Skingle M, Beattie D T, Scopes D I, Starkey S J, Connor H E, Feniuk W, Tyers M B
Glaxo Research and Development Ltd., Herts, UK.
Behav Brain Res. 1996;73(1-2):157-61. doi: 10.1016/0166-4328(96)00089-7.
GR127935 is the most potent 5-HT1D receptor antagonist yet described, possessing nanomolar affinity at human 5-HT1D receptors. Sumatriptan-induced contractions of the dog isolated basilar artery and saphenous vein are antagonised by GR127935 in an insurmountable manner indicative of its slow dissociation from the 5-HT1D receptor. 5-HT1D receptor-mediated hypothermia and rotational behaviour in guinea-pigs are antagonised potently, and with long duration, by GR127935, administered by a variety of routes. GR127935 also blocks central 5-HT1D autoreceptors in vitro and in vivo. GR127935 has much lower affinity at other 5-HT, and non-5-HT, receptors. In functional studies, GR127935 fails to affect 5-HT2 receptor-mediated 'wet dog shakes' in guinea-pigs and 5-HT1A receptor-mediated inhibition of 5-HT release in rat dorsal raphé nucleus. The compound has a good safety profile in all species tested. It is concluded that GR127935 is a useful pharmacological tool to characterise 5-HT1D receptor function.
GR127935是迄今所描述的最有效的5-羟色胺1D（5-HT1D）受体拮抗剂，对人5-HT1D受体具有纳摩尔亲和力。GR127935以难以克服的方式拮抗舒马曲坦诱导的犬离体基底动脉和隐静脉收缩，这表明其从5-HT1D受体的解离缓慢。通过多种途径给药的GR127935能有效且长时间地拮抗豚鼠中5-HT1D受体介导的体温过低和旋转行为。GR127935在体外和体内也能阻断中枢5-HT1D自身受体。GR127935对其他5-羟色胺（5-HT）受体和非5-HT受体的亲和力要低得多。在功能研究中，GR127935不会影响豚鼠中5-HT2受体介导的“湿狗摇晃”以及大鼠背缝核中5-HT1A受体介导的5-羟色胺释放抑制。该化合物在所有测试物种中都具有良好的安全性。结论是GR127935是表征5-HT1D受体功能的有用药理学工具。
