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

ID: ALA5154716

Journal: Eur J Med Chem

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

Authors: Nguyen T, Decker AM, Snyder RW, Tonetti EC, Gamage TF, Zhang Y.

Abstract: 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 = 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).

CiteXplore: 35101647

DOI: 10.1016/j.ejmech.2022.114149

Patent ID: ┄