Received for publication March 2, 2005.
Revised July 27, 2005.
Accepted for publication July 28, 2005.

Characterization of A Novel Bivalent Morphinan Possessing Kappa Agonist and Mu Agonist/Antagonist Properties

Abstract

Previous research has shown that compounds with mixed and µ activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan which was shown to be a -opioid receptor agonist and a µ-opioid receptor agonist/antagonist. MCL-145 is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K_i values of 0.078 nM and 0.20 nM for the and µ opioid receptors respectively, using radioligand binding assays (Neumeyer et al., 2003). In the guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding assay, MCL-145 produced an E_max value of 80% for the opioid receptor 42% for the µ opioid receptor. The EC₅₀ values obtained for this compound were 4.3 nM and 3.1 nM for the and µ opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the µ-selective antagonist, beta-funaltrexamine, and the -selective antagonist, nor-binaltorphimine. MCL-145 also acted as a µ antagonist, as measured by the inhibition of morphine-induced antinociception.

Key words: GTPgammaS, bivalent ligand, kappa opioid, mu opioid, novel opioid, tail withdrawal