Reavill C, Taylor S G, Wood M D, Ashmeade T, Austin N E, Avenell K Y, Boyfield I, Branch C L, Cilia J, Coldwell M C, Hadley M S, Hunter A J, Jeffrey P, Jewitt F, Johnson C N, Jones D N, Medhurst A D, Middlemiss D N, Nash D J, Riley G J, Routledge C, Stemp G, Thewlis K M, Trail B, Vong A K, Hagan J J
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, United Kingdom.
J Pharmacol Exp Ther. 2000 Sep;294(3):1154-65.
SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.
SB - 277011 - A（反式 - N - [4 - [2 - (6 - 氰基 - 1,2,3,4 - 四氢异喹啉 - 2 - 基)乙基]环己基] - 4 - 喹啉甲酰胺）是一种能够穿透血脑屏障、具有高亲和力且选择性的多巴胺D(3)受体拮抗剂。在中国仓鼠卵巢（CHO）细胞中分别转染人多巴胺D(3)或D(2长)（hD(3)，hD(2)）受体后进行的放射性配体结合实验表明，SB - 277011 - A对hD(3)受体具有高亲和力（pK(i)=7.95），对hD(2)受体以及其他66种以上的受体、酶和离子通道的选择性高达百倍。从转染大鼠多巴胺D(3)或D(2)受体的CHO细胞中也获得了类似的关于SB - 277011 - A的放射性配体结合数据。在微生理计功能测定中，SB - 277011 - A拮抗了喹吡罗诱导的过表达hD(3)受体的CHO细胞酸化增加（pK(b)=8.3），对hD(2)受体的选择性为80倍。中枢神经系统穿透性研究表明，SB - 277011 - A能够轻易进入大脑。在体内微透析研究中，SB - 277011 - A（2.8毫克/千克，口服）逆转了喹氯烷诱导的伏隔核中多巴胺外流减少，但对纹状体无此作用，这种区域选择性与多巴胺D(3)受体在大鼠脑中的分布一致。SB - 277011 - A（2 - 42.3毫克/千克，口服）不影响自发运动或兴奋剂诱导的运动亢进。SB - 277011 - A（4.1 - 42.2毫克/千克，口服）不能逆转阿扑吗啡或喹吡罗处理的大鼠的前脉冲抑制缺陷，但在口服剂量为3毫克/千克时能显著逆转隔离饲养大鼠的前脉冲抑制缺陷。SB - 277011 - A（2.5 - 78.8毫克/千克，口服）不产生僵住作用，也不升高血浆催乳素水平。因此，多巴胺D(3)受体阻断产生的非选择性多巴胺受体拮抗剂特有的行为效应很少。SB - 277011 - A对隔离诱导的前脉冲抑制缺陷的作用表明，阻断多巴胺D(3)受体可能有助于精神分裂症的治疗。
