O

(610) AM630

A series of tricyclic pyrazoles has been synthesised and their CB1 and CB2 affinity determined in mouse cerebellum membranes and mouse spleen ho-mogenate, respectively [387]. Table 6.51 describes some of the pertinent data.

Despite the close structural similarity between rimonabant (382) and the fused pyrazole analogues described by Mussinu and co-workers [276], the majority of the latter show a moderate-to-strong preference for the CB2 receptor. In particular, (612), the closest homologue to (382) within the series, shows very low nanomolar affinity (Ki = 0.34 nM) at CB2, while only comparatively modest CB1 affinity (2,050 nM). 6-Fluoro (613) and 6-bromo (614) analogues were also potent and selective CB2 ligands, while substitution of the larger 6-iodo group (615) resulted in a decrease in both affinity and selectivity. The unsubstituted analogue (618) exhibited a profile similar

Table 6.51 TRICYCLIC PYRAZOLE DERIVATIVES - CBj AND CB2 BINDING

DATA [387]

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