title: Effects of UMB24 and (+/-)-SM 21, putative sigma2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice.
abstract: Earlier studies have demonstrated that antagonism of sigma1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of sigma2 receptors is unclear because experimental tools to selectively target this subtype are unavailable. To begin addressing this need, we characterized UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) and (+/-)-SM 21 (3alpha-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies. Receptor binding studies confirmed that UMB24 and (+/-)-SM 21 display preferential affinity for sigma2 over sigma1 receptors. In behavioral studies, pretreatment of Swiss Webster mice with UMB24 or (+/-)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity, but not lethality. When administered alone, (+/-)-SM 21 produced no significant effects compared to control injections of saline, but UMB24 had locomotor depressant actions. Together, the data suggest that sigma2 receptor antagonists have the potential to attenuate some of the behavioral effects of cocaine, and further development of more selective, high affinity ligands are warranted.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. rmatsumo@olemiss.edu
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
authors.forename: Buddy
authors.initials: B
authors.lastname: Pouw
authors.forename: Aisha L
authors.initials: AL
authors.lastname: Mack
authors.forename: Antawan
authors.initials: A
authors.lastname: Daniels
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000633:toxicity; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D014326:Tropanes / Q000494:pharmacology*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: C519696:1-(2-phenethyl)-4-(2-pyridyl)piperazine; D002087:Butyrates; D000697:Central Nervous System Stimulants; D010879:Piperazines; D011725:Pyridines; D017480:Receptors, sigma; D014326:Tropanes; D050493:Vesicular Monoamine Transport Proteins; C107044:SM 21; D003042:Cocaine