David K. Grandy, Ph.D., Principal Investigator
The long-range goal of the proposed research is to develop novel medications that will treat and reverse the harmful health consequences of methamphetamine addiction and relapse.
Methamphetamine is a potent psychostimulant. While low doses can have some therapeutic value, high doses are extremely addictive. Methamphetamine affects levels of dopamine, norepinephrine, and serotonin in the brain as a consequence of interfering with proteins responsible for their reuptake, intracellular storage, & inactivation. Over the years considerable resources have been devoted to developing medications that act upon these targets. Unfortunately, there is still no efficacious pharmacological medication that treats methamphetamine addiction or relapse.
Recently, we reported methamphetamine is a potent and efficacious agonist in vitro of an orphan G protein-coupled receptor (GPCR) that we discovered and is now referred to as trace amine-associated receptor 1 (TAAR1). Herein we propose two preclinical, integrated, and interdisciplinary aims to test the hypothesis that TAAR1-selective drugs can ameliorate some of methamphetamine's behavioral and physiological effects.
The objective of Aim 1 is to design, synthesize, and evaluate in vitro novel TAAR1 agonists, antagonists, and partial agonists of our own design and synthesis. Four assays of increasing biological complexity will be used: (1) solution-binding to membranes containing recombinant TAAR1; (2) accumulation of cAMP in HEK-293 cells expressing recombinant TAAR1; (3) insulin release from rodent insulinoma cell lines endogenously expressing TAAR1; (4) effect on the tone of rodent brain arterioles.
The objective of Aim 2 is to generate founder mice lacking the mTAAR1 gene. Their descendents would be used in studies designed to evaluate the biological activity, specificity, and anti-methamphetamine properties of candidate TAAR1 antagonists & agonists.
We are uniquely positioned to carry out the proposed research for several reasons. We have extensive experience working with TAAR1 and have been cloning, mutating, expressing, and characterizing biogenic amine GPCRs in vitro and in vivo for almost 20 years, including the generation of transgenic mice. We discovered the TAAR1, published a comprehensive in vitro structure-activity profile of it, and in the process were the first to demonstrate isomers of methamphetamine are potent and full TAAR1 agonist in vitro.
Our efforts will directly benefit from a close collaboration with a synthetic organic chemist who recently joined our department and whose laboratory is located across the hall from the principal investigator. It is anticipated that with the successful completion of the proposed aims, novel TAAR1-selective compounds will eventually be developed that may serve as lead compounds in the development of medications that ameliorate methamphetamine’s detrimental health effects and even treat dependence and relapse.