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BEHAVIORAL PHARMACOLOGY

Characterization of a Novel Bivalent Morphinan Possessing Agonist and µ Agonist/Antagonist Properties

Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York (J.L.M., J.M.B.); and Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts (X.P., W.X., A.Z., S.S.N., J.L.N.)

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 that was shown to be a opioid receptor agonist and a µ opioid receptor agonist/antagonist. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had K_i values of 0.078 and 0.20 nM for the and µ opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5'-O -(3-[³⁵ S]thiotriphosphate) binding assay, MCL-145 produced an E_max value of 80% for the opioid receptor and 42% for the µ opioid receptor. The EC₅₀ values obtained for this compound were 4.3 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 -funaltrexamine and the -selective antagonist nor-binaltorphimine. MCL-145 also acted as a µ antagonist, as measured by the inhibition of morphine-induced antinociception.

Address correspondence to: Dr. Jean M. Bidlack, Department of Pharmacology and Physiology, Box 711, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642-8711. E-mail: jean_bidlack{at}urmc.rochester.edu