Sulfonamide derivatives as new potent and selective CB2 cannabinoid receptor agonists

A novel series of sulfonamide derivatives 3, the CB2 receptor agonists, was synthesized and evaluated for activity against the human CB2 receptor. We first identified sulfonamide 3a, which was obtained by random screening of our in-house chemical library as a moderately active (CB2 IC50 = 340 nM) CB2 receptor agonist. We then attempted to test its analogues to identify compounds with a high affinity for the CB2 receptor. One of these, compound 3f, exhibited high affinity for the human CB2 receptor (IC50 = 16 nM) and high selectivity for CB2 over CB1 (CB1 IC50/CB2IC50 = 106), and behaved as a full CB2 receptor agonist in the [35S]GTPγS binding assay (CB2 EC50 = 7.2 nM, Emax = 100%).