ABSTRACT
Neuromedin U (NMU) is an endogenous peptide, whose role in the regulation of feeding and energy homeostasis is well documented. Two NMU receptors have been identified: NMUR1, expressed primarily in the periphery, and NMUR2, expressed predominantly in the brain. We recently demonstrated that acute peripheral administration of NMU exerts potent but acute anorectic activity and can improve glucose homeostasis, with both actions mediated by NMUR1. Here, we describe the development of a metabolically stable analog of NMU, based on derivatization of the native peptide with high molecular weight poly(ethylene) glycol (PEG) ('PEGylation'). PEG size, site of attachment, and conjugation chemistry were optimized, to yield an analog which displays robust and long-lasting anorectic activity and significant glucose-lowering activity in vivo. Studies in NMU receptor-deficient mice showed that PEG-NMU displays an expanded pharmacological profile, with the ability to engage NMUR2 in addition to NMUR1. In light of these data, PEGylated derivatives of NMU represent promising candidates for the treatment of obesity and diabetes.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Neuropeptides/pharmacology , Obesity/drug therapy , Polyethylene Glycols/chemistry , Receptors, Neurotransmitter/agonists , Animals , Dose-Response Relationship, Drug , Glucose Tolerance Test , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuropeptides/administration & dosage , Neuropeptides/chemical synthesis , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/pharmacology , Receptors, Neurotransmitter/deficiency , Structure-Activity RelationshipABSTRACT
A variety of new prodrugs of 2'-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieved.
