Synthesis of oxytocin derivatives lipidated via a carbonate or carbamate linkage as a long-acting therapeutic agent for social impairment-like behaviors

Stanislav M. Cherepanov, Risako Miura, Anna A. Shabalova, Wataru Ichinose, Shigeru Yokoyama, Hayato Fukuda, Mizuki Watanabe, Haruhiro Higashida, Satoshi Shuto

Research output: Contribution to journalArticle

Abstract

In the course of our studies of hydrophobic oxytocin (OT) analogues, we newly synthesized lipidated OT (LOT-4a-c and LOT-5a-c), in which a long alkyl chain (C14-C16) is conjugated via a carbonate or carbamate linkage at the Tyr-2 phenolic hydroxy group and a palmitoyl group at the terminal amino group of Cys-1. These LOTs did not activate OT and vasopressin receptors. Among the LOTs, however, LOT-4c, having a C16-chain via a carbonate linkage at the phenolic hydroxyl group of the Tyr-2, showed very long-lasting action for the recovery of impaired social behavior in CD38 knockout mice, a rodent model of autistic phenotypes, whereas the effect of OT itself rapidly diminished. These results indicate that LOT-4c may serve as a potential prodrug in mice.

Original languageEnglish
Pages (from-to)3358-3363
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number15
DOIs
Publication statusPublished - 2019 Aug 1

Keywords

  • Lipidation
  • Long-acting
  • Oxytocin
  • Prodrug
  • Social impairment-like behavior

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Cherepanov, S. M., Miura, R., Shabalova, A. A., Ichinose, W., Yokoyama, S., Fukuda, H., Watanabe, M., Higashida, H., & Shuto, S. (2019). Synthesis of oxytocin derivatives lipidated via a carbonate or carbamate linkage as a long-acting therapeutic agent for social impairment-like behaviors. Bioorganic and Medicinal Chemistry, 27(15), 3358-3363. https://doi.org/10.1016/j.bmc.2019.06.018