High-affinity carbamate analogues of rnorphinan 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 mu, delta, and kappa opioid receptors. Functional activities of these compounds were measured in the [S-35]GTP gamma S binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for K receptor (K-i = 0.046 and 0.051 nM) and for mu receptor (K-i = 0.11 and 0.12 nM). Compound 1c showed the highest mu selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [S-35]GTP gamma S binding mediated by the kappa opioid receptor illustrated that all of these ligands were kappa agonists. At the mu receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c-e and 3c-e were lt agonists/antagonists. (c) 2007 Elsevier Ltd. All rights reserved.