Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid phenylamide (CP-272871) for the CB1 cannabinoid receptor

Meschler, Justin P.; Kraichely, Dennis M.; Wilken, Gerald H.; Howlett, Allyn C.

doi:10.1016/s0006-2952(00)00447-0

Cited by 101 publications

(90 citation statements)

References 21 publications

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“…constitutive activity) in transfected cell lines where the reporter system is a G protein-activated ion channel or an intracellular kinase (33,34). The ability of CB 1 to activate G proteins in the absence of exogenously applied agonist has also been shown for native CB 1 receptors in human and rat brain (35,36). Kearn and co-workers (37) have estimated that in WT CB 1 , the receptor populations are 70% inactive state (R) and 30% active state (R*).…”

Section: Functional Analysis Of Mutant Receptorsmentioning

confidence: 92%

“…This reduction cannot be explained simply by reduced ligand affinity, as the affinity of CP is not affected by this mutation, but its efficacy is affected. It is possible that because the WT CB 1 receptor itself exhibits a high level of constitutive activity (33)(34)(35) and because the F3.36(201)A mutant exhibits an increase in constitutive activity relative to WT CB 1, the population of F3.36(201)A mutant receptors is already shifted heavily toward R*. This should not interfere with agonist binding, as agonists have higher affinity for the R* state.…”

Section: Toggle Switch Residuesmentioning

confidence: 99%

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Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches

McAllister

Hurst

Barnett-Norris

et al. 2004

Journal of Biological Chemistry

146

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Section: Functional Analysis Of Mutant Receptorsmentioning

confidence: 92%

Section: Toggle Switch Residuesmentioning

confidence: 99%

Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches

McAllister

Hurst

Barnett-Norris

et al. 2004

Journal of Biological Chemistry

146

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“…Thus, its biochemical or behavioral effects generally are opposite in direction to effects produced by Δ 9 THC or other CB-1 agonists and can be antagonized by prior treatment with CB-1 agonists [2]. Biochemically, SR141716A can inhibit mitogen-activated protein kinase activity, adenylyl cyclase activity, and GTPγS binding in selected brain regions [3,4]. Behaviorally, relatively low doses of SR141716A (0.1 mg/kg i.v.…”

Section: Sr141716amentioning

confidence: 99%

“…The preceding discussion is of relevance to the clinical utility of CB1 antagonists with inverse agonist activity, including SR141716A or other currently available antagonists such as AM251, CP-272871, or Ave1625 [21,22,9,3,23]. As described above for SR141716A, antagonist/ inverse agonists that have been thoroughly investigated in laboratory and/or clinical studies appear to produce direct physiological and behavioral effects that may limit their therapeutic application.…”

Section: Inverse Vs Neutral Antagonismmentioning

confidence: 99%

Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties

Bergman

Delatte

Paronis

et al. 2008

Physiology & Behavior

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The CB1 inverse agonist/antagonist SR141716A recently has been introduced for the management of obesity (rimonabant; Acomplia) and appears to have beneficial effects. However, its utility may be hampered in some individuals by adverse effects including nausea or emesis or by mood depression. The recent development of biochemically 'neutral' antagonists such as AM4113 (Sink et al. 2007) has allowed an initial evaluation of the proposition that the adverse effects of SR141716A are associated with its inverse agonist activity. Thus far, data comparing SR141716A and AM4113 across several species indicate that both drugs produce dose-related direct effects on operant behavior within the same range of doses that serve to antagonize the behavioral and hypothermic effects of a CB1 agonist. However, initial observations suggest that AM4113 may not produce preclinical indications of nausea or emesis. Further studies with AM4113 and other novel CB1 antagonists differing in efficacy should amplify our understanding of the relationship between the pharmacological activity of CB1 antagonists and their behavioral effects. KeywordsSR141716A; rimonabant; AM4113; AM4054; inverse agonism; neutral antagonism; behavior; hypothermia A rapid succession of events in the first half of the 1990s including the discovery of the cannabinoid-1 (CB1) receptor and the isolation and synthesis of its endogenous ligands anandamide and 2-AG, energized the explosion of scientific interest in cannabinoid pharmacology and the development of novel ligands, including those that produced Δ 9 THClike effects and those could counter, i.e., antagonize, the effects of Δ 9 THC and other CB1 agonists at the CB1 receptor. It is interesting that, notwithstanding the acknowledged medicinal value of cannabis products with CB1 agonist actions, the first major therapeutic agent to emerge from these research efforts has been the CB1 antagonist/inverse agonist SR141716A (rimonabant; [1]). Perhaps it is not surprising that its initial therapeutic targets have been based a The preparation of this manuscript and portions of the work described herein were supported under NIH/NIDA DA19205 b Portions of the work described herein have been presented previously at the 2005 meeting of the College on Problems of Drug Dependence in Orlando, FL and at the

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“…In binding studies, rimonabant has an affinity for the CB 1 receptor in the low nanomolar range. In functional experiments, rimonabant is not a neutral antagonist but, rather, has been found to be an inverse agonist at the CB 1 receptor (Landsman et al 1997;MacLennan et al 1998;Meschler et al 2000;Thomas et al 2007).…”

Section: Direct Effects On Cannabinoid and Other Receptorsmentioning

confidence: 99%

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

Diepen

Schlicker

Michel

2008

Naunyn-Schmied Arch Pharmacol

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Rimonabant is an inverse agonist specific for cannabinoid receptors and selective for their cannabinoid-1 (CB 1 ) subtype. Although CB 1 receptors are more abundant in the central nervous system, rimonabant has many effects in the periphery, most of which are related to prejunctional modulation of transmitter release from autonomic nerves. However, CB 1 receptors are also expressed in, e.g., adipocytes and endothelial cells. Rimonabant inhibits numerous cardiovascular cannabinoid effects, including the decrease of blood pressure by central and peripheral (cardiac and vascular) sites of action, with the latter often being endothelium dependent. Rimonabant may also antagonize cannabinoid effects in myocardial infarction and in hypotension associated with septic shock or liver cirrhosis. In the gastrointestinal tract, rimonabant counteracts the cannabinoid-induced inhibition of secretion and motility. Although not affecting most cannabinoid effects in the airways, rimonabant counteracts inhibition of smoothmuscle contraction by cannabinoids in urogenital tissues and may interfere with embryo attachment and outgrowth of blastocysts. It inhibits cannabinoid-induced decreases of intraocular pressure. Rimonabant can inhibit proliferation of, maturation of, and energy storage by adipocytes. Among the many cannabinoid effects on hormone secretion, only some are rimonabant sensitive. The effects of rimonabant on the immune system are not fully clear, and it may inhibit or stimulate proliferation in several types of cancer. We conclude that direct effects of rimonabant on adipocytes may contribute to its clinical role in treating obesity. Other peripheral effects, many of which occur prejunctionally, may also contribute to its overall clinical profile and lead to additional indications as well adverse events.

show abstract

Inverse agonist properties of N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A) and 1-(2-chlorophenyl)-4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid phenylamide (CP-272871) for the CB1 cannabinoid receptor

Cited by 101 publications

References 21 publications

Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches

Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches

Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

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