In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties
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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 κ agonists and μ partial agonists. (−)(−)MCL-144 and (−)MCL-101 had much higher affinity for both the μ and κ opioid receptors compared to (+)(−)MCL-193. In vivo, (−)(−)MCL-144 and (+)(−)MCL-193 produced full dose–response curves, in the 55°C tail-flick test, with each compound having an ED50 value of 3.0 nmol after intracerebroventricular (i.c.v.) administration. The analgesic properties of both compounds were antagonized by the μ-selective antagonist, β-funaltrexamine and the κ-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 ED50 value 10-fold lower than (−)(−)MCL-144 (ED50 values = 0.3 nmol and 3.0 nmol, respectively).
KeywordsOpioid dimers Mu opioid Partial agonist Enantiomers
We thank Mr. Matthew Gardner and Dr. Frank Tarazi of McLean Hospital for assistance in preparation of the rat brain homogenate. Financial Support: This work was supported by grants K05-DA00360 (JMB), R01-DA14251 (JLN), T32 DA07232 (JLM), and T32 DA007252 (BSF) from the National Institute on Drug Abuse.
- 6.Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA (2000) Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci 20(22):RC110Google Scholar
- 11.Neumeyer JL, Bidlack JM, Zong R, Bakthavachalam V, Gao P, Cohen DJ, Negus SS, Mello NK (2000) Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives. Mixed κ agonists and μ agonists/antagonists as potential pharmacotherapeutics for cocaine dependence. J Med Chem 43:114–122PubMedCrossRefGoogle Scholar
- 14.Jannsen PA, Niemegeers CJ, Dorg JG (1963) The inhibitory effect of fentanyl and other morphine-like analgesics on the warm water induced tail withdrawal reflex in rats. Arzneim-Forsch 13:502–507Google Scholar
- 19.Rajeswaran WG, Cao Y, Huang X-P, Wroblewski ME, Colclough T, Lee S, Liu F, Nagy PI, Ellis J, Levine BA, Nocka KH, Messer WS Jr (2001) Design, synthesis, and biological characterization of bivalent 1-methyl–1, 2, 5, 6-tetrahydropyridyl-1, 2, 5-thiadiazole derivatives as selective muscarinic agonists. J Med Chem 44:4563–4576PubMedCrossRefGoogle Scholar
- 23.Martin WR (1967) Opioid antagonists. Pharmacol Rev 19:464–521Google Scholar
- 25.Portoghese PS, Larson DL, Yim CB, Sayre LM, Ronsisvalle G, Lipkowski AW, Takemori AE, Rice KC, Tam SW (1985) Stereo-structure activity relationship of opioid agonist and antagonist bivalent ligands. Evidence for bridging between vicinal opioid receptors. J Med Chem 28:1140–1141PubMedCrossRefGoogle Scholar