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 ®rst small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an a nity (K i ) for human CGRP receptors of 14.4+6.3 (n=4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 mg kg 71 (i.v.) inhibited the e ects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood¯ow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist.

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1 The novel Y1-selective argininamide derivative BIBO 3304 ((R)-N- [[4-(aminocarbonylaminomethyl)phenyl]methyl]-N 2 -(diphenylacetyl)-argininamide tri¯uoroacetate) has been synthesized and was examined for its subtype selectivity, its in vitro antagonistic properties and its food intake inhibitory properties. 2 BIBO 3304 displayed subnanomolar anity for both the human and the rat Y1 receptor (IC 50 values 0.38+0.06 nM and 0.72+0.42 nM, respectively). The inactive enantiomer of BIBO 3304 (BIBO 3457) had low anity for both the human and rat Y1 receptor subtype (IC 50 41000 nM). BIBO 3304 showed low anity for the human Y2 receptor, human and rat Y4 receptor as well as for the human and rat Y5 receptor (IC 50 values 41000 nM). 3 30 mg BIBO 3304 administered into the paraventricular nucleus inhibited the feeding response induced by 1 mg NPY as well as the hyperphagia induced by a 24 h fast implying a role for Y1 receptors in NPY mediated feeding. The inactive enantiomer had no eect. 4 BIBO 3304 inhibits neither the galanin nor the noradrenaline induced orexigenic response, but it blocked feeding behaviour elicited by both [Leu 31 , Pro 34 ]NPY and NPY (3 ± 36) suggesting an interplay between dierent NPY receptor subtypes in feeding behavior. 5 The present study reveals that BIBO 3304 is a subtype selective nonpeptide antagonist with subnanomolar anity for the Y1 receptor subtype that signi®cantly inhibits food intake induced by application of NPY or by fasting.

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