,000-fold selectivities over the sst2 receptor subtype as well as promising pharmacokinetic properties.

Konstanze Hurth; Albert Enz; Philipp Floersheim; Conrad Gentsch; Daniel Hoyer; Daniel Langenegger; Peter Neumann; Paul Pfäffli; Dieter Sorg; Robert Swoboda; Annick Vassout; Thomas Troxler



SAR of the arylpiperazine moiety of obeline somatostatin sst1 receptor antagonists.  


The SAR of over 50 derivatives of octahydrobenzo[g]quinoline (obeline)-type somatostatin sst(1) receptor antagonist 1 is presented, focusing on the modification of its arylpiperazine moiety. Sst(1) affinities in this series cover a range of five orders of magnitude with the best derivatives displaying subnanomolar sst(1) affinities and >10,000-fold selectivities over the sst(2) receptor subtype as well as promising pharmacokinetic properties. PMID:17512199

Hurth, Konstanze; Enz, Albert; Floersheim, Philipp; Gentsch, Conrad; Hoyer, Daniel; Langenegger, Daniel; Neumann, Peter; Pfäffli, Paul; Sorg, Dieter; Swoboda, Robert; Vassout, Annick; Troxler, Thomas



Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists  

Microsoft Academic Search

The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT2A receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC50s under 5 nM. Data from in

Jeffrey G Varnes; Daniel S Gardner; Joseph B Santella III; John V Duncia; Melissa Estrella; Paul S Watson; Cheryl M Clark; Soo S Ko; Patricia Welch; Maryanne Covington; Nicole Stowell; Eric Wadman; Paul Davies; Kimberley Solomon; Robert C Newton; George L Trainor; Carl P Decicco; Dean A Wacker



Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.  


A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer. PMID:22094279

Yamamoto, Satoshi; Matsunaga, Nobuyuki; Hitaka, Takenori; Yamada, Masami; Hara, Takahito; Miyazaki, Junichi; Santou, Takashi; Kusaka, Masami; Yamaoka, Masuo; Kanzaki, Naoyuki; Furuya, Shuichi; Tasaka, Akihiro; Hamamura, Kazumasa; Ito, Mitsuhiro



Synthetic approaches to site selective deuterium incorporation in a novel CRTh2 receptor antagonist clinical candidate.  


Selection of acidic or basic reaction conditions, combined with appropriate temperatures, allowed for site selective direct incorporation of deuterium at multiple positions in the 7-azaindole-3-acetic acid CRTh2 receptor antagonist clinical candidate NVP-QAV680. PMID:24452929

Sandham, David A; Page, Christopher J



Chronic H2 receptor antagonist treatment and pulmonary complications post cardiac surgery.  

PubMed Central

OBJECTIVE: To examine the effects of chronic H2 receptor antagonist treatment and pulmonary complications, length of stay in intensive care (ITU), high dependency (HDU), and stay in hospital in patients who undergo pulsatile cardiopulmonary bypass. DESIGN: An analysis from a prospective database of patients undergoing cardiac surgery with pulsatile perfusion during cardiopulmonary bypass. SETTING: Hammersmith Hospital, regional cardiothoracic surgical centre. SUBJECTS: 2,642 patients who had undergone cardiac surgery involving pulsatile perfusion. Of these, 255 were on H2 receptor antagonist treatment. MAIN OUTCOME: Time to extubation, re-intubation rate, incidence of pulmonary oedema, measures incidence of lobar collapse and consolidation, incidence of antibiotic treatment for pulmonary infection, length of ITU, HDU and total hospital stay. RESULTS: 75.8% of patients on H2 receptor antagonists compared with 74.5% of control patients had no respiratory complications after cardiac surgery (P > 0.5). There was no significant difference between collapse and consolidation (P > 0.5), collapse and consolidation requiring antibiotics (P > 0.5), re-intubation (P > 0.5), pulmonary oedema (P > 0.5), time to extubation (P > 0.5), length of ITU stay (P > 0.5), length of HDU stay (P > 0.5), length of hospital stay (P > 0.5), and mortality (P > 0.5). CONCLUSION: Chronic H2 receptor antagonist treatment has no effect on pulmonary complications after cardiac surgery.

Poullis, M.



Further studies on the pharmacological profile of the neuropeptide S receptor antagonist SHA 68  

Microsoft Academic Search

Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Previous studies demonstrated that the non-peptide molecule SHA 68 acts as a selective NPSR antagonist. In the present study the pharmacological profile of SHA 68 has been further investigated in vitro and in vivo. In cells expressing the mouse NPSR SHA 68 was inactive per se

Chiara Ruzza; Anna Rizzi; Claudio Trapella; Michela Pela’; Valeria Camarda; Valentina Ruggieri; Monica Filaferro; Carlo Cifani; Rainer K. Reinscheid; Giovanni Vitale; Roberto Ciccocioppo; Severo Salvadori; Remo Guerrini; Girolamo Calo’



Toxicity of H2-receptor antagonists to isolated rat hepatocytes: structure-activity relationships.  


Oxmetidine is a potent and specific antagonist of the histamine H2-receptor. Oxmetidine is also cytotoxic to isolated rat hepatocytes through inhibition of mitochondrial oxidative phosphorylation. The purpose of this investigation was to test a variety of H2-receptor antagonists that are structural analogs of oxmetidine in an attempt to identify a critical structural component or a physicochemical property of the molecule which may be responsible for cytotoxicity. Six histamine receptor H2-antagonists were tested. The minimum drug concentrations that caused 100% cell death (leakage of intracellular lactate dehydrogenase and loss of intracellular potassium) ranged from 0.87 to 22.50 mM for the analogs tested. At toxic concentrations, two of the least potent analogs, SK&F 92909 and SK&F 9205A both caused a rapid decrease in hepatocyte O2 consumption and ATP content which occurred before any evidence of cell injury. The potency of these molecules as cytotoxicants to isolated hepatocytes did not correlate with their potency as histamine H2-receptor antagonists whereas there was a significant correlation between increasing potency and increasing octanol/water partition coefficients. These data suggest that lipid solubility may be a key factor in the cytotoxicity of this class of drugs to isolated rat hepatocytes. PMID:2891842

Rush, G F; Alberts, D; Lupo, S; Yodis, L A; Brown, T H; Durant, G J



Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3.  


High-throughput screening identified a low molecular weight antagonist of CXCR3 displaying micromolar activity in a membrane filtration-binding assay. Systematic modification of the benzimidazole core and tethered acetophenone moiety established tractable SAR of analogs with improved physicochemical properties and sub-micromolar activity across both human and murine receptors. PMID:18242988

Hayes, Martin E; Wallace, Grier A; Grongsaard, Pintipa; Bischoff, Agnieszka; George, Dawn M; Miao, Wenyan; McPherson, Michael J; Stoffel, Robert H; Green, David W; Roth, Gregory P



III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl-piperazinyl-piperidine scaffold.  


The SAR of a novel pyrazinyl-piperazinyl-piperidine scaffold with CXCR3 receptor antagonist activity was explored. Optimization of the DMPK profile and reduction of hERG inhibition is described. Compound 16e with single-digit CXCR3 affinity, good rat PK and hERG profiles has been identified as a lead for further study. PMID:22018463

Kim, Seong Heon; Anilkumar, Gopinadhan N; Zawacki, Lisa Guise; Zeng, Qingbei; Yang, De-Yi; Shao, Yuefei; Dong, Guizhen; Xu, Xiaolian; Yu, Wensheng; Jiang, Yueheng; Jenh, Chung-Her; Hall, James W; Carroll, Carolyn Diianni; Hobbs, Doug W; Baldwin, John J; McGuinness, Brian F; Rosenblum, Stuart B; Kozlowski, Joseph A; Shankar, Bandarpalle B; Shih, Neng-Yang



Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis  

Microsoft Academic Search

Objective: Vulvar vestibulitis is a chronic inflammatory syndrome of unknown cause and pathogenesis. We examined the relation between vulvar vestibulitis and polymorphisms in the gene coding for the interleukin 1 receptor antagonist, a naturally occurring down-regulator of proinflammatory immune responses. Study Design: Cells from the lower genital tract of 68 women with vulvar vestibulitis, 343 women with no history of

Jan Jeremias; William J. Ledger; Steven S. Witkin



Lithium effectively complements vasopressin V2 receptor antagonist in the treatment of hyponatraemia of SIADH rats  

Microsoft Academic Search

Background. Although, pharmacological intervention with a selective arginine vasopressin (AVP) V2 receptor antagonist has been demonstrated to be effective for syndrome of inappropriate secretion of antidiuretic hormone (SIADH), its long-term administration has some therapeutic limitations. Lithium, a drug for bipolar disorders, has been known to cause nephro- genic diabetes insipidus by reducing kidney- specific apical water channel, aquaporin 2 (AQP2)

Itsuro Kazama; Tomohiro Arata; Mari Michimata; Ryo Hatano; Michiko Suzuki; Noriyuki Miyama; Satoru Sanad; Akira Sato; Susumu Satomi; Yutaka Ejima; Sei Sasaki; Mitsunobu Matsubara



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 ...


A Time-course Study with the Androgen Receptor Antagonist Flutamide in Fish  

EPA Science Inventory

Flutamide, a drug registered to treat some types of prostate cancer in humans, has been used for many years as a model androgen receptor (AR) antagonist in studies aimed at characterizing disruption of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis. Various studies hav...


Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788  

Microsoft Academic Search

The imidazodiazepine Ro 15-1788 is a benzodiazepine receptor antagonist that was initially reported to be lacking in intrinsic activity in a variety of test situations in which benzodiazepine-like effects can be identified. However, many recent studies have shown that this compound does indeed have intrinsic activity in a variety of behavioural, neurological, electrophysiological and biochemical preparations in both animals and

Sandra E. File; Sharon Pellow



An attempt to attenuate experimental pain in humans by dextromethorphan, an NMDA receptor antagonist  

Microsoft Academic Search

Dextromethorphan (100 mg, orally), an NMDA receptor antagonist, did not significantly attenuate pain intensity or unpleasantness induced by experimental ischemia or by topical capsaicin in healthy human subjects, nor did it increase the threshold for heat pain or mechanical pain. A dose of 200 mg produced marked side effects. Thus, systemically administered dextromethorphan does not attenuate pain at clinically applicable

Timo Kauppila; Mari Grönroos; Antti Pertovaara



Design, synthesis and evaluation of a novel cyclohexanamine class of neuropeptide Y Y1 receptor antagonists  

Microsoft Academic Search

A novel series of cyclohexanamine derivatives was designed and synthesized as potent and selective human neuropeptide Y Y1 receptor antagonists. Modification of high-throughput screening hit compound 1 resulted in the identification of compound 3i, which displays potent Y1 activity and good selectivity towards hERG K+ channel and serotonin transporter.

