CBi antagonists

Sanofi-Synthelabo) has stimulated a great deal of interest in the diseovery of eannabinoid CBi reeeptor antagonists. This seetion aims to eover the strue-tures and therapeutie applieations of CBi antagonists published to date. Reviews of CBi reeeptor antagonists and their therapeutie applieations have recently appeared in the literature [260-262]. 

An azetidine motif was also present in two series of CBi antagonist compounds disclosed by Vernalis Research [335, 336]. In the former, compound (560) was claimed to have an affinity of 285 nM in transfected HEK293 cells using tritium-labelled (382). Among the preferred indications were psychosis, schizophrenia, smoking cessation and eating disorders associated with excessive food intake. Compound (561) was claimed to have an affinity of 0.8 nM in the same binding assay [336]. 

Our current understanding of the potential therapeutic applications of CBi antagonists owes a great deal to the discovery of rimonabant (382). Indeed, clinical data demonstrating the efficacy of (382) in the treatment of obesity and nicotine addiction has provided a substantial driving force for the expanding research effort into this approach. 

Pre-clinical data support the potential application of CBi antagonists in the treatment of various other conditions. These include memory disorders [379], sexual dysfunction [380], neuro-inflammation [381] and asthma [382]. 

Le FoU B, Goldberg SR (2004) Rimonabant, a CBi antagonist, blocks nicotine-conditioned place preferences. Neuroreport 15 2139-2143... 

Femandez-Espejo E, Caraballo 1, de Fonseca FR, El Banoua F, Ferrer B, Flores JA, Galan-Rodriguez B (2005) Cannabinoid CBI antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism. Neurobiol Dis 18 591-601... 

Structural features of the central cannabinoid CBI receptor involved in the binding of the specific CBI antagonist SR 141716A. J Biol Chem 271 6941-6946... 

Very recently, Solvay Pharmaceuticals (Lange et al. 2004) reported a novel class of 3,4-disubstituted pyrazoline analogs exhibiting high CBi selectivity (e.g., 51, Fig. 12). Another novel class of CBi antagonists that has received only limited attention includes the 3-alkyl-5-arylhydantoins (Ooms et al. 2002). 

Fern4ndez-Espejo E, Caraballo 1, Rodriguez de Fonseca F, El Banoua P, Perrer B, Plores JA, Galan-Rodrlgncz B (2004) Homeostatic changes of anandamide synthesis, and functional effects of cannabinoid CBI antagonists in rats with severe hemiparkinsonism. Neurobiol Dis (in press)... 

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