Selective CBi Receptor Antagonists

Anandamide was shown to alleviate nociception in several behavioral animal models, e.g. the hot plate and formalin test (Calignano et al., 2001). A most interesting aspect of anandamide with respect to pain research is that it seems to bind to the hypothetical third cannabinoid receptor (Di Marzo et al., 2000b) In the hot plate test anandamide is still antinociceptive in CB/ mice, which is consistent with the observation that the selective CBi receptor antagonist SR 141716A does not block motor inhibitory and antinociceptive effects of anandamide in wild-type mice. 

It is well known that the acute consumption of THC causes tachycardia in humans without any significant effect on blood pressure, whilst the chronic ingestion of cannabinoids leads to hypotension and bradycardia (Benowitz and Jones 1975). Pharmacological studies using selective CBi receptor antagonists (Varga et al. 1995 Lake et al. 1997) have suggested that some of these cardiovascular responses are mediated by CBi receptors. 

Several studies have been reported on the application of conformational restraint to the 1,5-diaryl-pyrazole series in an attempt to provide compounds with modified properties. In one approach, a Sanofi-Synthelabo patent application claimed a series of conformationally restrained compounds, exemplified by compound (391). Compounds of the invention were stated to be CBi receptor antagonists with K[ values below 5 x 10 M and selectivity over CB2 receptors of at least 10-fold [274]. 

Clearly there is now incontrovertible evidence for the existence of a mammalian endocannabinoid system that consists of at least two types of cannabinoid receptor, CBi and CB2, and of endogenous agonists (endocannabinoids) for these receptors. Agonists that activate both these receptor types with similar potency or that show marked selectivity for one or other receptor type have been discovered, as have potent CBi- and CB2-selective cannabinoid receptor antagonists. Quantitative and sensitive in vitro and in vivo bioassays for these ligands are also available, and these have played a crucial role in determining the CBi and CB2 receptor affinities and intrinsic activities of a number of cannabinoids. There is good evidence that the endocannabinoid system can become Ionically active and that this is due in some instances to endocannabinoid release and in other instances to the ability of cannabinoid receptors to exist in a constitutively activity state, not only when over-... 

Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP, Wilkin JM, Nomikos GG (2003) The CBi receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex implications for therapeutic actions. Br J Pharmacol 138 544-553... 

Makriyannis and co-workers designed and synthesized a series of pyrazole derivatives to aid in the characterization of the CB receptor binding sites and also to serve as potentially useful pharmacological probes. Structural requirements for potent and selective brain cannabinoid CBi receptor antagonistic activity included (1) a para-substituted phenyl ring at the 5-position, (2) a carboxamido group at the 3-position, and (3) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring (Lan et al. 1999). 

Structurally diverse cannabinoids attenuate the EFS-induced contractions with a potency order (CP 55, 940 > W1N55, 212-2 > nabilone > A - THC > cannabinol > anandamide), similar to their affinity rank order for cannabinoid CBi receptors. In addition, the selective cannabinoid CBi receptor antagonist/inverse agonist SR141716A counters the inhibitory effects of cannabinoid agonists (4). 

A -THC and other synthetic caimabinoids rehably induce hyperphagia and increase food intake in laboratory animals (61-64). These hyperphagic actions are mediated via cannabinoid CB i receptors since they are selectively blocked by the cannabinoid CBi receptor antagonist SR141716A but not with the CB2 antagonist SR 144258 (71). 

Both cannabinoid CB1/CB2 receptor agonists (A -THC [Dronabinol] and nabilone [Cesamet]) and selective cannabinoid CBi receptor antagonists (e.g., SR141716A [Rimonabant]) can be clinically used to respectively increase and decrease appetite (1). 

Several groups have published on structural analogues of (382), one of the earliest being the disclosure of CP 272871 (383) from Pfizer, which displays lower affinity for the CBi receptor than (382), in addition to reduced selectivity over the CB2 receptor subtype. Both (382) and (383) have been shown to act as inverse agonists rather than neutral antagonists in vitro [265]. A recently published patent application from Sanofi-Aventis claims a series of 4-cyanopyrazole analogues of (382), with 42 specific examples [266]. 

CB2 receptor antagonists have received much less attention than their CBi counterparts, with only a relatively small number of compounds available and less clarity on their potential therapeutic role. A selection of the available compounds that have been shown to act as antagonists of the CB2 receptor and their suggested utilities will be covered in this section. 

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