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NEUROPHARMACOLOGY

2-Methoxymethyl-Salvinorin B Is a Potent Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A

Department of Pharmacology and Center for Substance Abuse Research (Y.W., Y.C., W.X., A.C., L.-Y.L.-C.) and Department of Pharmaceutical Sciences (S.M.R.), Temple University School of Medicine, Philadelphia, Pennsylvania; Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts (D.Y.W.L., Z.M.)

Salvinorin (Sal) A is a naturally occurring, selective opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxymethyl (MOM)-Sal B, were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed 3-fold higher affinity than U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate] and Sal A. It acted as a full agonist at KOPR in guanosine 5'-O-(3-[³⁵S]thio)triphosphate binding and was 5- and 7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05–1 mg/kg s.c.) caused immediate and dose-dependent immobility lasting 3 h, which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1–5 mg/kg s.c.). In addition, MOM-Sal B (0.5–5 mg/kg i.p.) produced antinociception (hot-plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot-plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer lasting in vivo effects than Sal A.

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}temple.edu