LIT-001

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LIT-001
Identifiers
  • (2S)-2-(dimethylcarbamothioyl)-N-[[2-methyl-4-(1-methyl-4,10-dihydropyrazolo[4,3-c][1,5]benzodiazepine-5-carbonyl)phenyl]methyl]pyrrolidine-1-carboxamide
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC28H33N7O2S
Molar mass531.68 g·mol−1
3D model (JSmol)
  • CC1=C(C=CC(=C1)C(=O)N2CC3=C(NC4=CC=CC=C42)N(N=C3)C)CNC(=O)N5CCC[C@H]5C(=S)N(C)C
  • InChI=1S/C28H33N7O2S/c1-18-14-19(11-12-20(18)15-29-28(37)34-13-7-10-24(34)27(38)32(2)3)26(36)35-17-21-16-30-33(4)25(21)31-22-8-5-6-9-23(22)35/h5-6,8-9,11-12,14,16,24,31H,7,10,13,15,17H2,1-4H3,(H,29,37)/t24-/m0/s1
  • Key:AOPORIRPXVMWSL-DEOSSOPVSA-N

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. ^ 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.
  2. ^ 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. PMID 30509888. S2CID 54559394.
  3. ^ 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.
  4. ^ 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.
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