Small lipidated anti-obesity compounds derived from neuromedin U

Ewa D Micewicz; Omar S O Bahattab; Gary B Willars; Alan J Waring; Mohamad Navab; Julian P Whitelegge; William H McBride; Piotr Ruchala

doi:10.1016/j.ejmech.2015.07.020

Small lipidated anti-obesity compounds derived from neuromedin U

Eur J Med Chem. 2015 Aug 28:101:616-26. doi: 10.1016/j.ejmech.2015.07.020. Epub 2015 Jul 14.

Authors

Ewa D Micewicz¹, Omar S O Bahattab², Gary B Willars², Alan J Waring³, Mohamad Navab⁴, Julian P Whitelegge⁵, William H McBride¹, Piotr Ruchala⁶

Affiliations

¹ Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
² Department of Cell Physiology and Pharmacology, University of Leicester, University Road, Leicester, LE1 9HN, UK.
³ Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA; Department of Physiology and Biophysics, University of California Irvine, 1001 Health Sciences Road, Irvine, CA 92697, USA.
⁴ Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
⁵ Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA; The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
⁶ Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA; The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA. Electronic address: pruchala@mednet.ucla.edu.

Abstract

A small library of truncated/lipid-conjugated neuromedin U (NmU) analogs was synthesized and tested in vitro using an intracellular calcium signaling assay. The selected, most active analogs were then tested in vivo, and showed potent anorexigenic effects in a diet-induced obese (DIO) mouse model. The most promising compound, NM4-C16 was effective in a once-weekly-dose regimen. Collectively, our findings suggest that short, lipidated analogs of NmU are suitable leads for the development of novel anti-obesity therapeutics.

Keywords: Antiobesity agents; Lipid-conjugated peptides; Neuromedin U receptor agonists; Obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Obesity Agents / chemical synthesis*
Anti-Obesity Agents / chemistry
Anti-Obesity Agents / pharmacology*
Calcium / metabolism
Dietary Fats / adverse effects
Disease Models, Animal
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Neuropeptides / chemistry*
Neuropeptides / pharmacology*
Obesity / drug therapy*
Obesity / metabolism
Signal Transduction
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Anti-Obesity Agents
Dietary Fats
Neuropeptides
Small Molecule Libraries
neuromedin U
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding