Exploring the determinants of trace amine-associated receptor 1's functional selectivity for the stereoisomers of amphetamine and methamphetamine

Edmund A. Reese, Yohei Norimatsu, Madeline S. Grandy, Katherine L. Suchland, James R. Bunzow, David K. Grandy

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Amphetamines are widely abused drugs that interfere with dopamine transport and storage. Recently, however, another mechanism of action was identified: stereoselective activation of the GαS protein-coupled trace amine-associated receptor 1 (TAAR1). To identify structural determinants of this stereoselectivity, we functionally evaluated six mutant receptors in vitro and then used homology modeling and dynamic simulation to predict drug affinities. Converting Asp102 to Ala rendered mouse and rat TAAR1 (mTAAR1 and rTAAR1, respectively) insensitive to β-phenylethylamine, amphetamine (AMPH), and methamphetamine (METH). Mutating Met268 in rTAAR1 to Thr shifted the concentration-response profiles for AMPH and METH isomers rightward an order of magnitude, whereas replacing Thr268 with Met in mTAAR1 resulted in profiles leftward shifted 10-30-fold. Replacing Asn287 with Tyr in rTAAR1 produced a mouselike receptor, while the reciprocal mTAAR1 mutant was rTAAR1-like. These results confirm TAAR1 is an AMPH/METH receptor in vitro and establish residues 102 (3.32) and 268 (6.55) as major contributors to AMPH/METH binding with residue 287 (7.39) determining species stereoselectivity.

Original languageEnglish (US)
Pages (from-to)378-390
Number of pages13
JournalJournal of Medicinal Chemistry
Volume57
Issue number2
DOIs
StatePublished - Jan 23 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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