Recent CB1 cannabinoid receptor antagonists and inverse agonists

Abstract

Antagonists or inverse agonists of the cannabinoid CB1 receptor (CB1R) reported from the 2006-2007 period are reviewed. The compounds are either variations of the archetypical cannabinoid CB1 inverse agonist rimonabant (SR141716) or are other structures less obviously related to the archetype. Many of the former class replace the core pyrazole ring of rimonabant with other ring systems to display/ arrange the appended binding/activity elements. A structure-activity relationship evolves from bioassays of these compounds that also provides a more detailed understanding of the molecular mechanism of the binding to and stabilization of the active and inactive states of the constitutively active CB1R. In addition to diverse variations of the core ring and appended substituents, conformationally constrained analogs with high affinity were revealed, a number of which do not fit a one-to-one atom correspondence with the putatively active conformations of the rimonabant template and other active analogs. Diphenylmethyl analogs were a repeated motif in structures where core rings were either absent or played less restrictive roles in structures pursuing higher conformational freedom. Bicyclic nitrogen heterocyclic ring systems as the central core structures were reported, as were linear structures including phenyl ureas and taranabant analogs. Finally, peptides in the hemopressin class were presented as CB1 antagonists. Drug Dev Res 70 : 601-615, 2009.

Enlarging the NSAIDs Family: Ether, Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Novel Anti-Inflammatory and Analgesic Agents

“…The diarylheterocyclic motif can also be found when dealing with cannabinoid receptor modulators. Rimonabant, a diaryl pyrazole, is the first prototype of this class of CB1 receptor modulators but there are a lot of closely related molecules which have been submitted to clinical testing [30]. In order to decrease the possibility of unwanted potentially unsafe interaction with other targets (i.e.…”

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The Bioisosteric Concept Applied to Cannabinoid Ligands

“…These studies have been widely reviewed [24,[28][29][30][31][32][33][34][35][36][37][38] and some specific examples of resulting bioisosteric analogs are depicted in Fig. In the last decade, a considerable number of papers and patent applications was published from major pharmaceutical companies describing the bioisosteric substitution of the central pyrazole moiety of rimonabant with 5-and 6-membered rings.…”