title: In vitro and in vivo pharmacological profile of the 5-benzyl analogue of 14-methoxymetopon, a novel mu opioid analgesic with reduced propensity to alter motor function.
abstract: Opioids are the most effective analgesics for pain management, and efficient pain control is a therapeutic priority. Herein, we describe the synthesis and pharmacological activities of the 5-benzyl analogue of the mu opioid analgesic 14-methoxymetopon (14-MM). The result of the replacement of the 5-methyl in 14-MM with a benzyl group on in vitro opioid receptor binding and functional profiles, and in vivo behavioural properties, i.e. nociception and motor activity, was investigated. In rodent brain membranes, the 5-benzyl derivative showed high affinity at the micro opioid receptor and decreased interaction with delta and kappa receptors, hence displaying a similar binding profile as 14-MM. It displayed potent agonist activity in vitro and in vivo. In in vitro guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTPgammaS) binding assay, it activated G-proteins in rat brain membranes through a micro opioid receptor-mediated mechanism having significantly enhanced potency compared to DAMGO (D-Ala(2),Me-Phe(4),Gly-ol(5)]enkephalin), and to the micro opioid agonist morphinans 14-MM, 14-O-methyloxymorphone (14-OMO) and morphine. In vivo, the 5-benzyl analogue of 14-MM elicited dose-dependent and naloxone-sensitive antinociceptive effects in hot-plate and tail-flick tests in mice after subcutaneous (s.c.) administration. Its analgesic potency was comparable to 14-MM, and was 50-fold higher than that of morphine. Contrary to morphine, 14-MM and 14-OMO, no motor dysfunction was produced by the new opioid in the mouse rotarod test at any of the tested doses. In summary, the 5-benzyl analogue of 14-MM emerged as a novel potent mu opioid antinociceptive agent with reduced propensity to cause unwanted motor impairment.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 52 a, A-6020 Innsbruck, Austria.
authors.forename: Mariana
authors.initials: M
authors.lastname: Spetea
authors.forename: Catalina R
authors.initials: CR
authors.lastname: Bohotin
authors.forename: Muhammad F
authors.initials: MF
authors.lastname: Asim
authors.forename: Kurt
authors.initials: K
authors.lastname: Stübegger
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidhammer
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009022:Morphine Derivatives / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D017450:Receptors, Opioid, mu; C081949:14-methoxymetopon