A selective sigma‐2 receptor ligand antagonizes cocaine‐induced hyperlocomotion in mice

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. Synapse 68:73–84, 2014 . © 2013 Wiley Periodicals, Inc.