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

Eur J Pharmacol. 2001 Mar 9;415(1):39-44. doi: 10.1016/s0014-2999(00)00934-1.


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 pK(i) 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 pA(2) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Calcitonin Gene-Related Peptide / pharmacology
  • Calcitonin Gene-Related Peptide Receptor Antagonists*
  • Cell Membrane / metabolism
  • Cerebral Arteries / drug effects*
  • Cerebral Arteries / metabolism
  • Cerebral Arteries / physiology
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Peptide Fragments / pharmacology
  • Piperazines / pharmacology*
  • Piperidines / pharmacology*
  • Tumor Cells, Cultured
  • Vasodilation / drug effects


  • 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidine-1-carboxylic acid (1-(3,5-dibromo-4-hydroxybenzyl)-2-oxo-2-(4-phenylpiperazin-1-yl)ethyl)amide
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Peptide Fragments
  • Piperazines
  • Piperidines
  • calcitonin gene-related peptide (8-37)
  • Cyclic AMP
  • Calcitonin Gene-Related Peptide