title: Synthesis and pharmacological characterization of a novel sigma receptor ligand with improved metabolic stability and antagonistic effects against methamphetamine.
abstract: Methamphetamine interacts with sigma receptors at physiologically relevant concentrations suggesting a potential site for pharmacologic intervention. In the present study, a previous sigma receptor ligand, CM156, was optimized for metabolic stability, and the lead analog was evaluated against the behavioral effects of methamphetamine. Radioligand binding studies demonstrated that the lead analog, AZ66, displayed high nanomolar affinity for both sigma-1 and sigma-2 receptors (2.4 ± 0.63 and 0.51 ± 0.15, respectively). In addition, AZ66 had preferential affinity for sigma receptors compared to seven other sites and a significantly longer half-life than its predecessor, CM156, in vitro and in vivo. Pretreatment of male, Swiss Webster mice with intraperitoneal (10-20 mg/kg) or oral (20-30 mg/kg) dosing of AZ66 significantly attenuated the acute locomotor stimulatory effects of methamphetamine. Additionally, AZ66 (10-20 mg/kg, i.p.) significantly reduced the expression and development of behavioral sensitization induced by repeated methamphetamine administration. Taken together, these data indicate that sigma receptors can be targeted to mitigate the acute and subchronic behavioral effects of methamphetamine and AZ66 represents a viable lead compound in the development of novel therapeutics against methamphetamine-induced behaviors.
authors.affiliation: Department Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, 26506, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seminerio
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robson
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Abdelazeem
authors.forename: Christophe
authors.initials: C
authors.lastname: Mesangeau
authors.forename: Seshulatha
authors.initials: S
authors.lastname: Jamalapuram
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Avery
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D052160:Benzothiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001665:Binding Sites; D000697:Central Nervous System Stimulants / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism*; D013457:Sulfur Compounds / Q000494:pharmacology*; D000097605:Sigma-1 Receptor
chemical_list: D052160:Benzothiazoles; D000697:Central Nervous System Stimulants; D008024:Ligands; D008694:Methamphetamine; D010879:Piperazines; D017480:Receptors, sigma; D013457:Sulfur Compounds; D000097605:Sigma-1 Receptor; C549191:3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo(d)thiazole-2(3H)-thione; C572761:3-(4-(4-cyclohexylpiperazin-1-yl)pentyl)-6-fluorobenzo(d)thiazol-2(3H)-one; C106107:sigma-2 receptor