LIT-001
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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]
LIT-001 is reported to be in the preclinical stage of development for potential treatment of autistic spectrum disorders in France.[5] It is under development by the University of Strasbourg and the Centre National de la Recherche Scientifique (French National Centre for Scientific Research).[5]
References
- ^ a b c d e f g h i j k l m n o Nashar PE, Whitfield AA, Mikusek J, Reekie TA (2022). "The Current Status of Drug Discovery for the Oxytocin Receptor". Oxytocin. Methods Mol Biol. Vol. 2384. pp. 153–174. doi:10.1007/978-1-0716-1759-5_10. ISBN 978-1-0716-1758-8. PMID 34550574. S2CID 239090096.
- ^ a b c d e f g h i j k l m n o p q r Gulliver D, Werry E, Reekie TA, Katte TA, Jorgensen W, Kassiou M (January 2019). "Targeting the Oxytocin System: New Pharmacotherapeutic Approaches". Trends Pharmacol Sci. 40 (1): 22–37. doi:10.1016/j.tips.2018.11.001. hdl:1959.4/unsworks_81554. PMID 30509888. S2CID 54559394.
- ^ a b c d Frantz MC, Pellissier LP, Pflimlin E, Loison S, Gandía J, Marsol C, Durroux T, Mouillac B, Becker JA, Le Merrer J, Valencia C, Villa P, Bonnet D, Hibert M (October 2018). "LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism" (PDF). J Med Chem. 61 (19): 8670–8692. doi:10.1021/acs.jmedchem.8b00697. PMID 30199637. S2CID 52181935.
- ^ Hilfiger L, Zhao Q, Kerspern D, Inquimbert P, Andry V, Goumon Y, Darbon P, Hibert M, Charlet A (February 2020). "A Nonpeptide Oxytocin Receptor Agonist for a Durable Relief of Inflammatory Pain". Sci Rep. 10 (1): 3017. doi:10.1038/s41598-020-59929-w. PMC 7033278. PMID 32080303.
- ^ a b "Delving into the Latest Updates on LIT-001 with Synapse". Synapse. 2 August 2024. Retrieved 18 August 2024.
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- Agonists: Peptide: Aspartocin
- Carbetocin
- Cargutocin
- Demoxytocin
- Lipo-oxytocin-1
- Merotocin
- Nacartocin
- Oxytocin
- PF-06478939
- PF-06655075 (PF1)
- TGOT
- Vasotocin (argiprestocin); Non-peptide: CA7
- LIT-001
- TC OT 39
- WAY-267464
- WJ0679
- Antagonists: Peptide: Atosiban
- Tocinoic acid; Non-peptide: Barusiban
- Cligosiban
- Epelsiban
- Erlosiban
- IX-01
- L-368,899
- L-371,257
- L-372,662
- Nolasiban
- Retosiban
- SSR-126768
- WAY-162720
- Catabolism inhibitors: Amastatin
- Bestatin (ubenimex)
- EDTA
- L-Methionine
- Leupeptin
- o-Phenanthroline
- Phosphoramidon
- Puromycin
V1A |
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V1B |
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V2 |
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Unsorted |
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- Carrier proteins: Neurophysin (I, II)