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| Drug class | Trace amine-associated receptor 1 (TAAR1)antagonist |
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| Chemical and physical data | |
| Formula | C19H11ClF3N5OS |
| Molar mass | 449.84 g·mol−1 |
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RTI-7470-44 is apotent andselectiveantagonist of the humantrace amine-associated receptor 1 (TAAR1) which is used inscientific research.[1][2][3][4] It was discovered in 2022 and is the first potent antagonist of the human TAAR1 to be identified, following the potent mouse TAAR1inverse agonistEPPTB in 2009.[3][4][5]
Theaffinity (Ki) of RTI-7470-44 for the human TAAR1 is 0.3 nM and its inhibitory potency (IC50Tooltip half-maximal inhibitory concentration) at the receptor is 8.4 nMin vitro.[2][4] It is about 90-fold less potent at the rat TAAR1 (IC50 = 748 nM) and 140-fold less potent at the mouse TAAR1 (IC50 = 1,190 nM) compared to the human TAAR1.[2][4] Surprisingly, RTI-7470-44 was found to be acompetitive antagonist of the human and mouse TAAR1 but anon-competitive antagonist of the rat TAAR1.[4]
| Species | Affinity (Ki, nM) | IC50Tooltip half-maximal inhibitory concentration (nM) | ImaxTooltip maximal inhibition (%) |
|---|---|---|---|
| Mouse | 139 | 1,190 | ND |
| Rat | ND | 748 | ND |
| Human | 0.3 | 8.4 | 101% |
The compound has favorablein vivodrug-like properties, including goodblood–brain barrierpermeability, moderatemetabolic stability, and a favorable preliminary profile ofoff-target activity (≥1–10 μM at 42 other targets).[1][3][4] It is far more potent (893-fold) as an antagonist of the human TAAR1 than the earlier TAAR1 inverse agonist EPPTBin vitro, which has dramatically lower potency (165–272-fold) at the human TAAR1 and rat TAAR1 compared to the mouse TAAR1.[4]
RTI-7470-44 has been found to increase the spontaneousfiring rate ofdopaminergicneurons in mouseventral tegmental area (VTA)slicesex vivo and to block the effects of the high-efficacy TAAR1partial agonistRO5166017 in this system.[1][3][4]
RTI-7470-44 was first described in thescientific literature in 2022.[2][4] It was identified viahigh throughput screening followed bystructure–activity optimization.[1][4]
On the other hand, HTS approaches [100] followed by structure-activity optimization allowed for the discovery of the hTAAR1 antagonist RTI-7470-44, endowed with a species-specificity preference over mTAAR1 (Figure 11A) [99]. RTI-7470-44 displayed good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. In addition, RTI-7470-44 increased the spontaneous firing rate of mouse ventral tegmental area (VTA) dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. [...] Figure 11. (A) Chemical structures of the available hTAAR1 agonists: EPPTB [98], RTI-7470-44 [99], and 4c [33], [...] RTI-7470-44: hTAAR1 IC50 = 0.0084 μM, mTAAR1 IC50 = 1.190 μM.
Studies have shown that there are considerable functional and pharmacological differences between hTA1 and TA1 in rats (rTA1) or mice (mTA1)12, with key implications for translating findings from preclinical models into human therapies. For instance, TYR has been reported to be ~30 times more potent at rTA1 than hTA1, and the antagonist EPPTB was shown to have an affinity of ~1 nM at mTA1 but does not appear to bind hTA132. Inversely, the recently reported TA1 antagonist RTI-7470-44 has an IC50 of about 8 nM at hTA1 but shows ~90-fold and ~140-fold reduced potencies at rTA1 and mTA1, respectively33.
Similar to EPPTB, RTI-7470-44 could increase the spontaneous firing rate of dopaminergic neurons in mice VTA slices and prevent the effects of TAAR1 agonist RO5166017 (Decker et [...] Furthermore, RTI-7470-44 has appropriate properties for in vivo use, including favorable preliminary off-target profile, moderate metabolic stability, and good blood-brain barrier permeability [...] However, currently there is no behavioral study that investigated the effects of RTI-7470-44. Compared to the limited literature on TAAR1 antagonists, many TAAR1 agonists have been [...]