Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment

Calcitonin gene-related peptide (CGRP) is a potent vasodilator in brain vessels and it has been implicated in the pathogenesis of migraine headache. Blocking post-junctional CGRP receptors, mediators of trigeminal-induced vasodilation, has been suggested as a potential antimigraine strategy. In this study, we tested the ability of a new non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the CGRP-induced dilation in human and/or bovine brain vessels and compared it to that of the antagonist α-CGRP 8–37. BIBN4096BS and α-CGRP 8–37 both blocked the α-CGRP-induced dilation in bovine middle artery segments with respective potency (p K B values) of 6.3 and 7.8. In human pial vessels, BIBN4096BS was particularly potent. When tested at 10 −14–10 −9 M concentrations, it induced a rightward shift in the α-CGRP concentration–response curve and yielded a biphasic Schild plot suggesting interaction with more than one receptor population, as was also indicated by the significant best fit of the α-CGRP-induced dilation in human brain vessels with a two receptor site interaction. Schild plot analysis in the linear portion of the BIBN4096BS inhibition curve revealed interaction with one high affinity site (p A 2 value ∼14). In bovine vessels, both α-CGRP 8–37 and BIBN4096BS concentration-dependently reversed a pre-established CGRP-induced dilation (∼59 and 85%, respectively), BIBN4096BS being ∼tenfold more potent than α-CGRP 8–37 (respective pIC 50 values of 7.5 and 6.75). In human middle cerebral and middle meningeal arteries, BIBN4096BS reversed the α-CGRP-induced dilation (≥70%) by interaction with two different receptor populations: it exhibited a high affinity for one population (pIC 50 value ∼13) and a lower affinity for the other (pIC 50 value ∼8). The present data demonstrate that BIBN4096BS is a very potent antagonist that could, depending on its bioavailability and in vivo affinity, be of potential benefit in the acute treatment of migraine headache by blocking and/or reversing the CGRP-mediated dilation of intracranial vessels induced by activation of trigeminovascular afferents.