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Inverse Agonists (inverse + agonist)

Distribution by Scientific Domains

Medical Sciences	57%
Chemistry	38%

Selected Abstracts

Discovery of a New Class of Non-imidazole Oxazoline-Based Histamine H3 Receptor (H3R) Inverse Agonists

CHEMMEDCHEM, Issue 7 2009
Sylvain Célanire Dr.
Abstract H3R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory. [source]

WAG/Rij rats show a reduced expression of CB1 receptors in thalamic nuclei and respond to the CB1 receptor agonist, R(+)WIN55,212-2, with a reduced incidence of spike-wave discharges

EPILEPSIA, Issue 8 2010
Clementina M. Van Rijn
Summary Purpose:, Genetically epileptic WAG/Rij rats develop spontaneous absence-like seizures after 3 months of age. We used WAG/Rij rats to examine whether absence seizures are associated with changes in the expression of type-1 cannabinoid (CB1) receptors. Methods:, Receptor expression was examined by in situ hybridization and western blot analysis in various brain regions of "presymptomatic" 2-month old and "symptomatic" 8-month-old WAG/Rij rats relative to age-matched nonepileptic control rats. Furthermore, we examined whether pharmacologic activation of CB1 receptor affects absence seizures. We recorded spontaneous spike-wave discharges (SWDs) in 8-month old WAG/Rij rats systemically injected with the potent CB1 receptor agonist, R(+)WIN55,212-2 (3,12 mg/kg, s.c.), given alone or combined with the CB1 receptor antagonist/inverse agonist, AM251 (12 mg/kg, s.c.). Results:, Data showed a reduction of CB1 receptor mRNA and protein levels in the reticular thalamic nucleus, and a reduction in CB1 receptor protein levels in ventral basal thalamic nuclei of 8-month-old WAG/Rij rats, as compared with age-matched ACI control rats. In vivo, R(+)WIN55,212-2 caused a dose-dependent reduction in the frequency of SWDs in the first 3 h after the injection. This was followed by a late increase in the mean SWD duration, which suggests a biphasic modulation of SWDs by CB1 receptor agonists. Both effects were reversed or attenuated when R(+)WIN55,212-2 was combined with AM251. Discussion:, These data indicate that the development of absence seizures is associated with plastic modifications of CB1 receptors within the thalamic-cortical-thalamic network, and raise the interesting possibility that CB1 receptors are targeted by novel antiabsence drugs. [source]

The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism , or inverse agonism , as potential obesity treatment and other therapeutic use

JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2007
S. Xie Pharm D student
Summary There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB1 (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity. [source]

Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2 2010
K. PRZYKLENK
Summary.,Background: Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype. Objective: To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina. Methods: In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury + stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin. Results: APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow,time area (index of coronary patency; normalized to baseline coronary flow) averaged 58,59% (P < 0.01) following administration of APD791 vs. 21,28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation. Conclusion: 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model. [source]

Protective effect of BR-16A, a polyherbal preparation against social isolation stress: possible GABAergic mechanism

PHYTOTHERAPY RESEARCH, Issue 7 2006
Anil Kumar
Abstract The antistress effects of BR-16A, a polyherbal preparation and its interaction with GABAergic modulators against social isolation-induced stress were investigated in the present study. Isolation stress was induced by keeping the mice (Laca strain) individually in each cage for 3 weeks and various drug treatments were given for a period of 5 days before the start of the experiments. The various behavioural parameters examined included pentobarbitone-induced sleep (sleep latency and duration), analgesia (tail-ßick test) and locomotor activity, respectively. BR-16A (100 mg/kg and 200 mg/kg) treatment for 5 days significantly reversed the social isolation stress-induced prolongation of onset and decrease in pentobarbitone-induced sleep, increased total motor activity and stress-induced antinociception. When diazepam (0.5 mg/kg), a benzodiazepine agonist, was co-administered with BR-16A (100 mg/kg), it significantly potentiated the reversal of pentobarbitone-induced shortening of sleep time effects; increased locomotor activity and stress induced antinociceptive effects. However, the sleep latency was not decreased significantly. Further, ßumazenil (2 mg/kg), a benzodiazepine receptor antagonist and FG 7142 (10 mg/kg), an inverse agonist, when co-administered with BR-16A (100 mg/kg), showed no significant reversal on pentobarbitone-induced hypnosis, locomotor activity and social isolation-induced antinociception compared with their effects per se. The present study demonstrated the antistress effects of BR-16A preparation against social isolation-induced stress. The present study also suggests that the GABAergic system may be involved in its antistress effect. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Primary events in dim light vision: a chemical and spectroscopic approach toward understanding protein/chromophore interactions in rhodopsin