Kaimei Cho; Makoto Ando; Kensuke Kobayashi; Hiroshi Miyazoe; Toshiaki Tsujino; Sayaka Ito; Tomoki Suzuki; Takeshi Tanaka; Shigeru Tokita; Nagaaki Sato



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



Interactive effects of neurohypophyseal neuropeptides with receptor antagonists on passive avoidance behavior: mediation by a cerebral neurohypophyseal hormone receptor?  

PubMed Central

The neurohypophyseal neuropeptides (Arg8)-vasopressin (AVP) and [pGlu4,Cyt6]AVP-(4-8) (where pGlu is pyroglutamic acid and Cyt is cystine) facilitate the retention of one-trial-learning passive avoidance behavior in rats when administered into the cerebral ventricle immediately after the learning trial. The fragment [pGlu4,Cyt6]AVP-(4-8) was considerably more effective than AVP. Oxytocin (OXT) and [pGlu4,Cyt6]OXT-(4-8) have the opposite effect and attenuate passive avoidance behavior also when administered into the cerebral ventricle after the learning trial. Again the fragment was more active than the parent molecule. The ancient arginine-containing neurohypophyseal hormone vasotocin in "high" doses (10ng) had a vasopressin-like effect and in "low" doses (0.1 ng) had an OXT-like effect on passive avoidance behavior. Because both vasopressinergic (V1) and oxytocinergic receptors have been demonstrated in the central nervous system, we asked whether specific antagonists of the V1, V2, and OXT receptor could antagonize the effects of these neuropeptides on passive avoidance behavior. The three antagonists were approximately equally active in blocking the effect of vasopressin, whereas the fragment [pGlu4]AVP-(4-8) and the high dose of vasotocin were more readily blocked by the OXT antagonist. The attenuating effect of OXT, the fragment [pGlu4,Cyt6]OXT-(4-8), and the low dose of vasotocin was markedly reduced by the OXT antagonist. This effect could also be reduced by pretreatment with the V1 antagonist but not with the V2 antagonist. These results suggest the existence of a separate neurohypophyseal hormone receptor complex in the brain affecting memory processes that differs from the peripheral V1, V2, and OXT receptor. Images

de Wied, D; Elands, J; Kovacs, G



Interactive effects of neurohypophyseal neuropeptides with receptor antagonists on passive avoidance behavior: mediation by a cerebral neurohypophyseal hormone receptor?  


The neurohypophyseal neuropeptides (Arg8)-vasopressin (AVP) and [pGlu4,Cyt6]AVP-(4-8) (where pGlu is pyroglutamic acid and Cyt is cystine) facilitate the retention of one-trial-learning passive avoidance behavior in rats when administered into the cerebral ventricle immediately after the learning trial. The fragment [pGlu4,Cyt6]AVP-(4-8) was considerably more effective than AVP. Oxytocin (OXT) and [pGlu4,Cyt6]OXT-(4-8) have the opposite effect and attenuate passive avoidance behavior also when administered into the cerebral ventricle after the learning trial. Again the fragment was more active than the parent molecule. The ancient arginine-containing neurohypophyseal hormone vasotocin in "high" doses (10ng) had a vasopressin-like effect and in "low" doses (0.1 ng) had an OXT-like effect on passive avoidance behavior. Because both vasopressinergic (V1) and oxytocinergic receptors have been demonstrated in the central nervous system, we asked whether specific antagonists of the V1, V2, and OXT receptor could antagonize the effects of these neuropeptides on passive avoidance behavior. The three antagonists were approximately equally active in blocking the effect of vasopressin, whereas the fragment [pGlu4]AVP-(4-8) and the high dose of vasotocin were more readily blocked by the OXT antagonist. The attenuating effect of OXT, the fragment [pGlu4,Cyt6]OXT-(4-8), and the low dose of vasotocin was markedly reduced by the OXT antagonist. This effect could also be reduced by pretreatment with the V1 antagonist but not with the V2 antagonist. These results suggest the existence of a separate neurohypophyseal hormone receptor complex in the brain affecting memory processes that differs from the peripheral V1, V2, and OXT receptor. PMID:1847526

de Wied, D; Elands, J; Kovács, G



Evaluation of adenine as scaffold for the development of novel P2X3 receptor antagonists.  


Ligands that selectively block P2X3 receptors localized on nociceptive sensory fibres may be useful for the treatment of chronic pain conditions including neuropathic pain, migraine, and inflammatory pain. With the aim at exploring the suitability of adenine moiety as a scaffold for the development of antagonists of this receptor, a series of 9-benzyl-2-aminoadenine derivatives were designed and synthesized. These new compounds were functionally evaluated at rat or human P2X3 receptors expressed in human embryonic kidney (HEK) cells and on native P2X3 receptors from mouse trigeminal ganglion sensory neurons using patch clamp recording under voltage clamp configuration. The new molecules behaved as P2X3 antagonists, as they rapidly and reversibly inhibited (IC50 in the low micromolar range) the membrane currents induced via P2X3 receptor activation by the full agonist ?,?-methyleneATP. Introduction of a small lipophilic methyl substituent at the 6-amino group enhanced the activity, in comparison to the corresponding unsubstituted derivative, resulting in the 9-(5-iodo-2-isopropyl-4-methoxybenzyl)-N(6)-methyl-9H-purine-2,6-diamine (24), which appears to be a good antagonist on recombinant and native P2X3 receptors with IC50 = 1.74 ± 0.21 ?M. PMID:23688699

Lambertucci, Catia; Sundukova, Mayya; Kachare, Dhuldeo D; Panmand, Deepak S; Dal Ben, Diego; Buccioni, Michela; Marucci, Gabriella; Marchenkova, Anna; Thomas, Ajiroghene; Nistri, Andrea; Cristalli, Gloria; Volpini, Rosaria



Cerebellar GABAA receptor selective for a behavioural alcohol antagonist  

Microsoft Academic Search

BENZODIAZEPINES are widely prescribed anxiolytics and anti-convulsants which bind with high affinity to sites on the GABAA receptor\\/Cl- channel complex and potentiate the effect of the neurotransmitter GABA (gamma-aminobutyric acid)1,2. The heterogeneity of benzodiazepine recognition sites in the central nervous system1,3,4 was revealed by studies showing different classes of GABAA receptor subunits (classes alpha, beta and gamma)5-7 and variant subunits

Hartmut Lüddens; Dolan B. Pritchett; Martin Köhler; Iris Killisch; Kari Keinänen; Hannah Monyer; Rolf Sprengel; Peter H. Seeburg



Lineweaver-burk analysis for the blocking effects of mammalian dopamine receptor antagonists on dopamine-induced currents in Achatina giant neurones  

Microsoft Academic Search

1.1. We had demonstrated (Emaduddin et al., 1995) the blocking effects of the three mammalian dopamine receptor antagonists, (±)-SKF83566 (mammalian dopamine D1-like receptor antagonist), (+)-UH232 (D2 and D3-like receptor antagonist) and (±)-sulpiride (D2-like receptor antagonist) on the dose (pressure duration)-response curves of dopamine in the three giant neurone types, LVMN (left visceral multiple spike neurone), d-RPeAN (dorsal-right pedal anterior neurone)

Muhammad Emaduddin; Hiroshi Takeuchi



Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix.  


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. PMID:8637885

Halmos, G; Schally, A V; Pinski, J; Vadillo-Buenfil, M; Groot, K



Immunotherapy and endothelin receptor antagonists for treatment of castration-resistant prostate cancer.  


Recently, novel therapies of prostate cancer, such as immunotherapy, endothelin receptor antagonists, novel androgen receptor antagonist and novel taxanes, and others have been introduced into clinical practice. This study was performed to summarize these results of immunotherapy and endothelin receptor antagonists in the treatment of castration-resistant prostate cancer (CRPC) and derive a more precise estimation of their effect on future treatment. The PubMed database, references of published trials, and review articles were searched. Two reviewers independently extracted data of these trials. We used hazard ratios (HRs) to assess the effects on overall survival (OS), progression-free survival (PFS), or time to disease progression (TTP), and relative risk (RR) for the different types of toxicity. In addition, 95% confidence intervals (CIs) give a sense of the precision of the estimate. Nine randomized controlled trials were ultimately identified. The pooled HR showed that immunotherapy could prolong OS significantly in patients with CRPC compared to placebo (HR?=?0.70, 95% CI: 0.58-0.83, p?receptor antagonists also had modest benefits (HR?=?0.90, 95% CI: 0.82-1.00, p?=?0.046). Nevertheless, there were no significant benefits from both therapies on PFS or TTP. In addition, immunotherapy led to more fatigue, pyrexia, chills, and endothelin receptor antagonists led to more peripheral edema, anemia, and dyspnea. Our article suggested that the very acceptable toxicity and improving OS in patients with CRPC made immunotherapy an attractive option for such patients. However, future studies with thoughtful clinical trial designs are warranted. PMID:23504603

Shao, Ning; Wang, Yang; Jiang, Wen Yu; Qiao, Di; Zhang, Shi Ge; Wu, Ye; Zhang, Xiang Xiang; Wang, Jiu Ling; Ding, Yi; Feng, Ning Han



The Novel Neuropeptide Y Y 1 Receptor Antagonist J-104870: A Potent Feeding Suppressant with Oral Bioavailability  

Microsoft Academic Search

Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the hypothalamus. Among the subtypes of NPY receptors, Y1 receptors may play a key role in feeding regulation. In the present study, we demonstrated that a novel Y1 antagonist, J-104870, shows high selectivity and potency for the Y1 receptor with an anorexigenic effect on

