title: A novel substituted piperazine, CM156, attenuates the stimulant and toxic effects of cocaine in mice.
abstract: Cocaine is a highly abused drug without effective pharmacotherapies to treat it. It interacts with sigma (sigma) receptors, providing logical targets for the development of medications to counteract its actions. Cocaine causes toxic and stimulant effects that can be categorized as acute effects such as convulsions and locomotor hyperactivity and subchronic effects including sensitization and place conditioning. In the present study, 3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3H)-thione (CM156), a novel compound, was developed and tested for interactions with sigma receptors using radioligand binding studies. It was also evaluated against cocaine-induced effects in behavioral studies. The results showed that CM156 has nanomolar affinities for each of the sigma receptor subtypes in the brain and much weaker affinities for non-sigma binding sites. Pretreatment of male Swiss-Webster mice with CM156, before administering either a convulsive or locomotor stimulant dose of cocaine, led to a significant attenuation of these acute effects. CM156 also significantly reduced the expression of behavioral sensitization and place conditioning evoked by subchronic exposure to cocaine. The protective effects of CM156 are consistent with sigma receptor-mediated actions. Together with previously reported findings, the data from CM156 and related sigma compounds indicate that sigma receptors can be targeted to alleviate deleterious actions of cocaine.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Yan-Tong
authors.initials: YT
authors.lastname: Xu
authors.forename: Nidhi
authors.initials: N
authors.lastname: Kaushal
authors.forename: Jamaluddin
authors.initials: J
authors.lastname: Shaikh
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wilson
authors.forename: Christophe
authors.initials: C
authors.lastname: Mésangeau
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013457:Sulfur Compounds / Q000494:pharmacology*
chemical_list: C549191:3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo(d)thiazole-2(3H)-thione; D010879:Piperazines; D017480:Receptors, sigma; D013457:Sulfur Compounds; D003042:Cocaine