Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2)

Salvinorin A is the only known non-nitrogenous and specific κ-opioid agonist. A series of salvinorin A derivatives were prepared and tested for in vitro activity at the κ-opioid receptor. Unsubstituted carbamate 9 was a potent κ-agonist (EC50 = 6.2 nM) and should be more stable than salvinorin A toward metabolic transformations. Compound 10, containing an N-methyl carbamate at C(2), showed partial agonist activity with 81% efficacy when compared with the full agonist U50,488H. No antagonist ligands were observed.