Akio Kanatani; Tetsuya Kanno; Akane Ishihara; Mikiko Hata; Aya Sakuraba; Takeshi Tanaka; Yoshimi Tsuchiya; Toshiaki Mase; Takahiro Fukuroda; Takehiro Fukami; Masaki Ihara



Comparison of the molecular interactions of two antagonists, MEN16132 or icatibant, at the human kinin B2 receptor  

PubMed Central

BACKGROUND AND PURPOSE Icatibant is a well-known kinin B2 receptor antagonist currently used for angiooedema attacks. MEN16132 is a non-peptide B2 receptor antagonist, more potent and long lasting than icatibant in different models. Here we studied the reasons for these differences between the two antagonists. EXPERIMENTAL APPROACH Rate of reversibility (over about 3 h) of the functional receptor blockade exerted by the antagonists was compared (inositol phosphates accumulation assay) in CHO cells expressing the human B2 receptor and in human synovial cells. Antagonist pretreated cells were washed with medium and the time taken to restore bradykinin (BK) response measured. Antagonist affinity was measured by radioligand binding to wild type and mutated B2 receptors. KEY RESULTS Recovery of BK-induced responses was slower in cells pretreated with MEN16132 than in those treated with icatibant. The affinity of icatibant (for the [3H]-BK or the B2 receptor antagonist [3H]-MEN11270 binding site) was compared to that of MEN16132 using a panel of point-mutated receptors with mutations located at the transmembrane regions of the B2 receptor, previously shown to decrease MEN16132 high affinity interaction. No consistent decrease of icatibant affinity was observed. From the different affinity of MEN16132 derivatives at wild type and W86A (transmembrane 2 region) receptors, and by evaluating its antagonist profile at the D266A/D284A double mutant receptor, a model of the MEN16132-B2 receptor complex is proposed. CONCLUSIONS AND IMPLICATIONS MEN16132 dissociated from the B2 receptor compartment more slowly than icatibant and interacted at a deeper level in transmembrane regions of the receptor.

Meini, S; Bellucci, F; Catalani, C; Cucchi, P; Giolitti, A; Giuliani, S; Quartara, L; Rotondaro, L; Zappitelli, S; Maggi, CA



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



Bazedoxifene-scaffold-based mimetics of solomonsterols a and B as novel pregnane x receptor antagonists.  


Pregnane X receptor (PXR), a member of the NR1I nuclear receptor family, acts as a xenobiotic sensor and a paramount transcriptional regulator of drug-metabolizing enzymes and transporters. The overexpression of PXR in various cancer cells indicates the importance of PXR as a drug target for countering multidrug resistance in anticancer treatments. We describe the discovery of novel bazedoxifene-scaffold-based PXR antagonists inspired by the marine sulfated steroids solomonsterol A and B as natural leads. A luciferase reporter assay on a PXR-transfected HepG2 cell line identified compounds 19-24 as promising PXR antagonists. Further structure-activity relationship studies of the most active PXR antagonist from the series (compound 20, IC50 = 11 ?M) revealed the importance of hydroxyl groups as hydrogen-bond donors for PXR antagonistic activity. PXR antagonists 20 and 24 (IC50 = 14 ?M), in addition to the downregulation of PXR expression, exhibited inhibition of PXR-induced CYP3A4 expression, which illustrates their potential to suppress PXR-regulated phase-I drug metabolism. PMID:24828006

Hodnik, Ziga; Peterlin Maši?, Lucija; Tomaši?, Tihomir; Smodiš, Domen; D'Amore, Claudio; Fiorucci, Stefano; Kikelj, Danijel



Synthesis and evaluation of 11?-(4-Substituted phenyl) estradiol analogs: Transition from estrogen receptor agonists to antagonists  

PubMed Central

Introduction As part of our program to develop estrogen receptor (ER) targeted imaging and therapeutic agents we chose to evaluate 11?-substituted estradiol analogs as a representative scaffold. Previous synthetic studies provided an entry into this class of compounds and other work indicated that 11?-(substituted aryl) estradiol analogs were potent antagonists of the ER. Little information existed about the specific structural features involved in the transition from agonism to antagonism for the 11?-aryl estradiol analogs or their potential as scaffolds for drug conjugation. Methods We prepared and characterized a series of 11?-(4-Substituted phenyl) estradiol analogs using modifications of existing synthetic methods. The new compounds, as well as standard steroidal agonists and antagonists, were evaluated as competitive ligands for the ER?-LBD. Functional assays used the induction of alkaline phosphatase in Ishikawa cells to determine potency of the compounds as ER agonists or antagonists. Results The synthetic strategy successfully generated a series of compounds in which the 4-substituent was sequentially modified from hydroxyl to methoxy to azidoethoxy/N,N-dimethylaminoethoxy and eventually to a prototypical 1,4-naphthoquinone-containing moiety. The new compounds all retained high relative binding affinity (RBA) for the ER?-LBD, ranging from 13–83% that of estradiol. No subtype selectivity was observed. More importantly, the transition from agonist to antagonist activity occurs at the 4-methoxy stage where the compound is a mixed antagonist. More notably, antagonism appeared to be more dependent upon the size of the 11?-substituent than upon the nature of the terminal group Conclusions We have developed a synthetic strategy that provides facile access to potent 11?-(4-substituted phenyl) estradiol analogs. The resultant compounds retain high affinity for the ER?-LBD and, more importantly, demonstrate potent antagonist activity in cells. Large functionalities distal to the 11?-phenyl ring had little additional effect on either affinity or efficacy, suggesting the incorporation of diverse imaging or biologically active groups can be attached without significantly compromising the ER-binding capacity. Future studies are in progress to exploit the 11?-aryl estradiol analogs as potential drug delivery systems and imaging agents.

Hanson, Robert N.; Hua, Edward; Hendricks, J. Adam; Labaree, David; Hochberg, Richard B.



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



Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks  

PubMed Central

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.

Schaffer, Lauge; Brissette, Renee E.; Spetzler, Jane C.; Pillutla, Renuka C.; ?stergaard, S?ren; Lennick, Michael; Brandt, Jakob; Fletcher, Paul W.; Danielsen, Gillian M.; Hsiao, Ku-Chuan; Andersen, Asser S.; Dedova, Olga; Ribel, Ulla; Hoeg-Jensen, Thomas; Hansen, Per Hertz; Blume, Arthur J.; Markussen, Jan; Goldstein, Neil I.



Assembly of high-affinity insulin receptor agonists and antagonists from peptide building blocks.  


Insulin is thought to elicit its effects by crosslinking the two extracellular alpha-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. PMID:12684539

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; Hansen, Per Hertz; Blume, Arthur J; Markussen, Jan; Goldstein, Neil I



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



Functional assays to define agonists and antagonists of the sigma-2 receptor.  


The sigma-2 receptor has been identified as a biomarker in proliferating tumors. To date there is no well-established functional assay for defining sigma-2 agonists and antagonists. Many sigma-2 ligands with diverse structures have been shown to induce cell death in a variety of cancer cells by triggering caspase-dependent and independent apoptosis. Therefore, in the current study, we used the cell viability assay and the caspase-3 activity assay to determine sigma-2 agonists and antagonists. Three classes of sigma-2 ligands developed in our laboratory were evaluated for their potency to induce cell death in two tumor cell lines, mouse breast cancer cell line EMT-6 and human melanoma cell line MDA-MB-435. The data showed that the EC50 values of the sigma-2 ligands using the cell viability assay ranged from 11.4?M to >200?M, which were comparable with the EC50 values obtained using the caspase-3 assay. Based on the cytotoxicity of a sigma-2 ligand relative to that of siramesine, a commonly accepted sigma-2 agonist, we have categorized our sigma-2 ligands into agonists, partial agonists, and antagonists. The establishment of functional assays for defining sigma-2 agonists and antagonists will facilitate functional characterization of sigma-2 receptor ligands and sigma-2 receptors. PMID:24333652

Zeng, Chenbo; Rothfuss, Justin M; Zhang, Jun; Vangveravong, Suwanna; Chu, Wenhua; Li, Shihong; Tu, Zhude; Xu, Jinbin; Mach, Robert H



Effect of neurokinin-I receptor antagonists on the function of 5-HT and noradrenaline neurons.  


Substance P antagonists have been proposed to be a new class of antidepressants. The present study aimed to determine the effect of the selective non-peptide rat neurokinin-1 (NK1) receptor antagonists WIN 51,708 and CP-96,345 on the firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. While WIN51,708 (2mg/kg, i.v.) and CP-96,345 (0.15 mg/kg, i.v.) did not modify the firing activity of 5-HT and NA neurons, both antagonists attenuated the suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of both types of neurons. In contrast, the responsiveness of 5-HT neurons to the i.v. administration of the 5-HT autoreceptor agonist LSD and the 5-HT1A receptor agonist 8-OH-DPAT remained unchanged. These findings suggest that NK1 receptor antagonists affect markedly the NA system via an attenuation of the function of alpha2-adrenoceptors on the cell body of NA neurons and, consequently, may also modulate 5-HT neurotransmission. PMID:10817615

Haddjeri, N; Blier, P



Emerging evidence for neurotensin receptor 1 antagonists as novel pharmaceutics in neurodegenerative disorders.  


The role that the tridecapeptide neurotensin (NT) plays in the modulation of the aminoacidergic transmission is analyzed in different rat brain regions. NT exerts its effects through the activation of different receptor subtypes, NTR1, NTR2 and NTR3. The contribution of NTR1 receptor in modulating and reinforcing glutamate signalling will be shown including the involvement of interactions between NT and N-methyl-D-aspartate (NMDA) receptors. Extracellular accumulation of glutamate and the excessive activation of glutamate receptors, in particular NMDA receptors, is known to represent an important factor in the induction of glutamate-mediated neuronal damage occurring in Parkinson's disease and in pathologic events such as hypoxia and ischemia. An enhancing action of NT on glutamate-induced neurodegenerative effects is shown and NTR1 receptor antagonists could therefore become novel pharmaceutics in the treatment of neurodegenerative disease. PMID:19929816

Ferraro, L; Tomasini, M C; Beggiato, S; Guerrini, R; Salvadori, S; Fuxe, K; Calzà, L; Tanganelli, S; Antonelli, T



Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.  


