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

Wataru Ichinose, Stanislav M. Cherepanov, Anna A. Shabalova, Shigeru Yokoyama, Teruko Yuhi, Hiroaki Yamaguchi, Ayu Watanabe, Yasuhiko Yamamoto, Hiroshi Okamoto, Shinichi Horike, Junpei Terakawa, Takiko Daikoku, Mizuki Watanabe, Nariyasu Mano, Haruhiro Higashida, Satoshi Shuto

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3297-3310
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number7
DOIs
Publication statusPublished - 2019 Apr 11
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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