McCall R B, Huff R, Chio C L, TenBrink R, Bergh C L, Ennis M D, Ghazal N B, Hoffman R L, Meisheri K, Higdon N R, Hall E
Department of Neurobiology and Structural, Analytical and Medicinal Chemistry, Pharmacia Corporation, Kalamazoo, MI 49001, USA.
Cephalalgia. 2002 Dec;22(10):799-806. doi: 10.1046/j.1468-2982.2002.00459.x.
The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.
本研究描述了一种高选择性5-HT1D受体激动剂PNU-142633的临床前药理学特性。PNU-142633与人5-HT1D受体结合的解离常数（Ki）为6 nM，与人5-HT1B受体结合的Ki大于18000 nM。在基于细胞传感器的实验中，PNU-142633在人5-HT1D受体上的内在活性经测定为5-HT的70%，而舒马曲坦为84%。在预防三叉神经节电刺激诱导的血浆蛋白外渗方面，PNU-142633与舒马曲坦效果相当，且效力比舒马曲坦高半对数。与舒马曲坦一样，与溶剂对照组相比，PNU-142633可减少三叉神经节电刺激引起的猫三叉神经尾侧核血流增加。在血管床中评估了PNU-142633的直接血管收缩潜力。舒马曲坦可增加颈动脉、脑膜动脉和冠状动脉的血管阻力，而PNU-142633未能改变这些血管床的阻力。结合PNU-142633在II期急性偏头痛研究中的临床发现对这些数据进行了讨论。
