A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine

Bengt von Mentzer, Andrew F. Russo, Zhang Zhongming, Adisa Kuburas, Patrick M. Killoran, Vera D’Aloisio, Laura Nizic, Vicky Capel, David A. Kendall, Christopher R. Coxon, Gillian A. Hutcheon

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Abstract

Objectives To investigate the formulation of the peptide-based antagonist (34Pro,35Phe)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 (34Pro,35Phe)CGRP27–37 exhibited a 10-fold increased affinity compared to αCGRP27–37. Administration of (34Pro,35Phe)CGRP27–37 to mice led to a significant decrease in CGRP-induced PPE confirming antagonistic properties in vivo. There was no degradation of (34Pro,35Phe)CGRP27–37 and no loss of antagonist potency during formulation and release from chitosan microparticles. Conclusions (34Pro,35Phe)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.
Original languageEnglish
Pages (from-to)1352-1360
Number of pages9
JournalJournal of Pharmacy and Pharmacology
Volume72
Issue number10
Early online date25 Jun 2020
DOIs
Publication statusPublished - Oct 2020

Keywords

  • aCGRP (8-37)
  • aCGRP (27-37)
  • cAMP
  • plasma extravasation
  • SK-N-MC

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry
  • Pharmacology

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