A new family of mammalian G protein-coupled receptors, detectable in several brain regions, has been identified. A member of this class, the human TA1 receptor, has been found to bind endogenous brain amines, present in small amounts (trace amines), for which no specific mode of action is currently known. The binding activates adenylyl cyclase to promote the production of cAMP, suggesting that the trace amines may act as neurotransmitters. In addition to binding endogenous trace amines, it has been found that the rat ortholog of TA1 binds agents associated with drug abuse. Specifically, compounds like ecstasy, and blue ice (amphetamines) and LSD (ergolines) were found to potently stimulate rat TA1 promoted cAMP accumulation. If the same holds true for the human TA1 receptor it may suggest that these receptors have a role in both the hallucinogenic activity of these compounds and in the addiction process. The goal of this proposal is to provide the tools necessary for development of medications to countermand the effects of these drugs. This requires an understanding of the effect of structural variation(s) on human TA receptor activation and on selectivity. Therefore, a group of drugs of abuse with known behavioral effects will be systematically evaluated for their potency and efficacy at human TA1 receptors and the results will be analyzed with appropriate computational chemistry tools. The results will guide a synthesis program designed to determine the molecular characteristics associated with potency and efficacy at the human TA1 receptor. Evaluation of active compounds in other neuromodulatory systems will assist in the determination of selectivity, an important consideration in medication development. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016327-04
Application #
7436214
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Singh, Hari
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$434,940
Indirect Cost
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
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Lewin, Anita H; Navarro, Hernan A; Mascarella, S Wayne (2008) Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1. Bioorg Med Chem 16:7415-23