title: A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice.
abstract: Cocaine functions, in part, through agonist actions at sigma-1 (σ1 ) receptors, while roles played by sigma-2 (σ2 ) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 µmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 µmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 µmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri, 65201; Department of Radiology and Radiopharmaceutical Sciences Institute, University of Missouri, Columbia, Missouri, 65211; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, 65211.
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Miller
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Green
authors.forename: Emily A
authors.initials: EA
authors.lastname: Fergason-Cantrell
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Watkinson
authors.forename: Terry L
authors.initials: TL
authors.lastname: Carmack
authors.forename: Kuo-Hsien
authors.initials: KH
authors.lastname: Fan
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Lever
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008024:Ligands; D008124:Locomotion / Q000187:drug effects*; D051379:Mice; D011485:Protein Binding; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D000097605:Sigma-1 Receptor
chemical_list: D001549:Benzamides; D003042:Cocaine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007546:Isoquinolines; D008024:Ligands; D017480:Receptors, sigma; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D000097605:Sigma-1 Receptor; C559072:5-bromo-N-(4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl)-2,3-dimethoxybenzamide; C106107:sigma-2 receptor
keywords: behavior; motor activity; psychostimulant; substance abuse