神经肽 B/W 受体 1 肽模拟激动剂：结构-活性关系和血浆稳定性。

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

机构信息

Center for Drug Discovery, RTI International, Research Triangle Park, NC, 27709, USA.

出版信息

Eur J Med Chem. 2022 Mar 5;231:114149. doi: 10.1016/j.ejmech.2022.114149. Epub 2022 Jan 21.

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: EC = 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).

神经肽 B 和 W（NPB 和 NPW）是神经肽 B/W 受体 1（NPBWR1）的内源性配体，该受体参与广泛的功能，包括调节疼痛和能量稳态。目前关于这两种神经肽的结构-活性关系（SAR）的信息很少。为了开发稳定且有效的 NPBWR1 肽模拟激动剂，我们通过截短、丙氨酸/甘氨酸和 d-氨基酸扫描以及用非天然氨基酸取代进行了系统的 SAR。在 NPBWR1 钙测定中的评估表明，C 端 GRAAGLL 和 N 端 WYK 区域构成了 NPBWR1 激动作用的两个表位药效团。用其去氨基 Trp 取代 N 端色氨酸得到化合物 30，其在 NPBWR1 处表现出与内源性 NPB 相当的纳摩尔效力（钙测定：EC=8 nM 对 13 nM，cAMP 测定：2.7 nM 对 3.5 nM），并增强了对大鼠血浆的代谢稳定性（39.1 分钟对 11.9 分钟）。