Discovery of Selective Pituitary Adenylate Cyclase 1 Receptor (PAC1R) Antagonist Peptides Potent in a Maxadilan/PACAP38-Induced Increase in Blood Flow Pharmacodynamic Model
| Autor: | Fang-Tsao Hong, Hongyan Li, Derek E. Piper, Leszek Poppe, Philip Wong, Todd Hager, Essa Hu, Jason Long, Jennifer Aral, Narender R. Gavva, Cen Xu, Les P. Miranda, Carl Davis, Dawn Zhu, Sonya G. Lehto, Licheng Shi, Kristin L. Andrews |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Migraine Disorders Vasodilator Agents Adenylate kinase Peptide Pharmacology 01 natural sciences Cyclase Rats Sprague-Dawley Mice 03 medical and health sciences In vivo Drug Discovery Animals Humans Receptor 030304 developmental biology chemistry.chemical_classification 0303 health sciences Antagonist Ligand (biochemistry) Rats 0104 chemical sciences Amino acid Molecular Docking Simulation 010404 medicinal & biomolecular chemistry chemistry Blood Circulation Insect Proteins Pituitary Adenylate Cyclase-Activating Polypeptide Molecular Medicine Peptides Receptors Pituitary Adenylate Cyclase-Activating Polypeptide Type I |
| Zdroj: | Journal of Medicinal Chemistry. 64:3427-3438 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, 6, as a starting point. C-terminal modifications of 6 improved the peptide metabolic stability in vitro and in vivo. SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the in vitro PAC1R inhibitory activity of the analogs to the pM IC90 range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs 17 and 18 exhibited robust in vivo efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide (18) with PAC1R extracellular domain is reported. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|