Neuropeptide B/W receptor 1 peptidomimetic agonists: Structure-activity relationships and plasma stability.
Eur J Med Chem
; 231: 114149, 2022 Mar 05.
Article
en En
| MEDLINE
| ID: mdl-35101647
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).
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neuropéptidos
/
Peptidomiméticos
Límite:
Animals
Idioma:
En
Revista:
Eur J Med Chem
Año:
2022
Tipo del documento:
Article
Pais de publicación:
FR
/
FRANCE
/
FRANCIA
/
FRANÇA