Characterization of the Calcitonin Gene-Related Peptide Receptor Antagonist Telcagepant (MK-0974) in Human Isolated Coronary Arteries

Ka yi Chan, L Edvinsson, S Eftekhari, PO Kimblad, SA Kane, J Lynch, RJ Hargreaves, René de Vries, Ingrid Van den Berg - Garrelds, Antoon Bogaerdt, Jan Danser, Antoinette Maassen van den Brink

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The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2- trifluoroethyl) azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1- yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration- dependent relaxation responses to human αCGRP were greater in distal coronary arteries (i.d. 600-1000 μm; E max = 83 ± 7%) than proximal coronary arteries (i.d. 2-3 mm; E max = 23 ± 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E max = 11 ± 3%), and coronary arterioles (i.d. 200-300 μm; E max = 15 ± 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 μM) antagonized αCGRP-induced relaxation competitively in distal coronary arteries (pA 2 = 8.43 ± 0.24) and proximal coronary arteries and coronary arterioles (1 μM telcagepant, giving pK B = 7.89 ± 0.13 and 7.78 ± 0.16, respectively). αCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.

Original languageEnglish
Pages (from-to)746-752
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Early online dateSep 2010
Publication statusPublished - Sep 2010

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Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics


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