This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties. PMID:24269482

Wilson, David M; Apps, James; Bailey, Nicholas; Bamford, Mark J; Beresford, Isabel J; Brackenborough, Kim; Briggs, Michael A; Brough, Stephen; Calver, Andrew R; Crook, Barry; Davis, Rebecca K; Davis, Robert P; Davis, Susannah; Dean, David K; Harris, Leanne; Heslop, Teresa; Holland, Vicky; Jeffrey, Phillip; Panchal, Terrance A; Parr, Christopher A; Quashie, Nigel; Schogger, Joanne; Sehmi, Sanjeet S; Stean, Tania O; Steadman, Jon G A; Trail, Brenda; Wald, Jeffrey; Worby, Angela; Takle, Andrew K; Witherington, Jason; Medhurst, Andrew D



Discovery of potent transient receptor potential vanilloid 1 antagonists: design and synthesis of phenoxyacetamide derivatives.  


We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411 nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33 nM). In addition, 15d ameliorated bladder overactivity in rats in vivo. PMID:23632270

Takahashi, Eiki; Hirano, Noriyuki; Nagahara, Takashi; Yoshikawa, Satoru; Momen, Shinobu; Yokokawa, Hiroshi; Hayashi, Ryoji



Neurokinin1 Receptor Antagonist (Aprepitant) Suppresses HIV1 Infection of Microglia\\/Macrophages  

Microsoft Academic Search

Neurokinin-1 receptor (NK-1R) antagonists suppress HIV-1 infection of macrophages in vitro. We have further investigated the\\u000a anti-HIV-1 activity of aprepitant, a Food and Drug Administration-approved NK-1R antagonist, and its cytotoxic effect in the\\u000a macrophage\\/microglia system. Aprepitant inhibited infection of macrophages with primary HIV-1 R5 strains (subtypes A, D, and\\u000a H; UG275, BZ163, and BCF-KITA), while it had little effect on

Xu Wang; Steven D. Douglas; Li Song; Yan-Jian Wang; Wen-Zhe Ho



The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists.  


A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrazolopyrimidine 2-methyl-5-((phenylthio)methyl)pyrazolo[1,5-a]pyrimidin-7-ol 1, resulting in the discovery of CXCR2 receptor antagonist 2-benzyl-5-(((2,3-difluorophenyl)thio)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol 14. The SAR was investigated by systematic variation of the pendant thiol, alkyl and pyrimidinol groups. Replacement of the pyrazolopyrimidine core with a triazolo alternative led to a dual series of antagonists with favourable biological and pharmacokinetic properties. PMID:24332493

Porter, David W; Bradley, Michelle; Brown, Zarin; Canova, Riccardo; Charlton, Steven; Cox, Brian; Hunt, Peter; Kolarik, David; Lewis, Sarah; O'Connor, Des; Reilly, John; Spanka, Carsten; Tedaldi, Lauren; Watson, Simon J; Wermuth, Roland; Press, Neil J



Identification and optimisation of novel sulfonamide, selective vasopressin V1B receptor antagonists.  


The synthesis and preliminary structure-activity relationships (SAR) of a novel class of vasopressin V(1B) receptor antagonists are described. Hit compound 5, identified via high throughput screening of the corporate collection, showed good activity in a V(1B) binding assay (K(i) 63 nM) but did not possess the lead-like physicochemical properties typically required in a hit compound. A 'deletion approach' on the HTS hit 5 was performed, with the focus on improvement of physicochemical properties, yielding the selective V(1B) antagonist 9f (K(i) 190 nM), with improved druglike characteristics. PMID:21601454

Baker, James; Bingham, Matilda; Blackburn-Munro, Ruth; Cai, Jiaqiang; Craighead, Mark; Gilfillan, Robert; Goan, Kate; Jaap, David; Milne, Rachel; Morphy, J Richard; Napier, Susan; Presland, Jeremy; Spinks, Gayle; Thomson, Fiona



Effects of the 5HT 7 receptor antagonist SB258741 in animal models for schizophrenia  

Microsoft Academic Search

The 5-HT7 receptor is targeted by several new antipsychotics such as clozapine and risperidone. We studied the effect of R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine (SB-258741), a specific 5-HT7 receptor antagonist, in three models for positive symptoms, d-amphetamine-induced hyperactivity and d-amphetamine- and phencyclidine (PCP)-disrupted prepulse inhibition (PPI) in rats, with the aim of investigating the role of this receptor in the clinical effect of antipsychotics.

B Pouzet; M Didriksen; J Arnt



Novel 3-Aryl Indoles as Progesterone Receptor Antagonists for Uterine Fibroids  

PubMed Central

We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.



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



Structure-based Discovery of Antagonists of Nuclear Receptor LRH-1*  

PubMed Central

Liver receptor homolog 1 (nuclear receptor LRH-1, NR5A2) is an essential regulator of gene transcription, critical for maintenance of cell pluripotency in early development and imperative for the proper functions of the liver, pancreas, and intestines during the adult life. Although physiological hormones of LRH-1 have not yet been identified, crystallographic and biochemical studies demonstrated that LRH-1 could bind regulatory ligands and suggested phosphatidylinositols as potential hormone candidates for this receptor. No synthetic antagonists of LRH-1 are known to date. Here, we identify the first small molecule antagonists of LRH-1 activity. Our search for LRH-1 modulators was empowered by screening of 5.2 million commercially available compounds via molecular docking followed by verification of the top-ranked molecules using in vitro direct binding and transcriptional assays. Experimental evaluation of the predicted ligands identified two compounds that inhibit the transcriptional activity of LRH-1 and diminish the expression of the receptor's target genes. Among the affected transcriptional targets are co-repressor SHP (small heterodimer partner) as well as cyclin E1 (CCNE1) and G0S2 genes that are known to regulate cell growth and proliferation. Treatments of human pancreatic (AsPC-1), colon (HT29), and breast adenocarcinoma cells T47D and MDA-MB-468 with the LRH-1 antagonists resulted in the receptor-mediated inhibition of cancer cell proliferation. Our data suggest that specific antagonists of LRH-1 could be used as specific molecular probes for elucidating the roles of the receptor in different types of malignancies.

Benod, Cindy; Carlsson, Jens; Uthayaruban, Rubatharshini; Hwang, Peter; Irwin, John J.; Doak, Allison K.; Shoichet, Brian K.; Sablin, Elena P.; Fletterick, Robert J.



Chemokine receptors and their antagonists in allergic lung disease  

Microsoft Academic Search

The trafficking and homing of leukocytes in normal homeostasis and in disease is under the control of a variety of cytokine and lipid mediators. One family of small cytokines particularly involved in inflammation which has been identified is the chemokine family. Their action is mediated by a large superfamily of seven transmembrane spanning G-protein coupled receptors. One of the hopes

T. N. C. Wells; A. E. I. Proudfoot



Conformational states of the nicotinic acetylcholine receptor from Torpedo californica induced by the binding of agonists, antagonists, and local anesthetics. Equilibrium measurements using tritium-hydrogen exchange  

SciTech Connect

The tritium-hydrogen exchange kinetics of Torpedo californica AChR, in native membrane vesicles at pH 7.4 and 0 degrees C, have been analyzed in the presence of agonists, partial agonists, local anesthetics, and competitive antagonists. The agonists carbamylcholine (10 microM-1 mM) and suberyldicholine (10 microM) and the partial agonists decamethonium (25 microM and 1 mM) and hexamethonium (1 mM) have no effect on the exchange kinetics, although at lower concentration carbamylcholine may slightly accelerate exchange. Nondesensitizing local anesthetics do affect the exchange behavior, dependent on concentration. Procaine at 500 microM moderately retards exchange while procaine at 10 mM and tetracaine at 5 mM slightly accelerate exchange. The competitive antagonist alpha-bungarotoxin retards exchange significantly, as does d-tubocurarine although to a lesser extent. These results suggest that the resting and desensitized conformations of the AChR are very similar in overall solvent accessibility and that at lower concentrations noncompetitive blockers such as procaine may stabilize a less solvent-accessible state of the AChR. The competitive antagonists alpha-bungarotoxin and d-tubocurare also stabilize a dynamically restricted, less solvent-accessible conformation of the acetylcholine receptor, demonstrating that a large conformational change accompanies binding of these toxins. Any change in conformation which may accompany desensitization is very different from these effects.

McCarthy, M.P.; Stroud, R.M.



On the role of P2X(7) receptors in dopamine nerve cell degeneration in a rat model of Parkinson's disease: studies with the P2X(7) receptor antagonist A-438079.  


The role of the ATP-gated receptor, P2X(7), has been evaluated in the unilateral 6-OHDA rat model of Parkinson's disease using the P2X(7) competitive antagonist A-438079. Nigral P2X(7) immunoreactivity was mainly located in microglia but also in astroglia. A-438079 partially but significantly prevented the 6-OHDA-induced depletion of striatal DA stores. However, this was not associated with a reduction of DA cell loss. Blockade of P2X(7) receptors may represent a novel protective strategy for striatal DA terminals in Parkinson's disease and warrants further future investigation. PMID:20387084

Marcellino, Daniel; Suárez-Boomgaard, Diana; Sánchez-Reina, María Dolores; Aguirre, José A; Yoshitake, Takashi; Yoshitake, Shimako; Hagman, Beth; Kehr, Jan; Agnati, Luigi F; Fuxe, Kjell; Rivera, Alicia



Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice  

PubMed Central

Adenosine, an ubiquitous neuromodulator, and its analogues have been shown to produce ‘depressant' effects in animal models believed to be relevant to depressive disorders, while adenosine receptor antagonists have been found to reverse adenosine-mediated ‘depressant' effect. We have designed studies to assess whether adenosine A2A receptor antagonists, or genetic inactivation of the receptor would be effective in established screening procedures, such as tail suspension and forced swim tests, which are predictive of clinical antidepressant activity. Adenosine A2A receptor knockout mice were found to be less sensitive to ‘depressant' challenges than their wildtype littermates. Consistently, the adenosine A2A receptor blockers SCH 58261 (1?–?10?mg?kg?1, i.p.) and KW 6002 (0.1?–?10?mg?kg?1, p.o.) reduced the total immobility time in the tail suspension test. The efficacy of adenosine A2A receptor antagonists in reducing immobility time in the tail suspension test was confirmed and extended in two groups of mice. Specifically, SCH 58261 (1?–?10?mg?kg?1) and ZM 241385 (15?–?60?mg?kg?1) were effective in mice previously screened for having high immobility time, while SCH 58261 at 10?mg?kg?1 reduced immobility of mice that were selectively bred for their spontaneous ‘helplessness' in this assay. Additional experiments were carried out using the forced swim test. SCH 58261 at 10?mg?kg?1 reduced the immobility time by 61%, while KW 6002 decreased the total immobility time at the doses of 1 and 10?mg?kg?1 by 75 and 79%, respectively. Administration of the dopamine D2 receptor antagonist haloperidol (50?–?200??g?kg?1 i.p.) prevented the antidepressant-like effects elicited by SCH 58261 (10?mg?kg?1 i.p.) in forced swim test whereas it left unaltered its stimulant motor effects. In conclusion, these data support the hypothesis that A2A receptor antagonists prolong escape-directed behaviour in two screening tests for antidepressants. Altogether the results support the hypothesis that blockade of the adenosine A2A receptor might be an interesting target for the development of effective antidepressant agents.

