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

共 50 条

[31] SM-216601, a Novel Parenteral 1β-Methylcarbapenem: Structure-activity Relationships of Antibacterial Activity and Neurotoxicity in Mice [J].

Yutaka Ueda ;

Masanori Itoh ;

Akira Sasaki ;

Makoto Sunagawa .

The Journal of Antibiotics, 2005, 58 :118-140

[32] Synthesis and structure-activity relationships of a new series of benzimidazoles as H-1-antihistaminic agents [J].

Cuberes, MR ;

Contijoch, M ;

Calvet, C ;

Alegre, J ;

Quintana, JR ;

Frigola, J .

CHEMICAL & PHARMACEUTICAL BULLETIN, 1997, 45 (08) :1287-1292

[33] Structure-activity relationships of flavonoids, isolated from Scutellaria baicalensis, binding to benzodiazepine site of GABAA receptor complex [J].

Wang, HY ;

Hui, KM ;

Chen, YJ ;

Xu, SX ;

Wong, JTF ;

Xue, H .

PLANTA MEDICA, 2002, 68 (12) :1059-1062

[34] Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties [J].

Ghonim, Aya E. ;

Ligresti, Alessia ;

Rabbito, Alessandro ;

Mahmoud, Ali Mokhtar ;

Di Marzo, Vincenzo ;

Osman, Noha A. ;

Abadi, Ashraf H. .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2019, 180 :154-170

[35] SYNTHESIS AND STRUCTURE-ACTIVITY STUDIES OF A SERIES OF 1-OXA-8-AZASPIRO[4.5]DECANES AS M(1) MUSCARINIC AGONISTS [J].

TSUKAMOTO, S ;

FUJII, M ;

YASUNAGA, T ;

MATSUDA, K ;

WANIBUCHI, F ;

HIDAKA, K ;

FURUYA, T ;

TAMURA, T .

CHEMICAL & PHARMACEUTICAL BULLETIN, 1995, 43 (05) :842-852

[36] Evaluation of phytocannabinoids from high-potency Cannabis sativa using in vitro bioassays to determine structure-activity relationships for cannabinoid receptor 1 and cannabinoid receptor 2 [J].

Husni, Afeef S. ;

McCurdy, Christopher R. ;

Radwan, Mohamed M. ;

Ahmed, Safwat A. ;

Slade, Desmond ;

Ross, Samir A. ;

ElSohly, Mahmoud A. ;

Cutler, Stephen J. .

MEDICINAL CHEMISTRY RESEARCH, 2014, 23 (09) :4295-4300

[37] Synthesis and Structure-Activity Relationships of a New Class of Oxadiazoles Targeting DprE1 as Antitubercular Agents [J].

Yadav, Veena D. D. ;

Boshoff, Helena I. I. ;

Trifonov, Lena ;

Roma, Jose Santinni O. ;

Ioerger, Thomas R. R. ;

Barry, Clifton E. E. ;

Oh, Sangmi .

ACS MEDICINAL CHEMISTRY LETTERS, 2023, 14 (09) :1275-1283

[38] Structure-activity relationships of fatty acid amide ligands in activating and desensitizing G protein-coupled receptor 119 [J].

Kumar, Pritesh ;

Kumar, Akhilesh ;

Song, Zhao-Hui .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2014, 723 :465-472

[39] Mechanism of Action and Structure-Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor [J].

Dengler, Daniela G. G. ;

Harikumar, Kaleeckal G. G. ;

Yen, Alice ;

Sergienko, Eduard A. A. ;

Miller, Laurence J. J. .

MEMBRANES, 2023, 13 (02)

[40] Selective endothelin A receptor antagonists .2. Discovery and structure-activity relationships of 5-ketopentanoic acid derivatives [J].

Astles, PC ;

Brown, TJ ;

Harris, NV ;

Harper, MF ;

McCarthy, C ;

Porter, B ;

Smith, C ;

Walsh, RJA .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1997, 32 (06) :515-522

← 1 2 3 4 5 →