A potent neuromedin U receptor 2-selective alkylated peptide. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: Nishizawa, Naoki; Kanematsu-Yamaki, Yoko; Funata, Masaaki; Nagai, Hiroaki; Shimizu, Ayako; Fujita, Hisashi; Sakamoto, Junichi; Takekawa, Shiro; Asami, Taiji
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 20(2017)
• Page Start: 4626
• Page End: 4629
• Publication Date: 2017-10-15
• Subjects: Ac acetyl -- Arg(Me) Nω-methylarginine -- Cha 3-cyclohexylalanine -- CNS central nervous system -- DIO diet-induced obese -- DMF N, N-dimethylformamide -- FLIPR fluorometric imaging plate reader -- Fmoc 9-fluorenylmethoxycarbonyl -- GIT gastrointestinal tract -- γGlu γ-glutamic acid -- HPLC high performance liquid chromatography -- HSA human serum albumin -- αMePhe α-methylphenylalanine -- Nal(2) 3-(2-naphthyl)alanine -- Nle norleucine -- NMU neuromedin U -- PEG polyethylene glycol -- PEG(2) O-(3-aminopropyl)-O'-(N-diglycolyl-3-aminopropyl)diethyleneglycol -- PEG(4) 15-amino-4, 7, 10, 13-tetraoxapentadecanoic acid -- PipAc piperazin-1-ylacetyl -- TFA trifluoroacetic acid -- Tra tranexamic acid; Neuromedin U (NMU) -- NMU-8 -- Polyethylene glycol (PEG) -- Diabetes -- Obesity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.09.019
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 [αMePhe 19, Nle 21, and Arg(Me) 24 ] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of17 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.