Structure-Activity Relationships of Neuromedin U. V. Study on the Stability of Porcine Neuromedin U-8 at the C-Terminal Asparagine Amide under Mild Alkaline and Acidic Conditions

Kawai, Takako; Shibata, Akira; Kurosawa, Katsuro; Sato, Yuki; Kato, Sachiko; Ohki, Kazuhiro; Hashimoto, Tadashi; Sakura, Naoki

doi:10.1248/cpb.54.659

Cited by 8 publications

(7 citation statements)

References 22 publications

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“…To understand the effect of amino acid substitution on agonistic activity, we conducted a SAR study based on nonselective agonist 1b . A previous study using isolated chicken crop smooth muscles reported that the C-terminus is important for activity (Figure B). Thus, we initially evaluated the importance of C-terminal Asn 6 -amide.…”

Section: Resultsmentioning

confidence: 86%

“…(B) Structure of hNMU-derived heptapeptide 1a and the SAR from previous studies. Arrows indicate the structural entities for potent biological activity of heptapeptide 1a . − Asterisk under Arg 3 indicates which residue should be useful to distinguish the selectivity toward NMUR1 and NMUR2 …”

Section: Introductionmentioning

confidence: 99%

“…(2) Substitution of Phe 2 by Tyr increases activity. (3) Arg 5 and the C-terminal Asn 6 -amide are indispensable for receptor binding and activation (Figure B). − An alanine scan study of tyrosyl- 1a demonstrated that Arg 3 and Arg 5 are necessary for the agonistic activity in murine NMU receptors . Substituting Arg 3 with Ala (EC 50 = 2411 and 156 nM for NMUR1 and NMUR2, respectively) decreases the agonistic activity of the peptide toward mouse NMUR1 (EC 50 = 9.5 nM) and NMUR2 (EC 50 = 3 nM) receptors, suggesting that Arg 3 is a critical residue for activity, whereas the drastic reduction of agonistic activity observed only in NMUR1 receptor would be a useful clue to distinguish between two receptors of NMUR1 and NMUR2 (Figure B).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Selective Hexapeptide Agonists to Human Neuromedin U Receptors Types 1 and 2

Takayama

Mori²,

Taketa

et al. 2014

J. Med. Chem.

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Neuromedin U (NMU) are bioactive peptides with a common C-terminal heptapeptide sequence (FLFRPRN-amide, 1a) among mammals, which is responsible for receptor activation, namely NMU receptor types 1 (NMUR1) and 2 (NMUR2). Among the various physiological actions of NMU, the anorexigenic effect has recently attracted attention in drug discovery efforts for treating obesity. Although several structure-activity relationship (SAR) studies have been reported, receptor-selective small peptide agonists have yet to be disclosed. Herein a SAR study of 1a-derived peptide derivatives is described. We initially screened both human NMUR1- and NMUR2-selective peptides in calcium-mobilization assays with cells transiently expressing receptors. Then we performed a precise assay with a stable expression system of receptors and consequently discovered hexapeptides 8d and 6b possessing selective agonist activity toward each respective receptor. Hexapeptide 6b, which selectively activates NMUR2 without significant NMUR1 activation, should aid in the development of anorexigenic drugs as well as advance NMU-related endocrinological research.

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Section: Resultsmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Selective Hexapeptide Agonists to Human Neuromedin U Receptors Types 1 and 2

Takayama

Mori²,

Taketa

et al. 2014

J. Med. Chem.

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“…These results, as well as the relatively short plasma half-life of both, PEG- and HSA-NmU conjugates reported elsewhere [40,41] (t 1/2 ≈11–54 h, depending on species) suggested that a key factor for the in vivo activity of NmU analogs/derivatives may be their resistance to enzymatic proteolysis. Alternatively, loss of their activity may involve partial hydrolysis of the N-terminal N 7 -amide to α- or β-monocarboxylic acid residues (X-Asn-OH or X-Asp-NH 2 ) via an aminosuccinimide intermediate [22]. Therefore we performed plasma stability studies for both NM4A and NM4-C 16 analogs using full length hNmU as a comparator [67–69].…”

Section: Resultsmentioning

confidence: 99%

Small lipidated anti-obesity compounds derived from neuromedin U

Micewicz

Bahattab

Willars

et al. 2015

European Journal of Medicinal Chemistry

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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.

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“…NMC shows sequence identity with the C-terminal part 18-27 of the gastricinhibitory polypeptide and sequence homology with the C-terminus of bombesin. Furthermore, elevations in body temperature and heart rate, as well as augmentation of stress responses, complete the spectrum of actions [359,360]. Neuromedin S (NMS) is a neuropeptide of different chain length with potent anorexigenic and circadian rhythm-modulating properties [357,358].…”

Section: Neuromedinsmentioning

confidence: 99%