Salvinorin A, TRK-820 and 3FLB) on Opioid Receptors in Vitro and Their Antipruritic and Antinociceptive Activities in Vivo
0022-3565/05/3121-220–230$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 312, No. 1 Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics 73668/1186283 JPET 312:220–230, 2005 Printed in U.S.A. Comparison of Pharmacological Activities of Three Distinct Ligands (Salvinorin A, TRK-820 and 3FLB) on Opioid Receptors in Vitro and Their Antipruritic and Antinociceptive Activities in Vivo Yulin Wang, Kang Tang, Saadet Inan, Daniel Siebert, Ulrike Holzgrabe, David Y.W. Lee, Peng Huang, Jian-Guo Li, Alan Cowan, and Lee-Yuan Liu-Chen Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania (Y.W., K.T., S.I., P.H., J.-G.L., A.C., L.-Y.L.-C.); The Salvia divinorum Research and Information Center, Malibu, California (D.S.); Institut fur Pharmazie und Lebensmittelchemie, Universitat Wurzburg, Germany (U.H.); and McLean Hospital, Harvard Medical School, Belmont, Massachusetts (D.Y.W.L.) Received July 3, 2004; accepted September 21, 2004 ABSTRACT Salvinorin A, TRK-820 (17-cyclopropylmethyl-3,14-dihydroxy-4,5␣- agonist on MOR and DOR, whereas salvinorin A and 3FLB epoxy-6-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydro- showed no activities on these receptors. Salvinorin A, TRK-820, chloride), and 3FLB (diethyl 2,4-di-[3-fluorophenyl]-3,7-dimethyl-3,7- and 3FLB caused internalization of the human KOR in a dose- diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate) are structurally dependent manner. Interestingly, although salvinorin A and distinctly different from U50,488H [(trans)-3,4-dichloro-N-methyl-N- U50,488H had similar potencies in stimulating [35S]GTP␥S bind- [2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate], ing, salvinorin A was about 40-fold less potent than U50,488H in the prototypic selective agonist.
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