Fluspirilene has been claimed to bind to a high affinity site in the calcium channel in skeletal muscle. We have investigated its calcium-antagonistic effects in smooth muscle and affinity for the channel in radioligand binding assays. 2. Fluspirilene was weakly active as an antagonist of Ca2(+)-induced contractions in K(+)-depolarized taenia preparations from the guinea-pig caecum, with threshold antagonism starting from concentrations of 30 nM. Nitrendipine, nicardipine and nimodipine were very potent antagonists in this model (threshold antagonism, greater than 1 nM). 3. In contrast, fluspirilene (10-1000 nM) was a potent non-competitive antagonist of the effects of Bay K 8644 (1-3000 nM) on Ca2(+)-induced contractions and, at 10 nM, selectively antagonised the effects of Bay K 8644, abolished the Ca2(+)-channel activator effects of CGP 28392, without changing the calcium antagonist effects of nitrendipine, or modifying the sensitivity of the tissues to Ca2+. In contrast, the dihydropyridines were more effective as antagonists of Ca2+ than of Bay K 8644. Fluspirilene therefore selectively antagonised the effects of dihydropyridine Ca2+ channel activators without affecting the antagonist potency. 4. In radioligand binding experiments, fluspirilene was a potent displacer of [3H]-PN-200-110 binding to rat cerebral cortical membranes (EC50 30 nM), albeit with a low Hill slope (0.66), and was more potent than other lipophilic diphenylalkylamines such as flunarizine and lidoflazine. Fluspirilene interacted non-competitively with [3H]-PN-200-110 and increased dissociation of the radioligand.
摘要
氟司必林据称可与骨骼肌钙通道中的高亲和力位点结合。我们已在平滑肌中研究了其钙拮抗作用，并通过放射性配体结合试验研究了其对该通道的亲和力。2. 氟司必林作为豚鼠盲肠K⁺去极化的绦虫制剂中Ca²⁺诱导收缩的拮抗剂活性较弱，从30 nM浓度开始出现阈值拮抗作用。尼群地平、尼卡地平和尼莫地平在该模型中是非常有效的拮抗剂（阈值拮抗作用，大于1 nM）。3. 相比之下，氟司必林（10 - 1000 nM）是Bay K 8644（1 - 3000 nM）对Ca²⁺诱导收缩作用的有效非竞争性拮抗剂，在10 nM时，选择性拮抗Bay K 8644的作用，消除了CGP 28392的Ca²⁺通道激活作用，而不改变尼群地平的钙拮抗作用，也不改变组织对Ca²⁺的敏感性。相比之下，二氢吡啶类作为Ca²⁺拮抗剂比作为Bay K 8644拮抗剂更有效。因此，氟司必林选择性拮抗二氢吡啶类Ca²⁺通道激活剂的作用，而不影响拮抗剂效力。4. 在放射性配体结合实验中，氟司必林是[³H]-PN - 200 - 110与大鼠大脑皮层膜结合的有效置换剂（EC₅₀ 30 nM），尽管希尔斜率较低（0.66），且比其他亲脂性二苯基烷基胺如氟桂利嗪和利多氟嗪更有效。氟司必林与[³H]-PN - 200 - 110非竞争性相互作用，并增加放射性配体的解离。
