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NEUROPHARMACOLOGY

[N-Allyl-Dmt¹]-Endomorphins Are µ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (E.D.M., S.D.B., L.H.L.); College of Pharmacy, Division of Medicinal and Natural Products Chemistry, S328, University of Iowa, Ames, Iowa (Y.J.); Department of Chemistry, Jilin University, Changchun, Jilin, People's Republic of China (T.L.); and Department of Medicinal Chemistry and High Technology Research Center, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe, Japan (Y.T., Y.O.)

[N-Allyl-Dmt¹]-endomorphin-1 and -2 ([N-allyl-Dmt¹]-EM-1 and -2) are new selective µ-opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2',6'-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5'-O-(3-[³⁵S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-Allyl-Dmt¹]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine- and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone- and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.

Address correspondence to: Dr. Ewa D. Marczak, Medicinal Chemistry Group, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, P.O. Box 12233, MD C304, Research Triangle Park, NC 27709. E-mail address: marczake{at}niehs.nih.gov

This article has been cited by other articles:

				Q. Li, Y. Okada, E. Marczak, W. A. Wilson, L. H. Lazarus, and H. S. Swartzwelder The Novel {micro}-Opioid Receptor Antagonist, [N-Allyl-Dmt1]Endomorphin-2, Attenuates the Enhancement of GABAergic Neurotransmission by Ethanol Alcohol Alcohol., January 1, 2009; 44(1): 13 - 19. [Abstract] [Full Text] [PDF]