Chemistry:LIT-001
 | |
| Identifiers | |
|---|---|
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C28H33N7O2S |
| Molar mass | 531.68 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
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]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 "The Current Status of Drug Discovery for the Oxytocin Receptor". Oxytocin. Methods Mol Biol. 2384. 2022. pp. 153–174. doi:10.1007/978-1-0716-1759-5_10. ISBN 978-1-0716-1758-8.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 "Targeting the Oxytocin System: New Pharmacotherapeutic Approaches". Trends Pharmacol Sci 40 (1): 22–37. January 2019. doi:10.1016/j.tips.2018.11.001. PMID 30509888.
- ↑ 3.0 3.1 3.2 3.3 "LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism". J Med Chem 61 (19): 8670–8692. October 2018. doi:10.1021/acs.jmedchem.8b00697. PMID 30199637. https://hal.science/hal-02366272/file/acs.jmedchem.8b00697.pdf.
- ↑ "A Nonpeptide Oxytocin Receptor Agonist for a Durable Relief of Inflammatory Pain". Sci Rep 10 (1): 3017. February 2020. doi:10.1038/s41598-020-59929-w. PMID 32080303.
 |  |
