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

Lars Edvinsson, Anette Sams, Inger Jansen-Olesen, Janos Tajti, Stefanie A. Kane, Ruth Z. Rutledge, Kenneth S. Koblan, Raymond G. Hill, Jenny Longmore

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Abstract

The cerebral circulation is innervated by calcitonin gene-related peptide (CGRP) containing fibers originating in the trigeminal ganglion. During a migraine attack, there is a release of CGRP in conjunction with the head pain, and triptan administration abolishes both the CGRP release and the pain at the same time. In the search for a novel treatment of migraine, a non-peptide 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 antagonist, Compound 1 (4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid [1-(3,5-dibromo-4-hydroxy-benzyl)-2-oxo-2-(4-phenyl-piperazin-1-yl)-ethyl]- amide). On SK-N-MC cell membranes, radiolabelled CGRP binding was displaced by both CGRP-(8-37) and Compound 1, yielding pKi values of 8.9 and 7.8, respectively. Functional studies with SK-N-MC cells showed that CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and Compound 1 with pA2 values of 7.8 and 7.7, respectively. Isolated human and guinea pig cerebral arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation in human cerebral arteries which was antagonized by both CGRP-(8-37) and Compound 1 in a competitive manner. In guinea pig basilar arteries, CGRP-(8-37) antagonised the CGRP-induced relaxation while Compound 1 had a weak blocking effect . The clinical studies of non-peptide CGRP antagonists are awaited with great interest.

Original languageEnglish
Pages (from-to)39-44
Number of pages6
JournalEuropean Journal of Pharmacology
Volume415
Issue number1
DOIs
Publication statusPublished - Mar 9 2001

Keywords

  • CGRP receptor
  • Cerebral vessel
  • Dilatation
  • Human
  • cAMP production

ASJC Scopus subject areas

  • Pharmacology

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    Edvinsson, L., Sams, A., Jansen-Olesen, I., Tajti, J., Kane, S. A., Rutledge, R. Z., Koblan, K. S., Hill, R. G., & Longmore, J. (2001). Characterisation of the effects of a non-peptide CGRP receptor antagonist in SK-N-MC cells and isolated human cerebral arteries. European Journal of Pharmacology, 415(1), 39-44. https://doi.org/10.1016/S0014-2999(00)00934-1