RTI-7470-44
RTI-7470-44 is a potent and selective antagonist of the human trace amine-associated receptor 1 which is used in scientific research. It was discovered in 2022 and is the first potent antagonist of the human TAAR1 to be identified, following the potent mouse TAAR1 inverse agonist EPPTB in 2009.
Pharmacology
The affinity of RTI-7470-44 for the human TAAR1 is 0.3nM and its inhibitory potency at the receptor is 8.4nM in vitro. It is about 90-fold less potent at the rat TAAR1 and 140-fold less potent at the mouse TAAR1 compared to the human TAAR1. Surprisingly, RTI-7470-44 was found to be a competitive antagonist of the human and mouse TAAR1 but a non-competitive antagonist of the rat TAAR1.| Species | Affinity | ||
| Mouse | 139 | 1,190 | |
| Rat | 748 | ||
| Human | 0.3 | 8.4 | 101% |
The compound has favorable in vivo drug-like properties, including good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary profile of off-target activity. It is far more potent as an antagonist of the human TAAR1 than the earlier TAAR1 inverse agonist EPPTB in vitro, which has dramatically lower potency at the human TAAR1 and rat TAAR1 compared to the mouse TAAR1.
RTI-7470-44 has been found to increase the spontaneous firing rate of dopaminergic neurons in mouse ventral tegmental area slices ex vivo and to block the effects of the high-efficacy TAAR1 partial agonist RO5166017 in this system.