Neuropeptide B/W receptor 1 peptidomimetic agonists: Structure-activity relationships and plasma stability

被引：3

作者：

Nguyen, Thuy ^{[1
]}

Decker, Ann M. M. ^{[1
]}

Snyder, Rodney W. W. ^{[1
]}

Tonetti, Emma C. C. ^{[1
]}

Gamage, Thomas F. F. ^{[1
]}

Zhang, Yanan ^{[1
]}

机构：

[1] RTI Int, Ctr Drug Discovery, Res Triangle Pk, NC 27709 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 231卷

关键词：

Neuropeptide B/W receptor 1; Neuropeptide B; Neuropeptide W; Structure-activity relationship; G protein coupled receptor; Plasma stability;

D O I：

10.1016/j.ejmech.2022.114149

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Neuropeptides B and W (NPB and NPW) are endogenous ligands of the Neuropeptide B/W Receptor 1 (NPBWR1) which has been implicated in a wide range of functions including regulation of pain and energy homeostasis. There is currently little information on the structure-activity relationships (SAR) of these two neuropeptides. In a quest to develop stable and potent NPBWR1 peptidomimetic agonists, we performed systematic SAR by truncation, Alanine/Glycine and D-amino acid scans, and replacement with unnatural amino acids. Evaluation in the NPBWR1 calcium assay revealed that the C-terminal GRAAGLL and N-terminal WYK regions constitute the two-epitope pharmacophore for NPBWR1 agonism. Replacement of the N-terminal Trp with its desaminoTrp residue resulted in compound 30 which exhibited nanomolar potency comparable to the endogenous NPB at NPBWR1 (Calcium assay: EC50 & nbsp;=& nbsp;8 nM vs. 13 nM, cAMP assay: 2.7 nM vs 3.5 nM) and enhanced metabolic stability against rat plasma (39.1 min vs. 11.9 min). (c) 2022 Elsevier Masson SAS. All rights reserved.

引用

页数：9

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