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LIT-001
LIT-001 is a small-molecule oxytocin receptor agonist and vasopressin receptor mixed agonist and antagonist that was first described in the literature in 2018.[1][2][3] Along with TC OT 39 and WAY-267464, it is one of the first small-molecule oxytocin receptor agonists to have been developed.[1][2] LIT-001 has greatly improved pharmacokinetic properties relative to oxytocin, reduces social deficits in animal models, and may have potential as a therapeutic agent in the treatment of social disorders like autism in humans.[1][2] PharmacologyLIT-001 has greater selectivity for the oxytocin receptor over the vasopressin V1A receptor than the related compounds TC OT 39 and WAY-267464.[1][2] It shows antagonism of the V1A receptor only at high concentrations.[1][2] LIT-001 additionally acts as an agonist of the vasopressin V2 receptor, with this action occurring at similar concentrations as for the oxytocin receptor.[2][1] This is unlikely to influence the oxytocin receptor-related behavioral effects of LIT-001, as V2 receptors are not expressed in the brain.[1][2] However, it may influence fluid homeostasis, analogously to vasopressin.[1][2] Given via peripheral administration, LIT-001 reduces social deficits in a mouse model of autism, specifically the μ-opioid receptor knockout mouse model.[1][2][3] It was the first small-molecule oxytocin receptor agonist to be shown to reduce social dysfunction in animals.[1][2] LIT-001 shows blood–brain barrier permeability and has a relatively long elimination half-life in rodents, giving it an advantageous drug profile relative to peptide oxytocin receptor agonists like oxytocin.[1][3][4] In the case of oxytocin, the amount estimated to enter the cerebrospinal fluid is only 0.002% with subcutaneous injection and at most 0.005% with intranasal administration, its half-life is only about 20 to 60 minutes, and it is not orally bioavailable, all of which greatly limit its potential usefulness as a central nervous system-acting medication.[1][2] These limitations of oxytocin may underlie limited effectiveness with oxytocin nasal spray in clinical trials.[1][2] Based on its positive social effects in animal models and its favorable pharmacokinetic properties, LIT-001 may have potential as a therapeutic agent in the treatment of social disorders in humans.[1][2][3] The affinity (Ki) of LIT-001 for the human oxytocin receptor, where it acts as an agonist, is 226 nM, and its half maximal effective concentration (EC50) is 25 nM.[2] At the human vasopressin V1A receptor, where LIT-001 is an antagonist, its affinity (Ki) and half maximal inhibitory concentration (IC50) are 1253 nM and 5900 nM, respectively.[2] Finally, at the human vasopressin V2 receptor, where the drug functions as an agonist, its affinity (Ki) and EC50 are 1666 nM and 41 nM, respectively.[2] Based on the preceding EC50 and IC50 values, LIT-001 shows 236-fold selectivity for activating the oxytocin receptor over antagonizing the V1A receptor, whereas it has no appreciable selectivity for activating the oxytocin receptor over activating the V2 receptor (only 1.64-fold greater preference).[2] ChemistryLIT-001 is a small-molecule compound with the molecular formula C28H33N7O2S, a molecular weight of 531.7 g/mol, and a predicted log P of 1.95 to 2.8.[5][6] It is similar in structure to the earlier small-molecule oxytocin receptor agonists TC OT 39 and WAY-267,464.[1][2] ResearchLIT-001 is reported to be in the preclinical stage of development for potential treatment of autistic spectrum disorders in France.[7] It is under development by the University of Strasbourg and the Centre National de la Recherche Scientifique (French National Centre for Scientific Research).[7] References
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