Watson J, Roberts C, Scott C, Kendall I, Collin L, Day N C, Harries M H, Soffin E, Davies C H, Randall A D, Heightman T, Gaster L, Wyman P, Parker C, Price G W, Middlemiss D N
Neuroscience Research and Department of Medicinal Chemistry, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW.
Br J Pharmacol. 2001 Jul;133(6):797-806. doi: 10.1038/sj.bjp.0704133.
A novel compound, SB-272183 (5-Chloro-2, 3-dihydro-6-[4-methylpiperazin-1-yl]-1[4-pyridin-4-yl]napth-1-ylaminocarbonyl]-1H-indole), has been shown to have high affinity for human 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with pK(i) values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors. [(35)S]-GTPgammaS binding studies showed that SB-272183 acts as a partial agonist at human recombinant 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with intrinsic activities of 0.4, 0.4 and 0.8 respectively, compared to 5-HT. SB-272183 inhibited 5-HT-induced stimulation of [(35)S]-GTPgammaS binding at human 5-HT(1A) and 5-HT(1B) receptors to give pA(2) values of 8.2 and 8.5 respectively. However, from [(35)S]-GTPgammaS autoradiographic studies in rat and human dorsal raphe nucleus, SB-272183 did not display intrinsic activity up to 10 microM but did block 5-HT-induced stimulation of [(35)S]-GTPgammaS binding. From electrophysiological studies in rat raphe slices in vitro, SB-272183 did not effect cell firing rate up to 1 microM but was able to attenuate (+)8-OH-DPAT-induced inhibition of cell firing to give an apparent pK(b) of 7.1. SB-272183 potentiated electrically-stimulated [(3)H]-5-HT release from rat and guinea-pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5-HT(1B) and 5-HT(1D) receptor antagonist, GR127935. Fast cyclic voltammetry studies in rat dorsal raphe nucleus showed that SB-272183 could block sumatriptan-induced inhibition of 5-HT efflux, with an apparent pK(b) of 7.2, but did not effect basal efflux up to 1 microM. These studies show that, in vitro, SB-272183 acts as an antagonist at native tissue 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors.
一种新型化合物SB - 272183（5 - 氯 - 2,3 - 二氢 - 6 - [4 - 甲基哌嗪 - 1 - 基] - 1[4 - 吡啶 - 4 - 基]萘 - 1 - 基氨基羰基] - 1H - 吲哚）已被证明对人5 - HT(1A)、5 - HT(1B)和5 - HT(1D)受体具有高亲和力，其pK(i)值分别为8.0、8.1和8.7，并且在一系列其他受体上的选择性至少为30倍。[(35)S] - GTPγS结合研究表明，与5 - HT相比，SB - 272183在人重组5 - HT(1A)、5 - HT(1B)和5 - HT(1D)受体上作为部分激动剂，内在活性分别为0.4、0.4和0.8。SB - 272183抑制5 - HT诱导的人5 - HT(1A)和5 - HT(1B)受体上[(35)S] - GTPγS结合的刺激，pA(2)值分别为8.2和8.5。然而，从大鼠和人背缝核的[(35)S] - GTPγS放射自显影研究来看，SB - 272183在高达10 microM时未显示内在活性，但确实阻断了5 - HT诱导的[(35)S] - GTPγS结合的刺激。从体外大鼠缝核切片的电生理研究来看，SB - 272183在高达1 microM时不影响细胞放电率，但能够减弱(+)8 - OH - DPAT诱导的细胞放电抑制，表观pK(b)为7.1。SB - 272183在100和1000 nM时增强了大鼠和豚鼠皮质切片中电刺激诱导的[(3)H] - 5 - HT释放，这与先前使用5 - HT(1B)和5 - HT(1D)受体拮抗剂GR127935获得的结果相似。大鼠背缝核的快速循环伏安法研究表明，SB - 272183可以阻断舒马曲坦诱导的5 - HT外流抑制，表观pK(b)为7.2，但在高达1 microM时不影响基础外流。这些研究表明，在体外，SB - 272183在天然组织5 - HT(1A)、5 - HT(1B)和5 - HT(1D)受体上作为拮抗剂起作用。
