Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2‑selective PEGylated Peptide

Neuromedin U (NMU) is a neuropeptide
that mediates a variety of
physiological functions via its receptors, NMUR1 and NMUR2. Recently,
there has been an increased focus on NMU as a promising treatment
option for diabetes and obesity. A short form of NMU (NMU-8) has potent
agonist activity for both receptors but is metabolically unstable.
Therefore, we designed and synthesized NMU-8 analogues modified by
polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a
linker. 3-(2-Naphthyl)­alanine substitution at position 19 increased
NMUR2 selectivity of NMU-8 analogues with retention of high agonist
activity. Compound 37, an NMUR2-selective PEG20k analogue
containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering
effect with concomitant inhibition of food intake in a dose-dependent
manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated
dosing for 2 weeks in mice with diet-induced obesity.