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

doi:10.1016/j.bmc.2019.06.018

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

Bioorg Med Chem. 2019 Aug 1;27(15):3358-3363. doi: 10.1016/j.bmc.2019.06.018. Epub 2019 Jun 10.

Authors

Stanislav M Cherepanov¹, Risako Miura², Anna A Shabalova¹, Wataru Ichinose², Shigeru Yokoyama¹, Hayato Fukuda², Mizuki Watanabe², Haruhiro Higashida³, Satoshi Shuto⁴

Affiliations

¹ Department of Basic Research on Social Recognition, Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan.
² Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
³ Department of Basic Research on Social Recognition, Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan. Electronic address: haruhiro@med.kanazawa-u.ac.jp.
⁴ Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Hokkaido University, Sapporo 060-0812, Japan. Electronic address: shu@pharm.hokudai.ac.jp.

PMID: 31229420
DOI: 10.1016/j.bmc.2019.06.018

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.

Keywords: Lipidation; Long-acting; Oxytocin; Prodrug; Social impairment-like behavior.

MeSH terms

Animals
Carbamates / chemistry
Carbamates / pharmacology*
Carbonates / chemistry
Carbonates / pharmacology*
Dose-Response Relationship, Drug
Female
Male
Mice
Mice, Inbred ICR
Mice, Knockout
Molecular Structure
Oxytocin / chemical synthesis
Oxytocin / chemistry
Oxytocin / pharmacology*
Paternal Behavior / drug effects*
Social Behavior
Structure-Activity Relationship

Substances

Carbamates
Carbonates
Oxytocin