Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class

Abstract

The demonstrated ability of amphetamine to functionally activate the rat trace amine associated receptor 1 (rTAAR1) and the subsequent reports of amphetamine activation of TAAR1 in rhesus monkey mouse, human, and human-rat chimeric TAAR1-expressing cell lines has led to speculation as to the role of this receptor in the central nervous system (CNS) responses associated with amphetamine and its analogs. The agonist potencies of ten pairs of enantiomeric amphetamines, including several with known CNS activity, at primate TAAR1 stably expressed in RD-HGA16 cells, robustly indicate the S-configuration to be associated with higher potency. Moreover, the rank order of potency to activate TAAR1 parallels the stimulant action reported by humans for the specific amphetamines. Taken together, these data suggest that TAAR1 is a stereoselective binding site for amphetamine and that activation of TAAR1 is involved in the modulation of the stimulant properties of amphetamine and its congeners. In addition, the observed parallel between hTAAR1 and rhTAAR1 responses supports the rhesus monkey as a highly translational model for developing novel TAAR1-directed compounds as therapeutics for amphetamine-related addictions.

In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1

“…The in vitro pharmacology of comparator compounds and some psychoactive substances (amphetamine, methamphetamine, MDMA) were previously determined by us and others (Borowsky et al, 2001;Bunzow et al, 2001;Reese et al, 2007;Wainscott et al, 2007;Lindemann et al, 2008;Lewin et al, 2011). The replication of those data for this study was an important validation of our assays.…”

“…One limitation of our study is that we did not consider stereoselectivity of the compounds by screening racemic mixtures for most substances. As with activity at other psychostimulant targets, such as monoaminergic reuptake transporters, TAAR1 has a stereoselective binding site, and the assessment of racemates could underestimate the activity of the more active isomer (Lewin et al, 2011).…”

Enantiomeric separations of illicit drugs and controlled substances using cyclofructan‐based (LARIHC) and cyclobond I 2000 RSP HPLC chiral stationary phases

“…At higher doses, (S)‐(+)‐amphetamine has stimulant properties that are stronger than R‐(−)‐amphetamine, and increases dopamine activity. Hence, (S)‐(+)‐amphetamine is several times more potent than the R‐(−)‐enantiomer in eliciting central nervous system effects . Also, the R‐(−)‐amphetamine produces more cardiovascular and peripheral effects than the (S)‐(+)‐amphetamine .…”

Avenues for the Development of Therapeutics That Target Trace Amine Associated Receptor 1 (TAAR1)

“…It was first observed by Bunzow et al (2001) 4 and then further expanded by Reese et al (2007) 12 and Lewin et al (2011) 37 that amphetamine and amphetamine-like drugs were pharmacological agonists at TAAR1. Wolinsky et al (2007) 17 and Lindemann et al (2008) 18 reported that deletion of the TAAR1 gene in mice results in the pharmacogenic phenotype of an enhanced locomotive response to amphetamine, coincident with an amphetamine-induced increase in the release of biogenic amines.…”