Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells.
Several lines of evidence suggest that a calcitonin-gene related peptide (CGRP) receptor antagonist may serve as a novel abortive migraine treatment. Here we present data on a human cell line and isolated human vessels for such an antagonist, BIBN4096BS. On SK-N-MC membranes, radiolabelled CGRP was displaced by both CGRP-(8-37) and BIBN4096BS, yielding pK(i) values of 8.5 and 11.4, respectively. Functional studies with SK-N-MC cells demonstrated that CGRP-induced cAMP production was antagonised by both CGRP-(8-37) and BIBN4096BS with pA(2) values of 7.8 and 11.2, respectively. Isolated human cerebral, coronary, and omental arteries were studied with a sensitive myograph technique. CGRP induced a concentration-dependent relaxation that was antagonized by both CGRP-(8-37) and BIBN4096BS in a competitive manner. CGRP was a weaker agonist on coronary arteries as compared to intracranial arteries; however, BIBN4096BS was an equally effective antagonist. In human omental arteries, CGRP did not induce relaxation. BIBN4096 had a pA(2) value of 10.1 in cerebral and 10.4 in coronary arteries. The results of clinical trials with BIBN4096BS for acute migraine attacks are awaited with great interest.
Edvinsson
Lars
L
Department of Internal Medicine, Lund University Hospital, 22185 Lund, Sweden. lars.edvinsson@med.lu.se
Alm
Rikard
R
Shaw
Duncan
D
Rutledge
Ruth Z
RZ
Koblan
Kenneth S
KS
Longmore
Jenny
J
Kane
Stefanie A
SA
D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D009852:Omentum / Q000098:blood supply*; D010879:Piperazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010879:Piperazines; D011799:Quinazolines; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant