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[摘要]：There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivs., e.g. I (R1 = 1-pentyl, Ph, PhCH2, R2 = H, R3 = Ph), and have identified and characterized several of them as novel analogs with high functional activity and selectivity at human CB2 receptors using [35S]GTP-g-S assays. Binding affinities at human CB2 and CB1 were detd. for compds. I (R1 = 2-cyclohexylethyl, 1-hexyl, 1-Bu, R2 = H, R3 = Ph; R1 = 1-hexyl, R2 = H, R3 = t-BuO; R1 = 1-hexyl, R2 = 7-I, R3 = Ph). Structure-activity relationship studies of this novel series led to optimization of our lead compd., compd. I (R1 = 1-hexyl, R2 = H, R3 = Ph) (II). Compd. II possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compds., including compds. I (R1 = 1-hexyl, R2 = H, R3 = cyclohexyl, t-BuO; R1 = 1-Bu, R2 = H, R3 = Ph), were also discovered. |
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