High-affinity carbamate analogues of morphinan at opioid receptors

Abstract

A series of carbamate analogues were synthesized from levorphanol ( 1a), cyclorphan ( 2a) or butorphan ( 3a) and evaluated in vitro for their binding affinity at μ, δ, and κ opioid receptors. Functional activities of these compounds were measured in the [ 35S]GTP γS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for κ receptor ( K i = 0.046 and 0.051 nM) and for μ receptor ( K i = 0.11 and 0.12 nM). Compound 1c showed the highest μ selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [ 35S]GTP γS binding mediated by the κ opioid receptor illustrated that all of these ligands were κ agonists. At the μ receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c– e and 3c– e were μ agonists/antagonists.