Metabolic Stability And Pharmacokinetics In Lead Optimization Of Potential Anti-Psychostimulant Pharmacotherapies

Drug addiction is a chronic disorder characterized by obsessive and uncontrollable drug-seeking behaviors. It is a major public health problem globally as well as in the United States. Apart from causing severe medical complications it also leads to several socioeconomic problems like healthcare expenditures, lost earnings and increase in drug-related crime. The discovery and development of potential pharmacotherapies to treat cocaine dependence has been a high priority for more than two decades but still there is US-FDA approved medication. This illustrates the need for the development of effective medication to treat cocaine and methamphetamine abuse. Sigma receptors have recently been identified as potential targets for the development of novel therapeutics. The affinity of cocaine and methamphetamine to sigma receptors represents that targeting these receptors using selective antagonists will be an effective strategy in the development of novel medications. This dissertation is primarily focused on the role of metabolism and pharmacokinetics in the lead optimization of novel sigma receptor antagonists to treat abuse of cocaine and methamphetamine. Taking this in to consideration, we first determined in vivo and in vitro properties of CM156, [3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo[d]thiazole-2(3h)-thione] a highly selective sigma receptor antagonist using a validated UPLC/MS method. However due to its poor in vivo and in vitro performance further research was halted. Several analogs were then synthesized by blocking the metabolic soft spots of CM156. We performed a preliminary screening of a series of the high affinity sigma receptor antagonists using in vitro metabolism studies and selected AZ66, 3-(4-(4-cyclohexylpiperazine-1-yl)pentyl)-6-fluorobenzo[ d]thiazole 2(3h)-one, as a lead compound. AZ66 is an optimized sigma receptor ligand with high metabolic stability that has been shown to mitigate behavioral effects of methamphetamine, suggesting that it can become a potential candidate to treat methamphetamine abuse. We determined its physicochemical properties such as solubility, pKa, Log PO/W and Log DPBS, (pH 7.4). We have also assessed its in vitro metabolic stability and in vivo pharmacokinetic parameters and absolute bioavailability in rats using a validated UPLC-MS/MS method. We conducted repeated dose pharmacokinetic studies and estimated the plasma steady state concentrations. More importantly we estimated its extent of central nervous system penetration using brain to plasma ratio studies in rats. The results of these in vitro and in vivo studies will lead to development of successful pharmacotherapies for cocaine and methamphetamine abuse.

Name thesis:degree_name

Ph.D. in Pharmaceutical Sciences

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmaceutics and Drug Delivery

Year dc:date.available

2013

Author dc:creator

• Jamalapuram, Seshulatha

Contributors dc:contributor

• Bonnie A. Avery
• Seongbong Jo
• Christopher R. McCurdy

• Pharmacy and Pharmaceutical Sciences

Repository record dc:identifier

https://egrove.olemiss.edu/etd/730

OAI identifier oai:identifier

oai:egrove.olemiss.edu:etd-1729