Yacoubi, Malika El; Ledent, Catherine; Parmentier, Marc; Bertorelli, Rosalia; Ongini, Ennio; Costentin, Jean; Vaugeois, Jean-Marie



Aldosterone, mineralocorticoid receptor and the metabolic syndrome: role of the mineralocorticoid receptor antagonists.  


Several lines of evidence suggest a detrimental effect of aldosterone excess on the development of metabolic alterations. Glucose metabolism derangements due to aldosterone action are frequently observed not only in patients with primary aldosteronism but also in patients with obesity. A contribution to the hyperaldosteronism observed in obese subjects can be attributed, at least in part, to the action of still unidentified adipocyte-derived factor. Aldosterone, through genomic and non-genomic actions contributes to induce several abnormalities: pancreatic fibrosis, impaired beta cell function, as well as reduced skeletal muscle and adipose tissue insulin sensitivity. Oxidative stress, systemic inflammation, together with these metabolic alterations may explain the appearance of the cardiometabolic syndrome and the progression of cardiovascular and renal diseases, in the presence of inappropriate aldosterone levels. The biological actions of aldosterone are mediated by mineralocorticoid receptor (MR), although MR can be activated through an aldosterone independent fashion. Besides salt-water homeostasis, MR activation promotes inflammation, endothelial dysfunction, cardiovascular remodelling and affects adipose tissue differentiation and function. Clinical and experimental studies have shown that MR blockade is able to suppress inflammation, to improve endothelium- dependent vasorelaxation, but most interestingly, to improve pancreatic insulin release as well as insulin-mediated glucose utilization. These actions indicate MR antagonists as a useful therapeutic tool able not only to reduce cardiovascular risk and renal damage, but also to improve metabolic sequaelae. PMID:22022770

Ronconi, Vanessa; Turchi, Federica; Appolloni, Gloria; di Tizio, Valentina; Boscaro, Marco; Giacchetti, Gilberta



Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity.  


This work reports the design and synthesis of novel alkylamides, characterized by a dibenzo[a,d]cycloheptene nucleus, as melatonin (MLT) receptor ligands. The tricyclic scaffold was chosen on the basis of previous quantitative structure-activity studies on MT1 and MT2 antagonists, relating selective MT2 antagonism to the presence of an aromatic substituent out of the plane of the MLT indole ring. Some dibenzo seven-membered structures were thus selected because of the noncoplanar arrangement of their benzene rings, and an alkylamide chain was introduced to fit the requirements for MLT receptor binding, namely, dibenzocycloheptenes with an acylaminoalkyl side chain at position 10 and dibenzoazepines with this side chain originating from the nitrogen atom bridging the two phenyl rings. Binding affinity at human cloned MT1 and MT2 receptors was measured by 2-[125I]iodomelatonin displacement assay and intrinsic activity by the GTPgammaS test. The majority of the compounds were characterized by higher affinity at the MT2 than at the MT1 receptor and by very low intrinsic activity values, thus confirming the importance of the noncoplanar arrangement of the two aromatic rings for selective MT2 antagonism. Dibenzocycloheptenes generally displayed higher MT1 and MT 2affinity than dibenzoazepines. N-(8-Methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-ylmethyl)propionamide (4c) and -butyramide (4d) were the most selective MT2 receptor antagonists of the series, with MT2 receptor affinity comparable to that of melatonin and as such among the highest reported in the literature for MLT receptor antagonists. The acetamide derivative 4b produced a noticeable reduction of GTPgammaS binding at MT2 receptor, thus being among the few inverse agonists described. PMID:15293992

Lucini, Valeria; Pannacci, Marilou; Scaglione, Francesco; Fraschini, Franco; Rivara, Sivia; Mor, Marco; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Piersanti, Giovanni; Diamantini, Giuseppe; Tarzia, Giorgio



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 common intracellular allosteric binding site for antagonists of the CXCR2 receptor  

PubMed Central

Background and purpose: We have previously shown that SB265610 (1-(2-bromo-phenyl)-3-(7-cyano-3H-benzotriazol-4-yl)-urea) behaves as an allosteric, inverse agonist at the C-X-C chemokine (CXCR)2 receptor. The aim of this study was to determine whether SB265610, in addition to two other known antagonists, bind to either of the two putative, topographically distinct, allosteric binding sites previously reported in the Literature. Experimental approach: Ten single point mutations were introduced into the CXCR2 receptor using site-directed mutagenesis. Three CXCR2 antagonists were investigated, SB265610, Pteridone-1 (2-(2,3 difluoro-benzylsulphanyl)-4-((R)-2-hydroxy-1-methyl-ethylamino)-8H-pteridin-7-one) and Sch527123 (2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1enylamino}-benzamide), and the effect of these mutations on their binding affinity and ability to inhibit interleukin-8-stimulated binding of [35S]GTP?S was examined. Key results: Seven of the nine mutations introduced into the C-terminal domain and intracellular loops of the receptor produced a significant reduction in affinity at least one of the antagonists tested. Of those seven mutations, three produced a significant reduction in the affinity of all three antagonists, namely K320A, Y314A and D84N. In all but one mutation, the changes observed on antagonist affinity were matched with effects on inhibition of interleukin-8-stimulated [35S]GTP?S binding. Conclusions and implications: These antagonists bind to a common intracellular, allosteric, binding site of the CXCR2 receptor, which has been further delineated. As many of these mutations are close to the site of G protein coupling or to a region of the receptor that is responsible for the transduction of the activation signal, our results suggest a molecular mechanism for the inhibition of receptor activation.

Salchow, K; Bond, ME; Evans, SC; Press, NJ; Charlton, SJ; Hunt, PA; Bradley, ME



Dopaminergic basis for the facilitation of brain stimulation reward by the NMDA receptor antagonist, MK-801.  


MK-801 (dizocilpine maleate), an antagonist of the NMDA receptor, was given alone or in combination with dopamine D1 and D2 receptor antagonists to rats self-stimulating in lateral hypothalamus to determine whether the dopamine neurons play a role in mediating the effects of MK-801. MK-801 given at a dose of 0.1 mg/kg i.p. to self-stimulators induced a prolonged facilitation of lever-pressing, but given to non-self-stimulators, the drug had no effects. Pretreatment of self-stimulators with the dopamine D1 receptor antagonist Schering 23390 (SCH 23390), 0.2 mg/kg given i.p. 15 min before MK-801, prevented the facilitation seen with MK-801, but did not suppress self-stimulation. SCH 23390 given alone suppressed self-stimulation. Pretreatment of self-stimulators with the dopamine D1/D2 receptor antagonist, haloperidol, 0.2 mg/kg given i.p. 15 min before MK-801, also prevented the facilitation of self-stimulation induced by MK-801 yet did not suppress self-stimulation. Haloperidol given alone suppressed self-stimulation. Pretreatment of self-stimulators with both SCH 23390 and haloperidol 15 min before MK-801 prevented the facilitation seen with MK-801 and suppressed self-stimulation. The combined treatment with SCH 23390 and haloperidol (without MK-801) suppressed self-stimulation, and the suppression lasted longer than the suppression seen when the two dopamine receptor antagonists were given as pretreatment, before MK-801. Pretreating self-stimulators with the combination of SCH 23390 and haloperidol 15 min before amphetamine (2 mg/kg) prevented the facilitatory response and suppressed responding for the brain reward. The suppression was of shorter duration than the suppression seen after the injection of SCH 23390 plus haloperidol. The treatment of self-stimulators with both MK-801 and amphetamine resulted in a greater and longer-lasting facilitation than the increase in responding produced by either drug alone. The similarity between the effects of MK-801 and those of amphetamine and between the effects of pretreatment with the dopamine receptor antagonists before MK-801 and before amphetamine suggests that dopaminergic activity played a significant role in the action underlying the effects of MK-801 on brain stimulation reward. PMID:8813611

Olds, M E



Design and Synthesis of 4-(4-Benzoylaminophenoxy)phenol Derivatives As Androgen Receptor Antagonists.  


We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 ?M), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 ?M), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 ?M). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents. PMID:24900588

Yamada, Ayumi; Fujii, Shinya; Mori, Shuichi; Kagechika, Hiroyuki



8-Substituted 2-alkynyl-N(9)-propargyladenines as A2A adenosine receptor antagonists.  


