059 Daridorexant: A dual, equipotent, and insurmountable antagonist of both orexin-1 and orexin-2 receptors

Abstract Introduction The orexin neuropeptide–receptor system is a central sleep and wake regulator in the brain. two receptor subtypes, OX1R OX2R, are expressed either alone or together all major wake-promoting brain areas. OX2R activation by orexins causes elevation of intracellular calcium, which enhances synaptic transmission secondary, monoaminergic wake- arousal-promoting neurotransmitter circuits. Orexin antagonists represent novel specific treatment insomnia, different from classical therapy that more broadly inhibits activity via GABAA activation. Here we describe molecular pharmacology daridorexant, an antagonist has proven highly effective improving daytime functioning insomnia patients. Methods Orexin-A(OxA)-induced calcium release assays OX1R- OX2R-expressing recombinant cell lines were applied to measure antagonistic potency kinetic properties daridorexant functional assays. Whole-cell competitive binding assays, using orthosteric tracer employed determine Ki daridorexant. Comparisons made with suvorexant lemborexant. Results In OxA-induced 2-h pre-incubation time, displayed apparent Kb values 0.5 nM (OX1R) 0.8 (OX2R) insurmountable antagonism on both receptors, demonstrating equipotent inhibition subtypes. On-target residence times (37oC) as occupancy half-lives (ROt1/2) 4 min 8 (OX2R). behaved potent antagonist. Also dual at OX1R/OX2R (appKb=0.7nM/1.0nM; ROt1/2=9 min/6 min) Interestingly, lemborexant interaction profile (appKb=13nM/0.4nM, ROt1/2<2min/<2min), i.e. it preferential very short on-target time little insurmountability. Conclusion Daridorexant displays desired target dual, equipotent, ensures equally efficient arousal-/wake-promoting Daridorexant′s long enough cause inhibition, but avoid pharmacodynamic effects after drug elimination. Support (if any) Funded Idorsia Pharmaceuticals Ltd.