LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

Abstract

Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V and V vasopressin receptor subtypes (V-R and V-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure-affinity and structure-efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.

A Nonpeptide Oxytocin Receptor Agonist for a Durable Relief of Inflammatory Pain

“…Besides, we confirm the capability of LIT-001 to cross the blood brain barrier to exert its action in the central nervous system 20 (Fig. 5).…”

“…Indeed, activation of OTR is known to induce a variety of molecular cascades 24 resulting in an important modulation of nociception 25 , social recognition and interactions 26,27 , anxiety 28 , feeding behavior 29 , and stress 30 , all important comorbidity factors in painful patients. www.nature.com/scientificreports www.nature.com/scientificreports/ Interestingly, a previous study has also shown that LIT-001 improved social interaction in a mouse model of autism 20 , reinforcing its putative interest as an analgesic molecule.…”

“…Those aspects point toward LIT-001, and future non-peptidergic agonists, as key candidates for clinical use. Although it displays a low micromolar affinity for this receptor, LIT-001 is a potent V2R agonist in functional assays 20 . The V2 receptor is peripheral and known to regulate water homeostasis.…”

“…Drugs. LIT-001 was prepared as described in Frantz et al 20 . For in vivo biological assays, it was dissolved in carboxymethyl cellulose (CMC, 1%) -NaCl (0.9%) and administered at the dose of 10 mg/kg.…”

“…Recently, a first non-peptide full agonist of oxytocin (LIT-001) has been reported to improve social interactions in a mouse model of autism after peripheral administration 20 . LIT-001 is a pyrazolobenzodiazepine derivative with a non-peptide chemical structure and a low molecular weight (MW) compared to oxytocin (MW = 531 vs. 1007, respectively, Fig.…”