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In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties

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Abstract

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).

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Acknowledgements

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.

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Author notes

  1. Jennifer L. Mathews

    Present address: Department of Pharmaceutical Sciences, Wegmans School of Pharmacy at St. John Fisher College, Rochester, NY, 14618, USA

  2. S. Stevens Negus

    Present address: Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980613, 410 North 12th Street, Richmond, VA, 23298-0613, USA

Authors and Affiliations

  1. 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

    Jennifer L. Mathews & Jean M. Bidlack

  2. Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 15 Mill St., Belmont, MA, 02178, USA

    Brian S. Fulton, S. Stevens Negus & John L. Neumeyer

Authors
  1. Jennifer L. Mathews
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  2. Brian S. Fulton
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  3. S. Stevens Negus
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  4. John L. Neumeyer
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  5. Jean M. Bidlack
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Correspondence to Jean M. Bidlack.

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Special issue article in honor of Dr. Ji-Sheng Han.

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Mathews, J.L., Fulton, B.S., Negus, S.S. et al. In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties. Neurochem Res 33, 2142–2150 (2008). https://doi.org/10.1007/s11064-008-9752-3

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  • DOI: https://doi.org/10.1007/s11064-008-9752-3

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