title: Characterization of a novel bivalent morphinan possessing kappa agonist and micro agonist/antagonist properties.
abstract: Previous research has shown that compounds with mixed kappa and mu 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 kappa opioid receptor agonist and a mu 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 kappa and mu 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 kappa opioid receptor and 42% for the mu opioid receptor. The EC(50) values obtained for this compound were 4.3 and 3.1 nM for the kappa and mu opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55 degrees C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the mu-selective antagonist beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. MCL-145 also acted as a mu antagonist, as measured by the inhibition of morphine-induced antinociception.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, NY 14642-8711, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Mathews
authors.forename: Xuemei
authors.initials: X
authors.lastname: Peng
authors.forename: Wennan
authors.initials: W
authors.lastname: Xiong
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
authors.forename: John L
authors.initials: JL
authors.lastname: Neumeyer
authors.forename: Jean M
authors.initials: JM
authors.lastname: Bidlack
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000737:chemistry / Q000494:pharmacology*; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011485:Protein Binding; D011869:Radioligand Assay; D011930:Reaction Time / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors*
chemical_list: D000701:Analgesics, Opioid; D005650:Fumarates; D009019:Morphinans; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C506840:bis(N-cyclobutylmethylmorphinan)fumarate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D019204:GTP-Binding Proteins