"Lipophilicity calculated using the CLIP method.

^Results expressed as the percentages of the displaced specific binding of [ 3H]-SR-141716A (mean 7 SEM, n = 3-5).

antagonists with no intrinsic activity, but competitively inhibiting HU210-induced [35S]-GTPgS binding in rat cerebellum homogenates.

A series of closely related thiohydantoins was subsequently investigated by Muccioli et al. [349]. The key data are summarised in Table 6.50.

Replacement of the oxygen in the 2-position of the hydantoin ring with sulfur was found to increase CBi receptor potency between 2- and 4-fold. As in the preceding series, ^ara-substitution of the phenyl rings was found to increase potency, with iodo-susbstitution, e.g. (602), showing greater affinity than Br-substitution, e.g. (598), which in turn was more potent than the corresponding chloro analogue (593) (R2 — z'Bu). Substitution on the N3-position was also found to have a pronounced influence on CBi binding affinity. Increasing the chain length to over six carbon atoms resulted in a marked loss of activity. Benzyl substitution (594) was better tolerated than the corresponding phenyl ethyl congener (595), while the truncated allyl group, typified by analogues (600) and (603), was found to be optimal in this series. The most potent thiohydantoin analogue identified was found to be considerably less potent than rimonabant (382) (Ki — 589 and 5.4 nM, respectively), however, the compounds were selective over the CB2 receptor. Compounds (593), (594) and (600)-(602) were examined in the [35S]-GTPyS binding assay and, like the related hydantoin series, found to behave as inverse agonists at the CBi receptor.


DATA [349]

O R2

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