High-affinity carbamate analogues of morphinan at opioid receptors

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]GTPγS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for κ receptor (Ki = 0.046 and 0.051 nM) and for μ receptor (Ki = 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]GTPγS 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.