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

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 V1a and V2 vasopressin receptor subtypes (V1a-R and V2-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.