GR127935 - A POTENT AND SELECTIVE 5-HT1D RECEPTOR ANTAGONIST

GR127935 is the most potent 5-HT1A receptor antagonist yet described, possessing nanomolar affinity at human 5-HT1D receptors. Sumatriptan-i nduced contractions of the dog isolated basilar artery and saphenous v ein are antagonised by GR127935 in an insurmountable manner indicative of its slow dissociation from the 5-HT1D receptor. 5-HT1D receptor-me diated hypothermia and rotational behaviour in guinea-pigs are antagon ised potently, and with long duration, by GR127935, administered by a variety of routes. GR127935 also blocks central 5-HT1D autoreceptors i n vitro and in vivo. GR127935 has much lower affinity at other 5-HT, a nd non-5-HT, receptors. In functional studies, GR127935 fails to affec t 5-HT2 receptor-mediated 'wet dog shakes' in guinea-pigs and 5-HT1A r eceptor-mediated inhibition of 5-HT release in rat dorsal raphe nucleu s. The compound has a good safety profile in all species tested. It is concluded that GR127935 is a useful pharmacological tool to character ise 5-HT1D receptor function.