Characterisation of the effects of a non-peptide CGRP receptor antagonist in SK-N-MC cells and isolated human cerebral arteries

The cerebral circulation is innervated by calcitonin gene-related peptide ( CGRP) containing fibers originating in the trigeminal ganglion. During a mi graine attack, there is a release of CGRP in conjunction with the head pain , and triptan administration abolishes both the CGRP release and the pain a t the same time. In the search for a novel treatment of migraine, a non-pep tide CGRP antagonist has long been sought. Here, we present data on a human cell line and human and guinea-pig isolated cranial arteries for such an a ntagonist, Compound 1 (4-(2-Oxo-2,3-dihydro-benzoinlidazol-1-y])-piperidine -1-carboxylic acid [1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2phenyl-piperazi n-1-yl)-ethyl]-amide). On SK-N-MC cell membranes, radiolabelled CGRP bindin g was displaced by both CGRP-(8-37) and Compound 1, yielding pK(i) values o f 8.9 and 7.8, respectively. Functional studies with SK-N-MC cells showed t hat CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and Co mpound 1 with pA(2) values of 7.8 and 7.7, respectively. Isolated human and guinea pig cerebral arteries were studied with a sensitive myograph techni que. CGRP induced a concentration-dependent relaxation in human cerebral ar teries which was antagonized by both CGRP-(8-37) and Compound 1 in a compet itive manner. In guinea pig basilar arteries, CGRP-(8-37) antagonised the C GRP-induced relaxation while Compound 1 had a weak blocking effect. The cli nical studies of non-peptide CGRP antagonists are awaited with great intere st. (C) 2001 Elsevier Science B.V. All rights reserved.