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 Grandy

    Research output: Contribution to journalArticle

    26 Citations (Scopus)

    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

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    Stereoisomerism
    Methamphetamine
    Amphetamine
    Phenethylamines
    Amphetamines
    Pharmaceutical Preparations
    Dopamine
    Trace amine-associated receptor 1
    Proteins
    In Vitro Techniques

    ASJC Scopus subject areas

    • Molecular Medicine
    • Drug Discovery

    Cite this

    Exploring the determinants of trace amine-associated receptor 1's functional selectivity for the stereoisomers of amphetamine and methamphetamine. / Reese, Edmund A.; Norimatsu, Yohei; Grandy, Madeline S.; Suchland, Katherine L.; Bunzow, James R.; Grandy, David.

    In: Journal of Medicinal Chemistry, Vol. 57, No. 2, 23.01.2014, p. 378-390.

    Research output: Contribution to journalArticle

    Reese, Edmund A. ; Norimatsu, Yohei ; Grandy, Madeline S. ; Suchland, Katherine L. ; Bunzow, James R. ; Grandy, David. / Exploring the determinants of trace amine-associated receptor 1's functional selectivity for the stereoisomers of amphetamine and methamphetamine. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 2. pp. 378-390.
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