RO5203648

Pharmacodynamics Actions RO5203648 binds to the mouse, rat, cynomolgus monkey, and human TAAR1 all with high affinity (Ki = 0.5–6.8nM). However, a subsequent study failed to replicate these findings under similar conditions. In addition, as previously described, RO5203648 did not affect methamphetamine-induced dopamine release and reuptake inhibition in synaptosomes in vitro. Concordant in-vivo findings have been made with amphetamines combined with TAAR1 agonists and antagonists as well as with TAAR1 overexpression. Conversely, most cathinones lack TAAR1 agonism, and this might enhance their effects compared to amphetamines. RO5203648 does not significantly affect basal locomotion. With chronic administration of RO5203648 and methamphetamine, RO5203648 dose-dependently and progressively decreased methamphetamine-induced hyperlocomotion. RO5203648 has also been found to suppress hyperlocomotion induced by the NMDA receptor antagonist L-687,414 or in genetically modified mice with a hypoactive NMDA receptor. RO5203648, as well as the TAAR1 full agonist RO5256390, have been found to suppress cocaine and methamphetamine self-administration, and hence presumably their rewarding and reinforcing effects. Pharmacokinetics RO5203648 showed favorable pharmacokinetics orally and intravenously in mice, rats, and monkeys. However, it was found to be very rapidly metabolized in human hepatocytes in vitro. ==Chemistry==

In terms of chemical structure, RO5203648 is a 2-aminooxazoline derivative. ==History==

RO5203648 was first described by 2012. It was the first selective TAAR1 partial agonist to be developed. The drug followed the first TAAR1 antagonist EPPTB and the first TAAR1 full agonist RO5166017. It was under investigation for potential clinical use in humans, but showed indication of very rapid human metabolism in vitro. As a result, it was deselected from development, and other compounds, such as the TAAR1 partial agonist RO5263397, were pursued instead. ==See also==