Structure-activity relationships of 2-alkynyladenine derivatives were explored by varying substituents at the 9-, 8- and 2-positions of the purine moiety in order to optimize A2A adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A2A antagonist activity, and the introduction of a halogen, aryl, or heteroaryl at the 8-position further enhanced activity. A series of 8-substituted 2-alkynyl-N(9)-propargyladenine derivatives exhibited potent antagonist activity, with IC50 values in the low nM range. Compound 4a from this series was found to be orally active at a dose of 3mg/kg in a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model of Parkinson's disease. PMID:24815000

Endo, Kazuki; Deguchi, Kazuki; Matsunaga, Hirokazu; Tomaya, Kota; Yamada, Kohei



Design and Synthesis of Cannabinoid Receptor 1 Antagonists for Peripheral Selectivity  

PubMed Central

Antagonists of cannabinoid receptor 1 (CB1) have potential for the treatment of several diseases such as obesity, liver disease and diabetes. Recently, development of several CB1 antagonists was halted due to adverse central nervous system (CNS) related side effects observed with rimonabant, the first clinically approved CB1 inverse agonist. However, recent studies indicate that regulation of peripherally expressed CB1 with CNS-sparing compounds is a viable strategy to treat several important disorders. Our efforts aimed at rationally designing peripherally restricted CB1 antagonists have resulted in compounds that have limited blood-brain barrier (BBB) permeability and CNS exposure in preclinical in vitro and in vivo models. Typically, compounds with high topological polar surface areas (TPSAs) do not cross the BBB passively. Compounds with TPSAs higher than rimonabant (rimonabant TPSA = 50) and excellent functional activity with limited CNS penetration were identified. These compounds will serve as templates for further optimization.

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



Subtype-selective N-methyl-D-aspartate receptor antagonists: benzimidazalone and hydantoin as phenol replacements.  


Previous work in our laboratories investigating compounds with structural similarity to ifenprodil (5) and 6 (CP101,606) resulted in compound 7 as a potent and selective antagonist of the NR1/2B subtype of the NMDA receptors. Replacement of the phenol group of 7 with a benzimidazalone group tethered by a three-carbon chain to 4-benzylpiperidine resulted in a slightly less active, but selective, compound. Lengthening the carbon tether resulted in a decrease in NR1/2B potency. Replacement of the phenol ring with a hydantoin resulted in weak antagonists. Compound 11a was one of the most potent NR1/2B antagonists from this study. Compound 11a also potentiated the effects of L-DOPA in a rat model of Parkinson's disease (the 6-hydroxydopamine-lesioned rat), dosed at 30 mg/kg orally. PMID:10794706

Schelkun, R M; Yuen, P W; Serpa, K; Meltzer, L T; Wise, L D; Whittemore, E R; Woodward, R M



A molecular basis for agonist and antagonist actions at GABA(C) receptors.  


We modelled the N-terminal ligand-binding domain of the rho1 GABA(C) receptor based on the Lymnaea stagnalis acetylcholine-binding protein (L-AChBP) crystal structure using comparative modelling and validated using flexible docking guided by known mutagenesis studies. A range of known rho1 GABA(C) receptor ligands comprising seven full agonists, 10 partial agonists, 43 antagonists and 12 inactive molecules were used to evaluate and validate the models. Of the 50 models identified, six models that allowed flexible ligand docking in accordance with the experimental data were selected and used to study detailed receptor-ligand interactions. The most refined model to accommodate all known active ligands featured a cavity comprising of a volume of 488 A(3). A detailed analysis of the interaction between the rho1 GABA(C) receptor model and the docked ligands revealed possible H-bonds and cation-pi interactions between the different ligands and binding site residues. Based on quantum mechanical/molecular mechanical (QM/MM) calculations, the model showed distinctive conformations of loop C that provided a molecular basis for agonist and antagonist actions. Agonists elicit loop C closure, while a more open loop C was observed upon antagonist binding. The model differentiates the role for key residues known to be involved in either binding and/or gating. PMID:18312293

Abdel-Halim, Heba; Hanrahan, Jane R; Hibbs, David E; Johnston, Graham A R; Chebib, Mary



Effects of Proton Pump Inhibitors and H2 Receptor Antagonists on the Ileum Motility  

PubMed Central

Objectives. To investigate the effects of proton pump inhibitors (PPIs) and H2 receptor antagonists on ileum motility in rats with peritonitis and compare changes with control group rats. Methods. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another of 8 rats underwent a sham operation and were accepted as controls. Twenty-four hours later after the operation, the rats were killed, and their ileum smooth muscle was excised and placed in circular muscle direction in a 10?mL organ bath. Changes in amplitude and frequency of contractions were analyzed before and after PPIs and H2 receptor blockers. Results. PPI agents decreased the motility in a dose-dependent manner in ileum in both control and intraabdominal sepsis groups. While famotidine had no significant effect on ileum motility, ranitidine and nizatidine enhanced motility in ileum in both control and intraabdominal sepsis groups. This excitatory effect of H2 receptor antagonists and inhibitor effects of PPIs were significantly high in control group when compared to the peritonitis group. The inhibitor effect of pantoprazole on ileum motility was significantly higher than the other two PPI agents. Conclusions. It was concluded that H2 receptor antagonists may be more effective than PPIs for recovering the bowel motility in the intraabdominal sepsis situation.

Kurt, Atilla; Altun, Ahmet; Bagcivan, Ihsan; Koyuncu, Ayhan; Topcu, Omer; Ayd?n, Cengiz; Kaya, Tijen



Novel Yeast-based Strategy Unveils Antagonist Binding Regions on the Nuclear Xenobiotic Receptor PXR*  

PubMed Central

The pregnane X receptor (PXR) is a master regulator of xenobiotic metabolism, and its activity is critical toward understanding the pathophysiology of several diseases, including inflammation, cancer, and steatosis. Previous studies have demonstrated that ketoconazole binds to ligand-activated PXR and antagonizes receptor control of gene expression. Structure-function as well as computational docking analysis suggested a putative binding region containing critical charge clamp residues Gln-272, and Phe-264 on the AF-2 surface of PXR. To define the antagonist binding surface(s) of PXR, we developed a novel assay to identify key amino acid residues on PXR based on a yeast two-hybrid screen that examined mutant forms of PXR. This screen identified multiple “gain-of-function” mutants that were “resistant” to the PXR antagonist effects of ketoconazole. We then compared our screen results identifying key PXR residues to those predicted by computational methods. Of 15 potential or putative binding residues based on docking, we identified three residues in the yeast screen that were then systematically verified to functionally interact with ketoconazole using mammalian assays. Among the residues confirmed by our study was Ser-208, which is on the opposite side of the protein from the AF-2 region critical for receptor regulation. The identification of new locations for antagonist binding on the surface or buried in PXR indicates novel aspects to the mechanism of receptor antagonism. These results significantly expand our understanding of antagonist binding sites on the surface of PXR and suggest new avenues to regulate this receptor for clinical applications.

Li, Hao; Redinbo, Matthew R.; Venkatesh, Madhukumar; Ekins, Sean; Chaudhry, Anik; Bloch, Nicolin; Negassa, Abdissa; Mukherjee, Paromita; Kalpana, Ganjam; Mani, Sridhar



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



Effects of dopamine receptor antagonists (D1 and D2) on the demand for smoked cocaine base in rhesus monkeys  

Microsoft Academic Search

Rationale: Previous studies suggest that dopamine antagonists may reduce the reinforcing effects of cocaine. However, the effects of\\u000a these antagonists on the demand for smoked cocaine base have not been quantified. Objectives: To evaluate the effects of selective D1 (SCH 23390) and D2 (raclopride) dopamine receptor antagonists on the demand for smoked cocaine base in rhesus monkeys using a behavioral

U. C. Campbell; Joshua S. Rodefer; Marilyn E. Carroll



Pharmacological profile of TP-680, a new cholecystokininA receptor antagonist.  

PubMed Central

1. The pharmacological characteristics of a newly developed serine derivative (R)-1-[3-(3-carboxypyridine-2-yl) thio-2-(indol-2-yl)carbonylamino]propionyl-4-diphenylmethyl- piperazine (TP-680), a cholecystokinin type A (CCKA) receptor antagonist, were studied and compared with those of MK-329 and loxiglumide. 2. TP-680 showed approximately 2 and 22 times greater selectivity for peripheral CCKA receptors relative to brain CCK (CCKB) receptors than MK-329 and loxiglumide, respectively, when IC50 values for inhibition of [125I]-CCK-8 binding in isolated acini and cerebral cortex were compared. 3. TP-680 was approximately 17 times less potent than MK-329, but was 106 times more potent than loxiglumide in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. The antagonism produced by TP-680 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. 4. TP-680 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase release as did MK-329 and loxiglumide. However, in contrast to MK-329 and loxiglumide, TP-680 suppressed the maximal responses of CCK-8-induced amylase release in a concentration-dependent fashion, indicating that TP-680 is an unsurmountable antagonist. 5. Repeated washing of acini after a 30 min treatment with TP-680 restored the responsiveness but not the sensitivity, causing a residual inhibition on the action of CCK-8. 6. The addition of loxiglumide prior to or together with application of TP-680 protected CCK receptors from unsurmountable and irreversible antagonism by TP-680. 7. Our results indicate that TP-680 is a potent and the most selective CCKA receptor antagonist for the pancreas reported to date.

Akiyama, T.; Tachibana, I.; Hirohata, Y.; Shirohara, H.; Yamamoto, M.; Otsuki, M.



[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



Acute NK? receptor antagonist administration affects reward incentive anticipation processing in healthy volunteers.  


The primary brain structures of reward processing are mainly situated in the mid-brain dopamine system. The nucleus accumbens (NAc) receives dopaminergic projections from the ventral tegmental area and works as a key brain region for the positive incentive value of rewards. Because neurokinin-1 (NK?) receptor, the cognate receptor for substance P (SP), is highly expressed in the NAc, we hypothesized that the SP/NK? receptor system might play a role in positive reward processing in the NAc in humans. Therefore, we conducted a functional MRI (fMRI) study to assess the effects of an NK? receptor antagonist on human reward processing through a monetary incentive delay task that is known to elicit robust activation in the NAc especially during gain anticipation. Eighteen healthy adults participated in two series of an fMRI study, taking either a placebo or the NK? receptor antagonist aprepitant. Behavioural measurements revealed that there was no significant difference in reaction time, hit rate, or self-reported effort for incentive cues between the placebo and aprepitant treatments. fMRI showed significant decrease in blood oxygenation-level-dependent signals in the NAc during gain anticipation with the aprepitant treatment compared to the placebo treatment. These results suggest that SP/NK? receptor system is involved in processing of positive incentive anticipation and plays a role in accentuating positive valence in association with the primary dopaminergic pathways in the reward circuit. PMID:23406545

Saji, Kanako; Ikeda, Yumiko; Kim, Woochan; Shingai, Yoshitoshi; Tateno, Amane; Takahashi, Hidehiko; Okubo, Yoshiro; Fukayama, Haruhisa; Suzuki, Hidenori



Genetic transfer of a nonpeptide antagonist binding site to a previously unresponsive angiotensin receptor.  

