Tradipitant

Tradipitant (LY686017) is a non-peptidyl tachykinin receptor 1 (TACR1/NK1R) antagonist optimized for superior metabolic stability and high oral bioavailability. Mechanistically, it functions via competitive antagonism of the preferred endogenous ligand, Substance P (SP), binding within the receptor’s transmembrane core to sterically hinder the recruitment of G-proteins and β-arrestins. This molecular blockade abolishes Gq/11-coupled signaling, thereby preventing phospholipase C activation, IP3/DAG release, intracellular calcium mobilization, and downstream MAPK/ERK phosphorylation cascades. Characterized by reversible binding with slow dissociation kinetics in striatal tissue that ensures sustained receptor occupancy, tradipitant demonstrates a Kd of 0.34 nM and a Bmax of 31.4 fmol/mg in guinea pig striatum. While highly selective for NK1R over NK2 and NK3 subtypes, it exhibits critical species-selectivity, possessing high affinity for human, guinea pig, and gerbil isoforms but insufficient affinity for mouse or rat NK1R. Translationally, this potent antagonism regulates gastric motility and improves the symptoms of motion sickness by inhibiting emetic signaling, while effectively suppressing spontaneous alcohol cravings and blunting stress-induced cortisol responses in clinical settings.