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 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.
Department of Internal Medicine, Lund University Hospital, S-22185 Lund, Sweden. lars.edvinsson@med.lu.se
L
L
Edvinsson
A
A
Sams
I
I
Jansen-Olesen
J
J
Tajti
S A
SA
Kane
R Z
RZ
Rutledge
K S
KS
Koblan
R G
RG
Hill
J
J
Longmore
D000818:Animals; D001667:Binding, Competitive; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002462:Cell Membrane / Q000378:metabolism; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014664:Vasodilation / Q000187:drug effects
C425984:4-(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; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010446:Peptide Fragments; D010879:Piperazines; D010880:Piperidines; C058636:calcitonin gene-related peptide (8-37); D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide