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. Along with TC OT 39 and WAY-267464, it is one of the first small-molecule oxytocin receptor agonists to have been developed. 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.

LIT-001 is similar in structure to TC OT 39. Compared to TC OT 39 and WAY-267464, LIT-001 has greater selectivity for the oxytocin receptor over the vasopressin V1A receptor. LIT-001 shows antagonism of the V1A receptor only at high concentrations. LIT-001 additionally acts as an agonist of the vasopressin V2 receptor, with this action occurring at similar concentrations as for the oxytocin receptor. This is unlikely to influence the oxytocin receptor-related behavioral effects of LIT-001, as V2 receptors are not expressed in the brain. However, it may influence fluid homeostasis, analogously to vasopressin.

Given via peripheral administration, LIT-001 reduces social deficits in a mouse model of autism, specifically the μ-opioid receptor knockout mouse model. It was the first small-molecule oxytocin receptor agonist to be shown to reduce social dysfunction in animals. 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. 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 60minutes, and it is not orally bioavailable, all of which greatly limit its potential usefulness as a central nervous system-acting medication. These limitations of oxytocin may underlie limited effectiveness with oxytocin nasal spray in clinical trials. 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.

The affinity (Ki) of LIT-001 for the human oxytocin receptor, where it acts as an agonist, is 226nM, and its half maximal effective concentration (EC50) is 25nM. At the human vasopressin V1A receptor, where LIT-001 is an antagonist, its affinity (Ki) and half maximal inhibitory concentration (IC50) are 1253nM and 5900nM, respectively. Finally, at the human vasopressin V2 receptor, where the drug functions as an agonist, its affinity (Ki) and EC50 are 1666nM and 41nM, respectively. 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).