A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine. (25th June 2020)

• Record Type: Journal Article
• Authors: von Mentzer, Bengt; Russo, Andrew F; Zhang, Zhongming; Kuburas, Adisa; Killoran, Patrick M; D'Aloisio, Vera; Nizic, Laura; Capel, Vicky; Kendall, David A; Coxon, Christopher R; Hutcheon, Gillian A
• Is Part Of: Journal of pharmacy and pharmacology. Volume 72:Number 10(2020)
• Page Start: 1352
• Page End: 1360
• Publication Date: 2020-06-25
• Subjects: aCGRP (8-37) -- aCGRP (27-37) -- cAMP -- plasma extravasation -- SK-N-MC; Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.13317
• Languages: English
• ISSNs: 0022-3573

Abstract

Abstract: Objectives: To investigate the formulation of the peptide-based antagonist ( 34 Pro, 35 Phe)CGRP27–37, of the human calcitonin gene-related peptide (CGRP) receptor as a potential nasally delivered migraine treatment. Methods: Peptide sequences were prepared using automated methods and purified by preparative HPLC. Their structure and stability were determined by LC-MS. Antagonist potency was assessed by measuring CGRP-stimulated cAMP accumulation in SK-N-MC, cells and in CHO cells overexpressing the human CGRP receptor. In vivo activity was tested in plasma protein extravasation (PPE) studies using Evans blue dye accumulation. Peptide-containing chitosan microparticles were prepared by spray drying. Key findings: ( 34 Pro, 35 Phe)CGRP27–37 exhibited a 10-fold increased affinity compared to αCGRP27–37 . Administration of ( 34 Pro, 35 Phe)CGRP27–37 to mice led to a significant decrease in CGRP-induced PPE confirming antagonistic properties in vivo . There was no degradation of ( 34 Pro, 35 Phe)CGRP27–37 and no loss of antagonist potency during formulation and release from chitosan microparticles. Conclusions: ( 34 Pro, 35 Phe)CGRP27–37 is a potent CGRP receptor antagonist both in vitro and in vivo, and it can be formulated as a dry powder with no loss of activity indicating its potential as a nasally formulated anti-migraine medicine.