THE CHEMICAL RECORD, Issue 2 2004
Nathan Fishkin
The visual pigment rhodopsin (bovine) is a 40,kDa protein consisting of 348 amino acids, and is a prototypical member of the subfamily A of G protein-coupled receptors (GPCRs). This remarkably efficient light-activated protein (quantum yield = 0.67) binds the chromophore 11- cis -retinal covalently by attachment to Lys296 through a protonated Schiff base. The 11- cis geometry of the retinylidene chromophore keeps the partially active opsin protein locked in its inactive state (inverse agonist). Several retinal analogs with defined configurations and stereochemistry have been incorporated into the apoprotein to give rhodopsin analogs. These incorporation results along with the spectroscopic properties of the rhodopsin analogs clarify the mode of entry of the chromophore into the apoprotein and the biologically relevant conformation of the chromophore in the rhodopsin binding site. In addition, difference UV, CD, and photoaffinity labeling studies with a 3-diazo-4-oxo analog of 11- cis -retinal have been used to chart the movement of the retinylidene chromophore through the various intermediate stages of visual transduction. © 2004 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 4: 120,135; 2004: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20000 [source]

Constitutive activity of cannabinoid-2 (CB2) receptors plays an essential role in the protean agonism of (+)AM1241 and L768242

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009
I Mancini
Background and purpose:, Cannabinoid-2 (CB2) receptor-selective agonists have shown anti-nociceptive activity in models of neuropathic and inflammatory pain, and the two agonists most widely used, (+/,)AM1241 [(2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl-methanone] and L768242 [(2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone] (GW405833), have been suggested to be protean agonists. Here we investigated the role of the constitutive activity of CB2 receptors in (+)AM1241 and L768242 protean agonism. Experimental approach:, Pharmacological profiles of CB2 receptor ligands were evaluated in Chinese hamster ovary cells expressing recombinant human (hCB2) or rat (rCB2) receptors, by measuring modulation of cAMP. To assess the influence of constitutive activity on pharmacological profile, constitutive activity was abolished by pretreatment with AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)], followed by extensive washing. Key results:, In cell lines expressing either hCB2 or rCB2 receptors, (+)AM1241 did not reverse forskolin stimulation of cAMP levels. Conversely, L768242 was an inverse agonist at both hCB2 and rCB2 receptors. Abolition of constitutive activity disclosed (+)AM1241 and L768242 agonist activity, while activity of CP55940 [5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol] was unaffected and AM630 became a neutral antagonist. In presence of constitutively active CB2 receptors, (+)AM1241 antagonized CP55940, but when constitutive activity was abolished, it acted as a partial agonist with additive or antagonistic behaviour, depending on concentration. Conclusions and implications:, These results show that (+)AM1241 and L768242 are protean agonists at both hCB2 and rCB2 receptors. Abolition of constitutive activity reveals the agonist activity of these compounds. Thus, differences between in vivo and in vitro profiles of CB2 receptor agonists could be due to different levels of constitutive activity in recombinant versus native CB2 receptors. [source]

Histamine H3 -receptor-mediated [35S]GTP,[S] binding: evidence for constitutive activity of the recombinant and native rat and human H3 receptors

