Middlemiss D N, Göthert M, Schlicker E, Scott C M, Selkirk J V, Watson J, Gaster L M, Wyman P, Riley G, Price G W
Department of Neurosciences, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
Eur J Pharmacol. 1999 Jun 30;375(1-3):359-65. doi: 10.1016/s0014-2999(99)00262-9.
A novel compound, SB-236057 (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl- 4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperid ine]) has been shown to have high affinity for human 5-hydroxytryptamine1B (5-HT1B) receptors (pKi = 8.2) and displays over 75 or more-fold selectivity for the human 5-HT1B receptor over other 5-HT receptors, including the human 5-HT1D receptor, and a range of other receptors, ion channels and enzymes. In functional studies using [35S]GTPgammaS binding, SB-236057 displayed negative intrinsic activity (pEC50 = 8.0) at human 5-HT1B receptors stably expressed in Chinese Hamster Ovary (CHO) cells and caused a rightward shift of agonist concentration response curves consistent with competitive antagonism (pA2 = 8.9). SB-236057 potentiated [3H]5-HT release from electrically stimulated guinea pig or human cortical slices. SB-236057 also abolished the inhibitory effect of exogenously superfused 5-HT on electrically-stimulated release from slices of the guinea pig cortex. These studies using SB-236057 confirm that, in both the guinea pig and human cerebral cortex, the terminal 5-HT autoreceptor is of the 5-HT1B subtype.
一种新型化合物SB - 236057（1'-乙基-5-(2'-甲基-4'-(5-甲基-1,3,4-恶二唑-2-基)联苯-4-羰基)-2,3,6,7-四氢螺[呋喃并[2,3-f]吲哚-3,4'-哌啶]）已被证明对人5-羟色胺1B（5-HT1B）受体具有高亲和力（pKi = 8.2），并且对人5-HT1B受体相对于其他5-HT受体，包括人5-HT1D受体以及一系列其他受体、离子通道和酶，表现出超过75倍或更高的选择性。在使用[35S]GTPγS结合的功能研究中，SB - 236057在中国仓鼠卵巢（CHO）细胞中稳定表达的人5-HT1B受体上显示出负性内在活性（pEC50 = 8.0），并导致激动剂浓度反应曲线向右移动，这与竞争性拮抗作用一致（pA2 = 8.9）。SB - 236057增强了电刺激的豚鼠或人皮质切片中[3H]5-HT的释放。SB - 236057还消除了外源性灌注的5-HT对豚鼠皮质切片电刺激释放的抑制作用。这些使用SB - 236057的研究证实，在豚鼠和人的大脑皮质中，终末5-HT自身受体均为5-HT1B亚型。
