RO5166017

RO5166017 is an agonist of trace amine-associated receptor 1 (TAAR1).¹ It binds to TAAR1 (K_is = 31, 24, 1.9, and 2.7 nM in HEK293 cells expressing the recombinant human, cynomolgus monkey, mouse, or rat receptor, respectively) and is greater than 15-fold selective for TAAR1 over a panel of 123 receptors, ion channels, and transporters at 10 µM. RO5166017 induces cAMP production in HEK293 cells expressing the recombinant human, cynomolgus monkey, mouse, or rat TAAR1 (EC₅₀s = 55, 97, 3.3, and 14 nM, respectively). It reduces the frequency of neuronal firing in mouse ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) slices (IC₅₀s = 1.73 and 2.99 nM, respectively), which endogenously express high levels of dopaminergic and serotonergic neurons, respectively. RO5166017 (0.3 mg/kg) inhibits stress-induced hyperthermia, indicating anxiolytic-like activity, as well as reduces cocaine-induced hyperlocomotion, in mice. It also impairs expression, but not reconsolidation, of cocaine-induced place preference in rats.²

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1. Revel, F.G., Moreau, J.-L., Gainetdinov, R.R., et al. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc. Natl. Acad. Sci. USA 108(20), 8485-8490 (2011).

2. Liu, J.-F., Thorn, D.A., Zhang, Y., et al. Effects of trace amine-associated receptor 1 agonists on the expression, reconsolidation, and extinction of cocaine reward memory. Int. J. Neuropsychopharmacol. 19(7), pyw009 (2016).