Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine.
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 (hrChTAAR1). Furthermore, because 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. EC50 values for S-(+)-METH were 0.89, 0.92, and 4.44 microM for rTAAR1, mTAAR1, and h-rChTAAR1, respectively. PEA was a potent and full agonist at each species of TAAR1, whereas 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, whereas both were partial agonists at rTAAR1. Taken together, these in vitro results suggest that, in vivo, TAAR1 could be a novel mediator of the effects of these drugs.
Reese
E A
EA
Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
Bunzow
J R
JR
Arttamangkul
S
S
Sonders
M S
MS
Grandy
D K
DK
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002678:Chimera; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D009924:Organ Culture Techniques; D010957:Plasmids; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000187:drug effects*; D013045:Species Specificity; D013237:Stereoisomerism; D010136:p-Hydroxyamphetamine / Q000494:pharmacology*; D000095383:Trace Amine-Associated Receptors
D000661:Amphetamine; D000697:Central Nervous System Stimulants; D000242:Cyclic AMP; D008694:Methamphetamine; D043562:Receptors, G-Protein-Coupled; D010136:p-Hydroxyamphetamine; D000095383:Trace Amine-Associated Receptors