title: 2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A.
abstract: Salvinorin (Sal) A is a naturally occurring, selective kappa 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 approximately 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-[(35)S]thio)triphosphate binding and was approximately 5- and approximately 7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three kappa 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 approximately 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.
authors: Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
authors: Yulin
authors: Y
authors: Wang
authors: Yong
authors: Y
authors: Chen
authors: Wei
authors: W
authors: Xu
authors: David Y W
authors: DY
authors: Lee
authors: Zhongze
authors: Z
authors: Ma
authors: Scott M
authors: SM
authors: Rawls
authors: Alan
authors: A
authors: Cowan
authors: Lee-Yuan
authors: LY
authors: Liu-Chen
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification; D018515:Plant Leaves; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology; D013995:Time
chemical_list: D000701:Analgesics, Opioid; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D010936:Plant Extracts; D017473:Receptors, Opioid, kappa; C508456:salvinorin B; C090499:salvinorin A