Semester

Summer

Date of Graduation

2012

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Rae R. Matsumoto.

Abstract

Methamphetamine is an addictive psychostimulant drug with an increasing prevalence of abuse worldwide. Recent evidence has linked methamphetamine exposure to a wide array of neurological complications some of which lead to neurodegenerative changes in the brain and hyperthermia. Currently, there are no FDA approved pharmacologic agents to treat the effects of methamphetamine. Recent evidence has suggested methamphetamine may, in part, produce some of its effects through sigma receptors making them a potential target for pharmacological intervention. While our lab has shown a number of selective sigma receptor ligands can provide neuroprotection against the neurotoxic and behavioral effects of methamphetamine, limitations such as metabolic instability have prevented the advancement of any lead compound to ladder drug development studies. To address this issue and pursue a lead therapeutic compound to aid against methamphetamine-induced complications, CM156, a previously studied selective sigma receptor ligand, was optimized for metabolic stability. Following the synthesis and evaluation of thirty CM156 analogs, a lead compound was identified. Radioligand binding studies demonstrated 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 sixty-four other sites and a significantly longer half life than its predecessor, CM156, in vitro and in vivo. To further characterize AZ66 as a potential lead compound, we evaluated AZ66 against the neurotoxic, behavioral, and cognitive effects produced by methamphetamine. Pretreatment of male, Swiss Webster mice with intraperitoneal (10-20 mg/kg) or oral (20-30 mg/kg) dosing of AZ66significantly attenuated the acute locomotor stimulatory effects of methamphetamine in addition to reducing the expression and development of behavioral sensitization induced by repeated methamphetamine administration. Furthermore, AZ66 significantly attenuated methamphetamine-induced striatal dopamine depletions, striatal dopamine transporter reductions, and hyperthermia. Additionally, neurotoxic dosing with methamphetamine caused significant memory impairment in the object recognition test which was attenuated when animals were pretreated with AZ66; similar trends were observed in the step-through passive avoidance test. The studies presented herein demonstrate that targeting sigma receptors can provide neuroprotective effects against methamphetamine and AZ66 may represent a promising lead compound for developing future therapeutics.

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