In vivo characterization of (-)(-)MCL-144 and (+)(-)MCL-193: isomeric, bivalent ligands with mu/kappa agonist properties.
Once opioid receptor dimers were postulated, a goal has been to synthesize and screen novel opioids, with the hope of furthering our knowledge of the structure-activity relationship of opioid ligands with the opioid receptors. The aim of the current study was to address whether two isomeric bivalent ligands would have pharmacological differences after central administration, in vivo. The two compounds, (-) bis(N-cyclobutylmethyl-morphinan-3-yl) sebacoylate dihydrochloride (MCL-144) and 1-((+)N-cyclobutylmethylmorphinan-3-yl)-10-((-) N-cyclobutylmethylmorphinan-3-yl)sebacolyate (MCL-193) are each linked by a 10-carbon chain ester. The active (-) enantiomer for both ligands is 3-hydroxy-N-cyclobutylmethyl morphinan ((-)MCL-101), a N-cyclobutylmethyl analogue of cyclorphan (J Med Chem 43:114-122, 2000). MCL-144 contains two active levo rotatory (-)(-) pharmacophores, while MCL-193 contains one active (-) and one inactive (+) pharmacophore of MCL-101. In vitro analysis demonstrated that all three compounds, (-)(-)MCL-144, (+)(-)MCL-193 and (-)MCL-101 were kappa agonists and mu partial agonists. (-)(-)MCL-144 and (-)MCL-101 had much higher affinity for both the mu and kappa opioid receptors compared to (+)(-)MCL-193. In vivo, (-)(-)MCL-144 and (+)(-)MCL-193 produced full dose-response curves, in the 55 degrees C tail-flick test, with each compound having an ED(50) value of 3.0 nmol after intracerebroventricular (i.c.v.) administration. The analgesic properties of both compounds were antagonized by the mu-selective antagonist, beta-funaltrexamine and the kappa-selective antagonist nor-binaltorphimine. Concomitant, i.c.v., administration of either (-)(-)MCL-144 or (+)(-)MCL-193 with morphine, did not significantly antagonize morphine-induced antinociception at any dose tested. In antinociceptive tests, (-)(-)MCL-144 and (+)(-)MCL-193 had the same pharmacological properties, demonstrating that having two active pharmacophores separated by a 10-carbon spacer group did not increase the antinociceptive efficacy of the compound. Additionally, it was also of interest to compare (-)(-)MCL-145 and (-)(-)MCL-144, as the only difference between these bivalent ligands is the spacer region connecting the two pharmacophores, yet (-)(-)MCL-145 produced an ED(50) value 10-fold lower than (-)(-)MCL-144 (ED(50) values = 0.3 nmol and 3.0 nmol, respectively).
Mathews
Jennifer L
JL
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, P.O. Box 711, 601 Elmwood Ave., Rochester, NY, 14642-8711, USA.
Fulton
Brian S
BS
Negus
S Stevens
SS
Neumeyer
John L
JL
Bidlack
Jean M
JM
D000473:Alkanes / Q000378:metabolism / Q000494:pharmacology*; D000700:Analgesics / Q000037:antagonists & inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005650:Fumarates / Q000378:metabolism / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006207:Half-Life; D008297:Male; D009019:Morphinans / Q000378:metabolism / Q000494:pharmacology*; D009020:Morphine / Q000037:antagonists & inhibitors; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism
C533415:1-(N-cyclobutylmethylmorphinan-3-yl)-10-(N-cyclobutylmethylmorphinan-3-yl)sebacolyate; D000473:Alkanes; D000700:Analgesics; D005650:Fumarates; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C506840:bis(N-cyclobutylmethylmorphinan)fumarate; C528102:bis(N-cyclobutylmethylmorphinan-3-yl) sebacoylate dihydrochloride; C051844:norbinaltorphimine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine