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Formula | C28H33N7O2S |
Molar mass | 531.68 g·mol−1 |
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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]
LIT-001 is similar in structure to TC OT 39. [1] [2] Compared to TC OT 39 and WAY-267464, LIT-001 has greater selectivity for the oxytocin receptor over the vasopressin V1A receptor. [1] [2] LIT-001 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]