A PHARMACOLOGICAL PROFILE OF THE SELECTIVE SILENT 5-HT1A RECEPTOR ANTAGONIST, WAY-100635
A PHARMACOLOGICAL PROFILE OF THE SELECTIVE SILENT 5-HT1A RECEPTOR ANTAGONIST, WAY-100635
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DOI：
10.1016/0014-2999(95)00234-c
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发表时间：
1995-07-25
影响因子：
5
通讯作者：
FLETCHER, A
中科院分区：
文献类型：
--
作者：
FORSTER, EA;CLIFFE, IA;FLETCHER, A
WAY-100635 (N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]N-2-(2-吡啶基)环己烷甲酰胺三盐酸盐)是一种非手性苯基哌嗪衍生物，能够以高亲和力和选择性与 5-HT1A 受体结合。 WAY-100635 取代了 5-HT1A 放射性配体 [H-3]8-OH-DPAT（8-羟基-2-（二正丙氨基）四氢化萘）与大鼠海马膜的特异性结合，pIC(50) 为 8.87。相对于其他 5-HT 受体亚型和主要神经递质受体、再摄取和离子通道位点的结合，这代表了超过 100 倍的选择性。在功能测定中，WAY-100635 是一种有效的 5-HT1A 受体拮抗剂，没有任何 5-HT1A 受体激动剂或部分激动剂活性的证据。在分离的豚鼠回肠中，WAY-100635 是 5-羧酰胺色胺 5-HT1A 受体激动剂作用的有效且高浓度的拮抗剂，表观 pA(2) 值（0.3 nM）为 9.71。 WAY-100635 以本身没有抑制作用的剂量阻断 8-OH-DPAT 对麻醉大鼠中缝背神经元放电的抑制作用。在行为模型中，WAY-100635本身没有诱导明显的行为变化，但有效拮抗大鼠和豚鼠中8-OH-DPAT诱导的行为综合征（最小有效剂量分别为皮下注射0.003 mg/kg，皮下注射ID50 = 0.01 mg/kg）。 WAY-100635 还可以阻断 8-OH-DPAT 在小鼠和大鼠中引起的体温过低，皮下 ID50 值为 0.01 mg/kg。这些数据表明WAY-100635将在5-HT1A受体功能的进一步研究中用作标准拮抗剂。
WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-2-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride) is an achiral phenylpiperazine derivative that binds with high affinity and selectivity to the 5-HT1A receptor. WAY-100635 displaced specific binding of the 5-HT1A radioligand, [H-3]8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) to rat hippocampal membranes with a pIC(50) of 8.87. This represented a greater than 100-fold selectivity relative to binding at other 5-HT receptor subtypes and major neurotransmitter receptor, reuptake and ion channel sites. In functional assays, WAY-100635 was a potent 5-HT1A receptor antagonist, with no evidence of any 5-HT1A receptor agonist or partial agonist activity. In the isolated guinea-pig ileum WAY-100635 was a potent and, at high concentrations, an insurmountable antagonist of the 5-HT1A receptor agonist action of 5-carboxamidotryptamine, with an apparent pA(2) value (at 0.3 nM) of 9.71. WAY-100635 blocked the inhibitory action of 8-OH-DPAT on dorsal raphe neuronal firing in the anaesthetised rat at doses which had no inhibitory action per se. In behavioural models, WAY-100635 itself induced no overt behavioural changes but potently antagonised the behavioural syndrome induced by 8-OH-DPAT in the rat and guinea-pig (minimum effective dose = 0.003 mg/kg s.c, and ID50 = 0.01 mg/kg s.c., respectively). WAY-100635 also blocked the hypothermia induced by 8-OH-DPAT in the mouse and rat with ID50 values of 0.01 mg/kg s.c. These data indicate that WAY-100635 will be used as a standard antagonist in further studies of 5-HT1A receptor function.