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NEUROPHARMACOLOGY

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

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.)

Salvinorin A, TRK-820 (17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-[N-methyl-trans-3-(3-furyl) acrylamido]morphinan hydrochloride), and 3FLB (diethyl 2,4-di-[3-fluorophenyl]-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane-9-one-1,5-dicarboxylate) are structurally distinctly different from U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate], the prototypic selective agonist. Here, we investigated their in vitro pharmacological activities on receptors expressed in Chinese hamster ovary cells and in vivo antiscratch and antinociceptive activities in mice. All three compounds showed high selectivity for the opioid receptor (KOR) over the µ opioid receptor (MOR) and opioid receptor (DOR) and nociceptin or orphanin FQ receptors. In the guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding assay, all three were full agonists on the KOR. The rank order of affinity and potency for the KOR was TRK-820 >> U50,488H salvinorin A >> 3FLB. TRK-820 acted as a partial agonist on MOR and DOR, whereas salvinorin A and 3FLB showed no activities on these receptors. Salvinorin A, TRK-820, and 3FLB caused internalization of the human KOR in a dose-dependent manner. Interestingly, although salvinorin A and U50,488H had similar potencies in stimulating [³⁵S]GTPS binding, salvinorin A was about 40-fold less potent than U50,488H in promoting internalization. Following 4-h incubation, all three compounds induced down-regulation of the human KOR, with salvinorin A causing a lower extent of down-regulation. Although TRK-820 was potent and efficacious against compound 48/80-induced scratching, salvinorin A showed low and inconsistent effects, and 3FLB was inactive. In addition, salvinorin A and 3FLB were not active in the acetic acid abdominal constriction test. The discrepancy between in vitro and in vivo results may be due to in vivo metabolism of salvinorin A and 3FLB and possibly to their effects on other pharmacological targets.

Address correspondence to: Dr. Lee-Yuan Liu-Chen, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. E-mail: lliuche{at}astro.temple.edu

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