Selective CB2 Receptor Antagonists

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. 

Bicyclic and tricyclic cannabinoids, (IV), prepared by Makriyannis (5) were effective as both CBj and CB2 agonists/antagonists and used as an effective and safe treatment option in pain management. Dibenzo[b,d]pyran derivatives, (V), effective as selective CB2 receptor agonists (V) also prepared by Makriyannis (6) were effective in treating... 

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-... 

GW-842166X (233) is a selective CB2 receptor full antagonist which has potent analgesic, anti-inflammatory and anti-hyperalgesic actions. It was selected as a clinical candidate after lead optimization of a pyrimidine ester 261 (GK02076, Fig. 9), identified in a focused screen as a partial agonist at the CB2 receptor with... 

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]. 

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]. 

Mouse vas deferens (MVD) seems to express CB1 and at least one CB2-like cannabinoid receptor type, as is demonstrated by the presence of CB1 and CB2-like mRNA as well as by data collected from experiments with cannabinoid receptor selective agonists and antagonists (Pertwee, 1999). Furthermore, evidence indicates that a CBl-like receptor exists in vascular endothelium, which upon activation produces significant hypotension (Wagner, 1999). This receptor differs from CB1 in its pharmacological response to some well-characterized cannabimimetics. 

Griffin G, Wray E, Tao Q, McAllister S, Rorrer W, Aung M, Martin B, Abood M (1999) Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528 further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. Eur J Pharmacol 377 117-125... 

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