PubMed Central

Mutational analysis based on the pharmacological differences between mammalian and amphibian angiotensin II receptors (AT receptors) previously identified 7 aa residues located in transmembrane domains (TMs) III (Val-108), IV (Ala-163), V (Pro-192, Thr-198), VI (Ser-252), and VII (Leu-300, Phe-301) of the rat AT receptor type 1b (rAT1b receptor) that significantly influenced binding of the nonpeptide antagonist Losartan. Further studies have shown that an additional 6 residues in the rAT1b receptor TMs II (Ala-73), III (Ser-109, Ala-114, Ser-115), VI (Phe-248), and VII (Asn-295) are important in Losartan binding. The 13 residues required for Losartan binding in the mammalian receptor were exchanged for the corresponding amino acids in the Xenopus AT receptor type a (xATa receptor) to generate a mutant amphibian receptor that bound Losartan with the same affinity as the rAT1b receptor (Losartan IC50 values: rAT1b, 2.2 +/- 0.2 nM: xATa, > 50 microM; mutant, 2.0 +/- 0.1 nM). To our knowledge, this is the first report of a gain-of-function mutant in which the residues crucial to formation of a ligand binding site in a mammalian peptide hormone receptor were transferred to a previously unresponsive receptor by site-directed mutagenesis. Ala substitutions and comparison of mammalian and amphibian combinatorial mutants indicated that TM III in the rAT1b receptor plays a key role in Losartan binding. Identification of residues involved in nonpeptide ligand binding will facilitate studies aimed at elucidating the chemical basis for ligand recognition in the AT receptor and peptide hormone receptors in general. Images Fig. 4

Ji, H; Zheng, W; Zhang, Y; Catt, K J; Sandberg, K



The 5-HT2 receptor antagonist ketanserine prevents electroconvulsive shock- and clonidine-induced amnesia.  


The 5-HT2-selective antagonist ketanserine was examined for its ability to prevent electroconvulsive shock (ECS)- or clonidine-induced performance deficit in the passive avoidance situation (step-down) in rats. The posttrain intraperitoneal injection of ketanserine at doses of 3 and 10 mg/kg prevented the ECS- or clonidine-provoked amnesia upon retention tests given 3 h, 24 h, and 7 days after training. The present data favor the view that the selective modification of 5-HT2 receptors after training can prevent the performance deficit in step-down-trained rats and suggest a role of the 5-HTergic neurotransmitter system in memory. The results of this study further suggest that 5-HTergic receptor antagonists might be useful in treatment of cognitive disorders. PMID:7886097

Genkova-Papazova, M; Lazarova-Bakarova, M; Petkov, V D



Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist  

PubMed Central

Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2?-oxo-1,1?,2?,3-tetrahydrospiro[indene-2,3?-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date.



Discovery of MK-3207: A Highly Potent, Orally Bioavailable CGRP Receptor Antagonist.  


Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved solubility at acidic pH and increased oral bioavailability in monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most potent orally active CGRP receptor antagonist described to date. PMID:24900170

Bell, Ian M; Gallicchio, Steven N; Wood, Michael R; Quigley, Amy G; Stump, Craig A; Zartman, C Blair; Fay, John F; Li, Chi-Chung; Lynch, Joseph J; Moore, Eric L; Mosser, Scott D; Prueksaritanont, Thomayant; Regan, Christopher P; Roller, Shane; Salvatore, Christopher A; Kane, Stefanie A; Vacca, Joseph P; Selnick, Harold G



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



P2X3 and P2X2/3 receptor antagonists.  


This review provides a concise summary of the molecular properties of the ligand-gated P2X receptors, in particular those containing the X3 subunit, as well as an overview comprising the most important patent applications on P2X3 and P2X2/3 receptor antagonists published since 2001. This review is mainly focused on small molecules with P2X3 and/or P2X2/3 antagonist properties. The most important classes of the patented compounds and conditions frequently claimed as their therapeutic targets are also discussed. Moreover, biological activity data from the cited patents and general prediction of druglikeness of the claimed compounds are also provided. PMID:24354979

Bölcskei, Hedvig; Farkas, Bence



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



An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist  

PubMed Central

Background Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1–receptor antagonist, with prominent involvement of skin and bone. Methods We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1–receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1–pathway genes including IL1RN. Results We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1–family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1? stimulation. Patients treated with anakinra responded rapidly. Conclusions We propose the term deficiency of the interleukin-1–receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1–receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. ( number, NCT00059748.)

Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; van Royen-Kerkhoff, Annet; Laxer, Ron; Tedgard, Ulf; Cowen, Edward W.; Pham, Tuyet-Hang; Booty, Matthew; Estes, Jacob D.; Sandler, Netanya G.; Plass, Nicole; Stone, Deborah L.; Turner, Maria L.; Hill, Suvimol; Butman, John A.; Schneider, Rayfel; Babyn, Paul; El-Shanti, Hatem I.; Pope, Elena; Barron, Karyl; Bing, Xinyu; Laurence, Arian; Lee, Chyi-Chia R.; Chapelle, Dawn; Clarke, Gillian I.; Ohson, Kamal; Nicholson, Marc; Gadina, Massimo; Yang, Barbara; Korman, Benjamin D.; Gregersen, Peter K.; van Hagen, P. Martin; Hak, A. Elisabeth; Huizing, Marjan; Rahman, Proton; Douek, Daniel C.; Remmers, Elaine F.; Kastner, Daniel L.; Goldbach-Mansky, Raphaela



Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist  

Microsoft Academic Search

Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted

Beth Borowsky; Margaret M. Durkin; Kristine Ogozalek; Mohammad R. Marzabadi; John DeLeon; Rainer Heurich; Harvey Lichtblau; Zoya Shaposhnik; Irena Daniewska; Thomas P. Blackburn; Theresa A. Branchek; Christophe Gerald; Pierre J. Vaysse; Carlos Forray



Exploring the binding features of polybrominated diphenyl ethers as estrogen receptor antagonists: docking studies  

Microsoft Academic Search

The polybrominated diphenyl ethers (PBDEs) accumulating in nature are known to be endocrine-disrupting compounds. Of first concern are those interacting with and altering activity of the human estrogen receptor alpha (hER?). In this study a docking study was carried out to explore the binding modes of PBDE compounds as hER? antagonists. It was found that some of the PBDE compounds

W. H. Yang; Z. Y. Wang; H. L. Liu; H. X. Yu



Effects of Leukotriene B 4 Receptor Antagonist on Experimental Autoimmune Uveoretinitis in Rats  

Microsoft Academic Search

Purpose: We evaluated the potential of leukotriene B4 receptor antagonist (LTB4 RA) as an anti-inflammatory agent on experimental autoimmune uveoretinitis (EAU).Materials and Methods: LTB4 RA was administered to Lewis rats twice a day on days 0–10, 0–5, and 6–10 after immunization. Rats treated on days 0–10 after immunization were subdivided into three groups according to the dosage of LTB4 RA.

Satoko Toriyama



The angiotensin II receptor antagonist candesartan cilexetil (TCV-116) ameliorates retinal disorders in rats  

Microsoft Academic Search

Aims\\/hypothesis. The results of the EUCLID trial (EURODIAB Controlled Trial of Lisinopril in Insulin-dependent Diabetes Mellitus) highlighted\\u000a the importance of the renin-angiotensin system in the pathogenesis of diabetic retinopathy. Candesartan cilexetil (TCV-116),\\u000a a potent angiotensin II (AII) receptor antagonist, has beneficial effects on hypertension as well as on heart, renal and cerebrovascular\\u000a disease. We aimed to evaluate the effectiveness of

Y. Nagisa; A. Shintani; S. Nakagawa



A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients  

Microsoft Academic Search

Objectives: The cytokine interleukin (IL)-1 mediates ischaemic brain damage in rodents. The endogenous, highly selective, IL-1 receptor antagonist (IL-1ra) protects against ischaemic cerebral injury in a range of experimental settings, and IL-1ra causes a marked reduction of cell death when administered peripherally or at a delay in transient cerebral ischaemia. We report here the first randomised, double blind, placebo controlled

H C A Emsley; C J Smith; R F Georgiou; A Vail; S J Hopkins; N J Rothwell; P J Tyrrell



Protection by NMDA receptor antagonists against seizures induced by intracerebral administration of 4-aminopyridine  

Microsoft Academic Search

The effects of NMDA receptor antagonists on the convulsant action of the administration of 4-aminopyridine in the rat lateral cerebral ventricle (i.c.v. injection) and motor cerebral cortex ( injection) were studied. 4-Aminopyridine administration in both regions induced various preconvulsive symptoms, such as salivation, tremors, chewing and rearing, followed by continuous clonic convulsions and, only after i.c.v. injection, running fits and

Alberto Morales-Villagrán; Mónica E. Ureña-Guerrero; Ricardo Tapia



Effects of olopatadine hydrochloride, a histamine h(1) receptor antagonist, on histamine-induced skin responses.  


Effects of olopatadine hydrochloride, a histamine H(1) receptor antagonist, on histamine-induced skin responses were evaluated in 10 healthy subjects in comparison with placebo, fexofenadine hydrochloride, and bepotastine besilate. Olopatadine significantly suppressed histamine-induced wheal, flare, and itch, starting 30 minutes after oral administration. Olopatadine was more effective than fexofenadine and bepotastine. None of the drugs studied impaired performance of word processing tasks. These results suggest that olopatadine can suppress skin symptoms caused by histamine soon after administration. PMID:20886023

Hashimoto, Takashi; Ishii, Norito; Hamada, Takahiro; Dainichi, Teruki; Karashima, Tadashi; Nakama, Takekuni; Yasumoto, Shinichiro



Effects of Olopatadine Hydrochloride, a Histamine H1 Receptor Antagonist, on Histamine-Induced Skin Responses  

PubMed Central

Effects of olopatadine hydrochloride, a histamine H1 receptor antagonist, on histamine-induced skin responses were evaluated in 10 healthy subjects in comparison with placebo, fexofenadine hydrochloride, and bepotastine besilate. Olopatadine significantly suppressed histamine-induced wheal, flare, and itch, starting 30 minutes after oral administration. Olopatadine was more effective than fexofenadine and bepotastine. None of the drugs studied impaired performance of word processing tasks. These results suggest that olopatadine can suppress skin symptoms caused by histamine soon after administration.