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2002
A Rouleau
Constitutive activity of the recombinant and native rat and human H3 receptors (H3Rs) was studied using H3R-mediated [35S]GTP,[S] binding and [3H]-arachidonic acid release. Ciproxifan, an inverse agonist at the rat H3R (rH3R), decreased [3H]arachidonic acid release from CHO cells expressing moderate densities (,200,300 fmol mg,1 protein) of the human H3R (hH3R). This effect occurred with the same magnitude than at the rH3R. The expression of the hH3R was associated with an increase in [35S]GTP,[S] binding to membranes of CHO cells. Ciproxifan decreased [35S]GTP,[S] binding to membranes of CHO (hH3R) cells. Both effects were correlated to receptor density and revealed that constitutive activity of the hH3R, although lower than that of the rH3R in this assay, was again observed at physiological densities (<500 fmol mg,1 protein). Ciproxifan was less potent at the human than the rat receptor, not only as an antagonist (Ki=45 nM), but also as an inverse agonist (EC50=15 nM). Constitutive activity of the hH3R was also evidenced using inhibition of [35S]GTP,[S] binding by unlabelled GTP,S. The expression of the hH3R generated a high affinity binding for GTP,S which was increased by imetit, but partially decreased by ciproxifan, therefore acting as a partial inverse agonist. [35S]GTP,[S] binding to rat brain membranes was decreased in several regions by thioperamide, ciproxifan and FUB 465, three inverse agonists at the H3R, whose effects were blocked by proxyfan, a neutral antagonist. [35S]GTP,[S] binding was also decreased by an A1 -adenosine receptor inverse agonist, but remained unchanged in the presence of inverse agonists at D2/D3 dopamine, H1 and H2 histamine, ,2 -adrenergic and , opioid receptors. In conclusion, the present study shows that the recombinant rat and human H3 receptors expressed at physiological densities display constitutive activity and suggests that constitutive activity of native H3Rs is one of the highest among G-protein-coupled receptors present in rat brain. British Journal of Pharmacology (2002) 135, 383,392; doi:10.1038/sj.bjp.0704490 [source]

An Overview of SR121463, a Selective Non-Peptide Vasopressin V2 Receptor Antagonist

CARDIOVASCULAR THERAPEUTICS, Issue 3 2001
C. Serradeil-Le Gal
ABSTRACT SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V2 receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V2 receptors and exhibits a remarkably selective V2 receptor profile. SR121463 and [3H]SR121463 are used, therefore, as selective probes for characterization and labeling of V2 receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V2 receptor mutant. In vitro, SR1 21463 rescued misfolded V2 AVP receptor mutants by increasing cell surface expression and restoring V2 function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V2 (or V2 -like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V2 receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V2 receptors. Pure V2 receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V2 receptors (e.g., glaucoma). [source]

Pyrazine Arotinoids with Inverse Agonist Activities on the Retinoid and Rexinoid Receptors

CHEMBIOCHEM, Issue 7 2009
José García
Abstract RAR and RXR agonists: A collection of pyrazine-based RAR/RXR ligands were prepared by a series of palladium catalyzed cross-coupling reactions and characterized. Structure,activity relationships were elucidated. Retinoic acid receptor (RAR) ,/,-subtype-selective and retinoid X receptor (RXR) inverse agonist activities are described for pyrazine acrylic acid arotinoid, 14,d. Heterocyclic arotinoids derived from central-region dihalogenated pyrazine scaffolds have been synthesized by consecutive halogen and/or position-selective palladium-catalyzed cross-coupling reactions. Pyrazines were further functionalized as alkyl ethers or methylamines prior to the last Pd-catalyzed reactions. Transient transactivation studies with the retinoic acid receptor (RAR) ,, ,, and , subtypes and with retinoid X receptor (RXR) , revealed distinct agonist, antagonist, and inverse agonist activities for these compounds. Of interest are the RAR,,,-selective inverse agonists with pyrazine acrylic acid structures, in particular 14,c, which is RAR,-selective, and 14,d, a pan-RAR/RXR inverse agonist with more affinity for the RAR subtypes that enhance the interaction of RAR with cognate corepressors. [source]

The molecular receptive range of an olfactory receptor in vivo (Drosophila melanogaster Or22a)

