Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior
- Yu-Jun Wang,
- Yi-Min Tao,
- Fu-Ying Li,
- Yu-Hua Wang,
- Xue-Jun Xu,
- Jie Chen,
- Ying-Lin Cao,
- Zhi-Qiang Chi,
- John L. Neumeyer,
- Ao Zhang and
- Jing-Gen Liu
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China (Y.-J.W., Y.-L.C.); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (Y.-M.T., F.-Y.L., Y.-H.W., X.-J.X., J.C., Z.-Q.C., A.Z., J.-G.L.); and Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Massachusetts (J.L.N.).
- Address correspondence to:
Dr. Jing-Gen Liu, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai 201203, China. E-mail: jgliu{at}mail.shcnc.ac.cn
Abstract
ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed κ- and μ-opioid activity and identified to act as a full κ-agonist and a partial μ-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by κ- and μ-, but not δ-opioid, receptors. In addition to its agonist profile on the μ-receptor, ATPM also acted as a μ-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED50 value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed κ-agonist and μ-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. κ-Agonists with some μ-activity appear to offer some advantages over selective κ-agonists for the treatment of heroin abuse.
Footnotes
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This work was supported by the National Basic Research Program Grant from the Ministry of Science and Technology of China [Grants G2003CB515400, 2007CB935804, 30772625]; the National Science Fund for Distinguished Young Scholar from the National Natural Science Foundation of China [Grant 30425002]; the Chinese National Science Foundation [Grant 06ZR14102]; the Chinese Academy of Sciences [Grant KSCXI/YW/R/68]; and the National Institutes of Health National Institute on Drug Abuse [Grant DA-014251].
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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.108.142802.
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ABBREVIATIONS: (-)U50,488H, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide; ATPM, (-)-3-amino-thiazolo-[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride; nor-BNI, nor-binaltorphimine; β-FNA, β-funaltrexamine; FR, fixed ratio; U69,593, (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide; GTPγS, guanosine-5′-O-(3-thio)triphosphate; PD117302, (±)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzo[b]thiophene-4-acetamide; Mr2033, (±)-(1-R/S,5-R/S,2=R/S)-5,9-dimethyl-2′-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan; MCL-101, 3-hydroxy-N-cyclobutylmethylmorphinan S-(+)-mandelate; Mr2034, (-)-(1R,5R,9R,2′S)-5,9-dimethyl-2′-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan-d-tartrate; U69593, (5a,7a,8b)-(-)-N-methyl-N-(7-1-pyrrolidinyl)1-oxaspiro(4,5) dec-8-yl)benzeacetamide.
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- Received June 26, 2008.
- Accepted January 8, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
