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.
Stanislav M Cherepanov  1 ,  Risako Miura  2 ,  Anna A Shabalova  1 ,  Wataru Ichinose  2 ,  Shigeru Yokoyama  1 ,  Hayato Fukuda  2 ,  Mizuki Watanabe  2 ,  Haruhiro Higashida  3 ,  Satoshi Shuto  4
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: [email protected].
  • 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: [email protected].
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.