PT - JOURNAL ARTICLE AU - Jennifer L. Mathews AU - Xuemei Peng AU - Wennan Xiong AU - Ao Zhang AU - S. Stevens Negus AU - John L. Neumeyer AU - Jean M. Bidlack TI - Characterization of a Novel Bivalent Morphinan Possessing κ Agonist and μ Agonist/Antagonist Properties AID - 10.1124/jpet.105.084343 DP - 2005 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 821--827 VI - 315 IP - 2 4099 - http://jpet.aspetjournals.org/content/315/2/821.short 4100 - http://jpet.aspetjournals.org/content/315/2/821.full SO - J Pharmacol Exp Ther2005 Nov 01; 315 AB - Previous research has shown that compounds with mixed κ 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 κ 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 Ki values of 0.078 and 0.20 nM for the κ 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 Emax value of 80% for the κ 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 κ 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 β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. MCL-145 also acted as a μ antagonist, as measured by the inhibition of morphine-induced antinociception. The American Society for Pharmacology and Experimental Therapeutics