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BEHAVIORAL PHARMACOLOGY

N-Methylacetamide Analog of Salvinorin A: A Highly Potent and Selective -Opioid Receptor Agonist with Oral Efficacy

Molecular Pharmacology Laboratory (C.B., D.N.P., T.A.M., M.R.R., B.M.C.), Behavioral Genetics Laboratory (J.A.D., T.A.P., W.A.C.), Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts; Pharmacokinetics and Drug Metabolism, AMGEN Inc., Cambridge, Massachusetts (L.B., Z.Z.); Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina (B.L.R.); and National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology (W.X., L.-Y.L.-C.), Temple University School of Medicine, Philadelphia, Pennsylvania

Several preclinical studies indicate that selective -opioid receptor (KOR) antagonists have antidepressant-like effects, whereas KOR agonists have opposite effects, suggesting that each might be useful in the treatment of mood abnormalities. Salvinorin A (salvA) is a valuable KOR agonist for further study due to its high potency and receptor selectivity. However, it has short lasting effects in vivo and limited oral bioavailability, probably due to acetate metabolism. We compared the in vitro receptor binding selectivity of salvA and four analogs containing an ethyl ether (EE), isopropylamine (IPA), N-methylacetamide (NMA), or N-methylpropionamide (NMP) at C-2. All compounds showed high binding affinity for the KOR (K_i = 0.11–6.3 nM), although only salvA, EE, and NMA exhibited KOR selectivity. In a liver microsomal assay, salvA was least stable, whereas NMA and IPA displayed slower metabolic transformations. Intraperitoneal (i.p.) administration of salvA, NMA, and NMP dose-dependently elevated brain reward thresholds in the intracranial self-administration (ICSS) test, consistent with prodepressive-like KOR agonist effects. NMA and NMP were equipotent to salvA but displayed longer lasting effects (6- and 10-fold, respectively). A dose of salvA with prominent effects in the ICSS test after i.p. administration (2.0 mg/kg) was inactive after oral administration, whereas the same oral dose of NMA elevated ICSS thresholds. These studies suggest that, although salvA and NMA are similar in potency and selectivity as KOR agonists in vitro, NMA has improved stability and longer lasting actions that might make it more useful for studies of KOR agonist effects in animals and humans.

Address correspondence to: Dr. Cécile Béguin, Department of Psychiatry, McLean Hospital, MRC 322A, 115 Mill Street, Belmont, MA 02478. E-mail: cbeguin{at}mclean.harvard.edu

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				Y. Wang, Y. Chen, W. Xu, D. Y.W. Lee, Z. Ma, S. M. Rawls, A. Cowan, and L.-Y. Liu-Chen 2-Methoxymethyl-Salvinorin B Is a Potent {kappa} Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1073 - 1083. [Abstract] [Full Text] [PDF]