Abstract
Previous research has shown that compounds with mixed κ and μ 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 κ opioid receptor agonist and a μ 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 Ki values of 0.078 and 0.20 nM for the κ and μ 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 Emax value of 80% for the κ opioid receptor and 42% for the μ opioid receptor. The EC50 values obtained for this compound were 4.3 and 3.1 nM for the κ and μ opioid receptors, respectively. In vivo MCL-145 produced a full dose-response curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the μ-selective antagonist β-funaltrexamine and the κ-selective antagonist nor-binaltorphimine. MCL-145 also acted as a μ antagonist, as measured by the inhibition of morphine-induced antinociception.
Footnotes
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This work was supported by Grants K05-DA00360 and T32 DA07232 (to J.M.B.) and DA014251 (to J.L.N.) from the National Institute on Drug Abuse. Part of this work was presented as a meeting abstract: Mathews JL, Xiong W, Gu X-H, Neumeyer JL, and Bidlack JM (2003) In vivo characterization of MCL-145: a morphinan derivative possessing mixed kappa agonist and mu agonist/antagonist properties, in Abstracts of 34th International Narcotics Research Conference (no. 153), Perpignan, France, July 6–11, 2003; available at http://www.inrcworld.org.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.084343.
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ABBREVIATIONS: U50,488, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate; MCL-101, 3-hydroxy-N-cyclobutylmethyl morphinan S-(+)-mandelate; Mr2034, (-)-(1R,5R,9R,2′S)-5,9-dimethyl-2′-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan-D-tartrate; MCL-145, bis(N-cyclobutylmethylmorphinan) fumarate; GTPγS, guanosine-5′-O-(3-thio)triphosphate; CHO, Chinese hamster ovary; hKOR, human κ opioid receptor; hMOR, human μ opioid receptor; ICI 174,864, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (where Aib is α-aminoisobutyric acid); β-FNA, β-funaltrexamine; nor-BNI, nor-binaltorphimine; CL, confidence limits; U69,593, (5α,7α,8β)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide.
- Received March 1, 2005.
- Accepted July 28, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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Characterization of a Novel Bivalent Morphinan Possessing κ Agonist and μ Agonist/Antagonist Properties
