title: Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries.
abstract: 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 alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; 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 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP 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.
authors.affiliation: Division of Pharmacology, Vascular, and Metabolic Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: K Y
authors.initials: KY
authors.lastname: Chan
authors.forename: L
authors.initials: L
authors.lastname: Edvinsson
authors.forename: S
authors.initials: S
authors.lastname: Eftekhari
authors.forename: P O
authors.initials: PO
authors.lastname: Kimblad
authors.forename: S A
authors.initials: SA
authors.lastname: Kane
authors.forename: J
authors.initials: J
authors.lastname: Lynch
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: R
authors.initials: R
authors.lastname: de Vries
authors.forename: I M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: A J
authors.initials: AJ
authors.lastname: van den Bogaerdt
authors.forename: A H J
authors.initials: AH
authors.lastname: Danser
authors.forename: A
authors.initials: A
authors.lastname: Maassenvandenbrink
mesh_terms: D000328:Adult; D000368:Aged; D001381:Azepines / Q000009:adverse effects / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D003331:Coronary Vessels / Q000033:anatomy & histology / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D023303:Oxazolidinones / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; C525458:telcagepant; D000242:Cyclic AMP