Synthesis and in vitro pharmacological studies of new C(2) modified salvinorin A analogues

A series of salvinorin A derivatives modified at the C(2) position were prepared and screened for binding and functional activities at the human κ-opioid receptor. A highly selective κ-agonist (EC 50 = 0.6 nM) was identified. Salvinorin A is the most potent naturally occurring opioid agonist yet discovered with high selectivity and affinity for κ-opioid receptor. To explore its structure and activity relationships, a series of salvinorin A derivatives modified at the C(2) position were prepared and studied. These salvinorin A derivatives were screened for binding and functional activities at the human κ-opioid receptor. Compound 4, containing a methoxymethyl group at the 2-position, was a full κ-agonist with an EC 50 value at 0.6 nM, which is about 7 times more potent than salvinorin A.