CB1 Cannabinoid Antagonists: Structure-Activity Relationships and Potential Therapeutic Applications

Abstract

During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.

A review of recent progress (2002-2012) on the biological activities of pyrazoles

“…A large number of analogues have been described in which all the substituents have been modified: the methyl at C-4, the aromatic rings and their substituents, and the piperidine which has been substituted by other rings and by alkyl chains. [105][106][107] Worth mentioning are 105 (OL-1302) with a pentyl chain at the phenyl ring, 108 107 (AM251) obtained by replacing the 5-phenyl chloro substituent by iodine which is used as a reference compound in cannabinoid studies, 109 and 108 (SR147778) which reduced food intake in rats. 110 Besides, different groups have reported conformationally restricted analogs of Rimonabant such as 106, 111 110 with nanomolar affinity for the hCB1 receptor, 112 referred also as NESS0327 in another publication 113 and 111.…”

Toward the design of cannabinoid CB1 receptor inverse agonists and neutral antagonists

“…Additional structural categories of CB 1 antagonists recently have been reviewed by [Jagerovic et al, 2008]. …”

“…The major therapeutic use for cannabinoid inverse agonists/antagonists has centered on the treatment of metabolic syndrome and obesity [Antel et al, 2006;Cervino et al, 2007] [Jagerovic et al, 2008]. AVE-1625 (Sanofi-Aventis) is currently undergoing different Phase II clinical trials for the treatment of cognitive impairment in patients diagnosed with schizophrenia and for safety and tolerance in patients with Alzheimer's disease (http://www.clinical trizals.gov) [Jagerovic et al, 2008]. Other areas in which CB 1 antagonists may hold therapeutic promise are for the treatment of bone diseases associated with increased osteoclast activity [Idris et al, 2005] and for the treatment of hepatic fibrosis [Teixeira-Clerc et al, 2006].…”

N-substituted-1,2,3-triazoles: synthesis, characterization and evaluation as cannabinoid ligands

“…These receptors are involved in many biochemical processes and are thus interesting therapeutic targets. [2][3][4] In particular, the CB1 receptor is involved in many different food-intake related disorders such as bulimia or obesity. 5,6 Unfortunately, rimonabant (Figure 1), the first potent and selective CB1…”