Neuroleptics of the diphenylbutylpiperidine series are potent calcium channel inhibitors.
Neuroleptics of the diphenylbutylpiperidine series are potent calcium channel inhibitors.
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DOI：
10.1073/pnas.83.19.7513
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发表时间：
1986-10
影响因子：
11.1
通讯作者：
J. Galizzi;M. Fosset;G. Romey;P. Laduron;M. Lazdunski
中科院分区：
文献类型：
--
作者：
J. Galizzi;M. Fosset;G. Romey;P. Laduron;M. Lazdunski
[3H]Fluspirilene 是二苯基丁基哌啶系列的精神安定分子，以高亲和力与骨骼肌横管膜结合，Kd 为 0.11 +/- 0.04 nM，[3H]fluspirilene 结合与 (-)-[3H]desmethoxyverapamil [(-)[3H]D888] 的结合之间存在 1:1 化学计量比，(-)-[3H]desmethoxyverapamil [(-)[3H]D888] 是最有效的 Ca2+ 通道抑制剂。 Ca2+ 通道抑制剂，例如 D888、维拉帕米、加洛帕米、贝普地尔或地尔硫卓，除了拮抗 (-)[3H]-D888 结合外，还可拮抗 [3H]fluspirilene 结合。抗精神病药，尤其是二苯基丁基哌啶家族的抗精神病药，也拮抗 (-)[3H]D888 结合和 [3H]fluspirilene 结合。 [3H]fluspirilene 结合实验中发现的亲和力与 (-)[3H]D888 结合实验中发现的亲和力之间存在极好的相关性。对这些交叉抑制特性的分析表明，[3H]fluspirilene 结合的位点与苯烷基胺衍生物（加洛帕米、维拉帕米、地尔硫卓和苄普地尔）的位点不同。电压钳实验表明，fluspirilene 是电压依赖性 Ca2+ 通道的有效抑制剂，在 0.1-0.2 nM 附近实现半最大效应，在 1 nM 时几乎完全阻断。氟螺林阻断几乎没有电压依赖性。
[3H]Fluspirilene, a neuroleptic molecule of the diphenylbutylpiperidine series, binds to skeletal muscle transverse tubule membranes with a high affinity corresponding to a Kd of 0.11 +/- 0.04 nM, A 1:1 stoichiometry was found between [3H]fluspirilene binding and the binding of (-)-[3H]desmethoxyverapamil [(-)[3H]D888], one of the most potent Ca2+ channel inhibitors. Ca2+ channel inhibitors such as D888, verapamil, gallopamil, bepridil, or diltiazem antagonize [3H]fluspirilene binding besides antagonizing (-)[3H]-D888 binding. Neuroleptics, especially those of the diphenylbutylpiperidine family, also antagonize both (-)[3H]D888 binding and [3H]fluspirilene binding. There is an excellent correlation between affinities found from [3H]fluspirilene binding experiments and those found from (-)[3H]D888 binding experiments. Analysis of the properties of these cross-inhibitions indicates that [3H]fluspirilene binds to a site that is not identical to that for phenylalkylamine derivatives (gallopamil, verapamil, diltiazem, and bepridil). Voltage-clamp experiments have shown that fluspirilene is an efficient inhibitor of the voltage dependent Ca2+ channel, achieving a half-maximal effect near 0.1-0.2 nM and nearly complete blockade at 1 nM. Fluspirilene blockade has little voltage dependence.