A potent neuromedin U receptor 2-selective alkylated peptide

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4626-4629. doi: 10.1016/j.bmcl.2017.09.019. Epub 2017 Sep 9.

Abstract

Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU.

Keywords: Diabetes; NMU-8; Neuromedin U (NMU); Obesity; Polyethylene glycol (PEG).

MeSH terms

  • Alkylation
  • Amino Acid Sequence
  • Animals
  • Appetite Depressants / chemistry
  • Appetite Depressants / metabolism*
  • Appetite Depressants / pharmacology
  • Eating / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptides / agonists
  • Peptides / metabolism*
  • Receptors, Neurotransmitter / antagonists & inhibitors
  • Receptors, Neurotransmitter / metabolism*
  • Structure-Activity Relationship

Substances

  • Appetite Depressants
  • Peptides
  • Receptors, Neurotransmitter
  • neuromedin U receptor