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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 11, 2007; DOI: 10.1124/jpet.106.115402

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Received for publication October 20, 2006.
Revised January 9, 2007.
Accepted for publication January 10, 2007.

TRACE AMINE-ASSOCIATED RECEPTOR 1 DISPLAYS SPECIES-DEPENDENT STEREOSELECTIVITY FOR ISOMERS OF METHAMPHETAMINE, AMPHETAMINE, and PARA-HYDROXYAMPHETAMINE

Edmund A Reese 1, James R Bunzow 1, Seksiri Arttamangkul 1, Mark S Sonders 2, David K Grandy 1*

1 Oregon Health & Science University 2 Columbia University

* Address correspondence to: E-mail: grandyd{at}ohsu.edu

Abstract

The synthetic amines methamphetamine (METH), amphetamine (AMPH), and their metabolite para-hydroxyamphetamine (POHA) are chemically and structurally related to the catecholamine neurotransmitters and a small group of endogenous biogenic amines collectively referred to as the trace amines (TAs). Recently it was reported that METH, AMPH, POHA, and the TAs para-tyramine (TYR) and {beta}-phenylethylamine (PEA) stimulate cAMP production in human embryonic kidney (HEK-293) cells expressing rat Trace Amine-Associated Receptor 1 (rTAAR1). The discovery that METH and AMPH activate the rTAAR1 motivated us to study the effect of these drugs on the mouse TAAR1 (mTAAR1) and a human-rat chimera (h-rChTAAR1). Furthermore, since S(+) isomers of METH and AMPH are reported to be more potent and efficacious in vivo than R(-), we determined the enantiomeric selectivity of all three species of TAAR1. In response to METH, AMPH, or POHA exposure the accumulation of cAMP by HEK-293 cells stably expressing different species of TAAR1 was concentration- and isomer-dependent. EC50s for S(+)-METH were 0.89 µM, 0.92 µM, and 4.44 µM for rTAAR1, mTAAR1, and h-rChTAAR1, respectively. PEA was a potent and full agonist at each species of TAAR1 while TYR was a full agonist for the rodent TAAR1s but was a partial agonist at h-rChTAAR1. Interestingly, both isomers of METH were full agonists at mTAAR1 and h-rChTAAR1 while both were partial agonists at rTAAR1. Taken together these in vitro results suggest that, in vivo, TAAR1 could be a novel mediator of these drugs’ effects.


Key words: HEK-293, cAMP, efficacy, human, potency, rodent


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[Abstract] [Full Text] [PDF]


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