LIT-002, A HIGHLY POTENT AND SELECTIVE NONPEPTIDE OXYTOCIN RECEPTOR AGONIST THAT IMPROVES SOCIAL INTERACTION IN MOUSE MODELS OF AUTISM

Oxytocin (OT) and its receptor (OT-R) have long been implicated in the regulation of social behavior and represent a potential therapeutic target for autism spectrum disorders (ASD). However, the clinical use of OT is limited by poor pharmacokinetic properties and insufficient receptor selectivity. Here, we report the design, synthesis and pharmacological characterization of LIT-002, a second-generation non-peptide OT-R agonist with markedly improved potency compared to the first lead compound LIT-001.
Systematic chemical optimization generated a series of analogs, leading to the identification of LIT-002 as a subnanomolar full OT-R agonist. Functional signaling assays indicated robust OT-R activation, including G protein engagement, β-arrestin recruitment, and receptor internalization. Molecular modeling supported a binding mode consistent with the observed structure–activity relationships and receptor subtype selectivity.
LIT-002 was further evaluated in vivo and demonstrated efficacy in two mouse models relevant to ASD: Oprm1 knockout mice and mice exposed in utero to valproic acid. Following peripheral administration, LIT-002 improved social interaction measures in a dose- and time-dependent manner, and repeated low-dose treatment produced sustained behavioral benefits in ASD-like animals. Pharmacokinetic analyses indicated detectable brain exposure despite limited brain penetration.
Altogether, LIT-002 establishes a new benchmark for non-peptide OT-R agonism and provides a strong rationale to pursue translational development to target social dysfunction in ASD.