Hashimoto, Takashi; Ishii, Norito; Hamada, Takahiro; Dainichi, Teruki; Karashima, Tadashi; Nakama, Takekuni; Yasumoto, Shinichiro



SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice  

Microsoft Academic Search

Antinociceptive effects of cannabinoids are well documented. However, the physiological role of endogenous cannabinoids in nociception is unknown. We evaluated the effects of the cannabinoid receptor antagonist SR 141716A (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide) on mouse hot plate latencies. Intrathecal injection of SR 141716A evoked a significant thermal hyperalgesia. These results suggest that the cannabinoid system tonically regulates thermal nociceptive thresholds. Furthermore, the absence

Jennelle Durnett Richardson; Lin Aanonsen; Kenneth M Hargreaves



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



Eriodictyol: a flavonoid antagonist of the TRPV1 receptor with antioxidant activity.  


The transient potential vanilloid 1 receptor (TRPV1) is a calcium-permeable channel responsible for the transduction and modulation of acute and chronic pain signaling. As such, this receptor is a potential target for the treatment of a number of pain disorders. However, AMG517, a TRPV1 antagonist, presents several clinical limitations that include the induction of severe hyperthermia. The aim of this study was to investigate the possible interaction of the flavonoid eriodictyol with the TRPV1 receptor and to determine its putative antinociceptive and hyperthermic effects. Eriodictyol was able to displace [(3)H]-resiniferatoxin binding (IC(50)=47; 21-119nM) and to inhibit calcium influx mediated by capsaicin (IC(50)=44; 16-125nM), suggesting that eriodictyol acts as a TRPV1 antagonist. Moreover, eriodictyol induced antinociception in the intraplantar capsaicin test, with maximal inhibition of 49±10 and 64±4% for oral (ID(50)=2.3; 1.1-5.7mg/kg) and intrathecal (ID(50)=2.2; 1.7-2.9nmol/site) administration, respectively. Eriodictyol did not induce any change in body temperature or locomotor activity. Orally administered eriodictyol (4.5mg/kg) prevented the nociception induced by intrathecal injections of capsaicin, as well as the non-protein thiol loss and 3-nitrotyrosine (3-NT) formation induced by capsaicin in spinal cord. Eriodictyol also reduced the thermal hyperalgesia and mechanical allodynia elicited by complete Freund's adjuvant (CFA) paw injection. In conclusion, eriodictyol acts as an antagonist of the TRPV1 receptor and as an antioxidant; it induces antinociception without some of the side effects and limitations such as hyperthermia that are expected for TRPV1 antagonists. PMID:21087598

Rossato, Mateus Fortes; Trevisan, Gabriela; Walker, Cristiani Isabel Banderó; Klafke, Jonatas Zeni; de Oliveira, Ana Paula; Villarinho, Jardel Gomes; Zanon, Ricardo Basso; Royes, Luiz Fernando Freire; Athayde, Margareth Linde; Gomez, Marcus Vinicius; Ferreira, Juliano



Interleukin1 Receptor Antagonist Expression in Human Endothelial Cells and Atherosclerosis  

Microsoft Academic Search

The proinflammatory cytokine interleukin (IL)-1 is expressed mainly within the endothelium of atherosclerotic plaques and may be linked with inflammatory mechanisms of atherogenesis. IL-1 action is complex and regulated in part by its naturally occurring inhibitor, the IL-1 receptor antagonist (IL-1ra). Therefore, we studied differential and specific isoform expression of IL-1ra in the endothelium of diseased coronary arteries and in

Rachael Dewberry; Hazel Holden; David Crossman; Sheila Francis



Bartonella quintana lipopolysaccharide is a natural antagonist of Toll-like receptor 4  

Microsoft Academic Search

Bartonella quintana is a gram-negative microorganism that causes trench fever and chronic bacteremia. B. quintana lipopolysaccharide (LPS) was unable to induce the production of proinflammatory cytokines in human monocytes. Interestingly, B. quintana LPS is a potent antagonist of Toll-like receptor 4 (TLR4), as it inhibited both mRNA transcription and the release of tumor necrosis factor alpha, interleukin 1beta (IL-1beta), and

Calin Popa; Shahla Abdollahi-Roodsaz; Leo A. B. Joosten; Nozomi Takahashi; Tom Sprong; Giovanni Matera; Maria Carla Liberto; Alfredo Foca; Marcel van Deuren; Bart Jan Kullberg; Wim B. van den Berg; Mihai G. Netea



NPS 1506, a moderate affinity uncompetitive NMDA receptor antagonist: preclinical summary and clinical experience  

Microsoft Academic Search

Summary.   NPS Pharmaceuticals, Inc. (NPS) has synthesized a series of open-channel blockers with varying potencies at the NMDA receptor.\\u000a NPS 1506 (Fig. 1) is a moderate affinity antagonist that inhibits NMDA\\/glycine-induced increases in cytosolic calcium in cultured\\u000a rat cerebellar granule cells (IC50 = 476 nM) and displaces the binding of [3H]MK-801 to rat cortical membranes (IC50 = 664 nM).

A. L. Mueller; L. D. Artman; M. F. Balandrin; E. Brady; Y. Chien; E. G. DelMar; A. Kierstead; T. B. Marriott; S. T. Moe; J. L. Raszkiewicz; B. VanWagenen; D. Wells



Synthesis of novel melanocortin 4 receptor agonists and antagonists containing a succinamide core  

Microsoft Academic Search

A novel series of piperazines appended to a succinamide backbone were synthesized and found to have a high affinity for the melanocortin-4 receptor (IC50s ranging from <0.1 to 200 nM). Both agonists and antagonists of MC4R were prepared by modifying the groups attached to the right-hand side of the succinamide. This series also exhibits a high level of selectivity (up

Ning Xi; Clarence Hale; Michael G. Kelly; Mark H. Norman; Markian Stec; Shimin Xu; James W. Baumgartner; Christopher Fotsch



A new CCK-B\\/gastrin receptor antagonist acts as an agonist on the rat pancreas  

Microsoft Academic Search

Summary  The new CCK-B\\/gastrin receptor antagonist PD 136450 is of potential value in treating neurologic and psychiatric disorders.\\u000a We investigated possible side effects on the rat pancreas using acute and chronic administration schedules. In chronic experiments,\\u000a four groups of rats were given either PD 136450, the proton pump inhibitor BY 308 (in order to induce hypergastrinemia), a\\u000a combination of both, or

Irmtraut Koop; Rolf Eissele; Stefan Richter; Horst Patberg; Frank Meyer; Joachim Mössner; Rudolf Arnold; Herbert Koop



Synthesis of Selective 5HT6 and 5HT7 Receptor Antagonists  

Microsoft Academic Search

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of

Elizabeth A Raux



Neurokinin1 Receptor Antagonist (Aprepitant) Inhibits Drug-Resistant HIV1 Infection of Macrophages in vitro  

Microsoft Academic Search

Background  Despite the success of antiretroviral therapy in controlling HIV replication, treatment failure may ultimately occur in more\\u000a than 50% of the individuals on antiretroviral therapy. Cellular targets offer an attractive alternative, as it may be more\\u000a difficult for HIV to develop resistance to alternative cellular inhibitory pathways. We have previously shown that CP-96,345,\\u000a a neurokinin-1 receptor (NK-1R) antagonist, inhibits HIV-1

Xu Wang; Steven D. Douglas; Jian-Ping Lai; Florin Tuluc; Pablo Tebas; Wen-Zhe Ho



Nonpeptide Corticotropin-Releasing Hormone Receptor Type 1 Antagonists and Their Applications in Psychosomatic Disorders  

Microsoft Academic Search

Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are

Carlo Contoreggi; Kenner C. Rice; George Chrousos



Structural insights into Resveratrol's antagonist and partial agonist actions on estrogen receptor alpha  

PubMed Central

Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ER?) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ER?) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ER? ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ER? monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ER? in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ER? dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ER? are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ER?. Conclusions Our Molecular Dynamics simulation of RES-ER? structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity.



Correlation between ex vivo receptor occupancy and wake-promoting activity of selective H3 receptor antagonists.  


The histamine H3 receptor (H3R) modulates the release of neurotransmitters that are involved in vigilance, cognition, and sleep-wake regulation. H3R antagonism has been proposed as a novel approach to the treatment of cognitive and attention deficit as well as sleep disorders. It is apparent that H3R antagonists produce pharmacological effects in preclinical animal models across a wide dose range. Several H3R antagonists were reported to be effective at producing cognitive enhancing effects at low doses, while producing robust wake enhancement at higher doses. To better understand the effect of H3R antagonists across a broad dose range, an ex vivo receptor binding assay has been used to estimate the degree of H3R occupancy in vivo. The H3R antagonists ciproxifan, thioperamide, GSK189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride), and ABT-239 ([4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile) produced wake-promoting activity in vivo and a dose-dependent inhibition of H3R binding ex vivo. For ciproxifan, thioperamide, and GSK189254, a relatively low level of cumulative wake activity was linearly correlated with up to 80% of the receptor occupancy. In contrast, an abrupt break from linearity and a robust increase of waking activity was observed at doses that produce greater than 80% occupancy. Our results suggest a relatively small increase of waking activity at low levels of receptor occupancy that may be consistent with reported enhancement of attention and cognitive function. Robust waking activity at higher levels of H3R occupancy may be mechanistically different from activities at low levels of H3R occupancy. PMID:18305012

Le, Siyuan; Gruner, John A; Mathiasen, Joanne R; Marino, Michael J; Schaffhauser, Hervé