Open AccessA CGRP receptor antagonist peptide formulated for nasal administration to treat migraine
Author(s) -
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.
Publication year - 2020
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13317
Subject(s) - calcitonin gene related peptide , antagonist , in vivo , chemistry , pharmacology , receptor , peptide , receptor antagonist , extravasation , calcitonin , potency , migraine , in vitro , medicine , endocrinology , neuropeptide , biochemistry , immunology , biology , microbiology and biotechnology
Objectives To investigate the formulation of the peptide‐based antagonist ( 34 Pro, 35 Phe)CGRP 27–37 , 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)CGRP 27–37 exhibited a 10‐fold increased affinity compared to αCGRP 27–37 . Administration of ( 34 Pro, 35 Phe)CGRP 27–37 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)CGRP 27–37 and no loss of antagonist potency during formulation and release from chitosan microparticles. Conclusions ( 34 Pro, 35 Phe)CGRP 27–37 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.