DEVELOPMENTAL NEUROBIOLOGY, Issue 14 2006
Daniela Pelz
Abstract Understanding how odors are coded within an olfactory system requires knowledge about its input. This is constituted by the molecular receptive ranges (MRR) of olfactory sensory neurons that converge in the glomeruli of the olfactory bulb (vertebrates) or the antennal lobe (AL, insects). Aiming at a comprehensive characterization of MRRs in Drosophila melanogaster we measured odor-evoked calcium responses in olfactory sensory neurons that express the olfactory receptor Or22a. We used an automated stimulus application system to screen [Ca2+] responses to 104 odors both in the antenna (sensory transduction) and in the AL (neuronal transmission). At 10,2 (vol/vol) dilution, 39 odors elicited at least a half-maximal response. For these odorants we established dose-response relationships over their entire dynamic range. We tested 15 additional chemicals that are structurally related to the most efficient odors. Ethyl hexanoate and methyl hexanoate were the best stimuli, eliciting consistent responses at dilutions as low as 10,9. Two substances led to calcium decrease, suggesting that Or22a might be constitutively active, and that these substances might act as inverse agonists, reminiscent of G-protein coupled receptors. There was no difference between the antennal and the AL MRR. Furthermore we show that Or22a has a broad yet selective MRR, and must be functionally described both as a specialist and a generalist. Both these descriptions are ecologically relevant. Given that adult Drosophila use approximately 43 ORs, a complete description of all MRRs appears now in reach. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source]

Neuroanatomical basis for therapeutic applications of cannabinoid receptor 1 antagonists

DRUG DEVELOPMENT RESEARCH, Issue 8 2009
Brian F. Thomas
Abstract The CB1 receptor is a Class A G-protein coupled receptor that has a high density and widespread distribution within the central nervous system. Because of its neuroanatomical distribution, the endocannabinoid system can modulate a wide variety of psychological and physiological functions. For example, CB1 receptors are found in brain regions regulating motor activity, cognitive processes, pain, satiety, appetitive behaviors and reward. In correspondence with this distribution, modulation of the endocannabinoid system has been shown to produce changes in coordination, executive function, memory, mood, perception, wakefulness, nociception and appetite. Administration of cannabinoid agonists has also been therapeutically used to reduce nausea, and is also known to decrease body temperature and neuronal excitability, pointing to additional roles for endocannabinoids in these and other physiological/neurological processes. The ongoing elucidation and characterization of the neuroanatomical circuitry within which the CB1 cannabinoid receptor and endocannabinoids are localized to modulate these psychological and physiological processes continues to suggest therapeutic applications for cannabinoid antagonists and inverse agonists. Drug Dev Res 70:527,554, 2009. © 2009 Wiley-Liss, Inc. [source]

Structure,activity relationships of inverse agonists for G-protein-coupled receptors

MEDICINAL RESEARCH REVIEWS, Issue 4 2005
Willem Soudijn
Abstract It has been recently established that G-protein-coupled receptors (GPCRs) can be constitutively active, i.e., they can be active in the absence of an agonist. This activity can be inhibited by so-called inverse agonists. For a number of GPCRs, such inverse agonists have been developed and studied, now enabling for the first time a study into their structure,activity relationships. © 2005 Wiley Periodicals, Inc. [source]

Differential effects of CB1 neutral antagonists and inverse agonists on gastrointestinal motility in mice

NEUROGASTROENTEROLOGY & MOTILITY, Issue 7 2010
M. A. Storr
Abstract Background, Cannabinoid type 1 (CB1) receptors are involved in the regulation of gastrointestinal (GI) motility and secretion. Our aim was to characterize the roles of the CB1 receptor on GI motility and secretion in vitro and in vivo by using different classes of CB1 receptor antagonists. Methods, Immunohistochemistry was used to examine the localization of CB1 receptor in the mouse ileum and colon. Organ bath experiments on mouse ileum and in vivo motility testing comprising upper GI transit, colonic expulsion, and whole gut transit were performed to characterize the effects of the inverse agonist/antagonist AM251 and the neutral antagonist AM4113. As a marker of secretory function we measured short circuit current in vitro using Ussing chambers and stool fluid content in vivo in mouse colon. We also assessed colonic epithelial permeability in vitro using FITC-labeled inulin. Key Results,In vivo, the inverse agonist AM251 increased upper GI transit and whole gut transit, but it had no effect on colonic expulsion. By contrast, the neutral antagonist AM4113 increased upper GI transit, but unexpectedly reduced both colonic expulsion and whole gut transit at high, but not lower doses. Conclusions & Inferences, Cannabinoid type 1 receptors regulate small intestinal and colonic motility, but not GI secretion under physiological conditions. Cannabinoid type 1 inverse agonists and CB1 neutral antagonists have different effects on intestinal motility. The ability of the neutral antagonist not to affect whole gut transit may be important for the future development of CB1 receptor antagonists as therapeutic agents. [source]