Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

The nonapeptide hormone
oxytocin (OT) has pivotal brain roles in
social recognition and interaction and is thus a promising therapeutic
drug for social deficits. Because of its peptide structure, however,
OT is rapidly eliminated from the bloodstream, which decreases its
potential therapeutic effects in the brain. We found that newly synthesized
OT analogues in which the Pro7 of OT was replaced with N-(p-fluorobenzyl)­glycine (2) or N-(3-hydroxypropyl)­glycine (5)
exhibited highly potent binding affinities for OT receptors and Ca2+ mobilization effects by selectively activating OT receptors
over vasopressin receptors in HEK cells, where 2 was
identified as a superagonist (EMax = 131%)
for OT receptors. Furthermore, the two OT analogues had a remarkably
long-acting effect, up to 16–24 h, on recovery from impaired
social behaviors in two strains of CD38 knockout mice that exhibit
autism spectrum disorder-like social behavioral deficits, whereas
the effect of OT itself rapidly diminished.