Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist

H Doods, G Hallermayer, D Wu, M Entzeroth, K Rudolf, W Engel, W Eberlein, H Doods, G Hallermayer, D Wu, M Entzeroth, K Rudolf, W Engel, W Eberlein

Abstract

Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators known. This peptide is increased during migraine attacks and has been implicated in the pathogenesis of migraine headache. Here we report on the first small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an affinity (Ki) for human CGRP receptors of 14.4 +/- 6.3 (n = 4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 micrograms kg-1 (i.v.) inhibited the effects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood flow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist.

Figures

Figure 1
Figure 1
Structural formula of BIBN4096BS.
Figure 2
Figure 2
(A) Concentration-dependent inhibition of BIBN4096BS and CGRP of the specific binding of 125I-CGRP to membranes obtained from the human neuroblastoma cell line SK-N-MC or from rat spleen. (B) Stimulation of cyclic AMP formation in SK-N-MC cells by CGRP alone and in the presence of 10 nM BIBN4096BS. Data are means±s.e.mean.
Figure 3
Figure 3
(A) Representative recording to illustrate the changes in blood pressure and LDF-Flux following electrical trigeminal ganglion stimulation. (B) Dose-dependent inhibition of the facial skin vasodilation induced by trigeminal ganglion stimulation in the marmoset by BIBN4096BS. Data are means±s.e.mean.

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