Weiss B, Prozialeck W, Cimino M, Barnette M S, Wallace T L
Ann N Y Acad Sci. 1980;356:319-45. doi: 10.1111/j.1749-6632.1980.tb29621.x.
A number of psychotropic drugs, particularly the phenothiazines and related antipsychotic compounds, inhibit a variety of calmodulin-dependent enzymes. The mechanism by which these compounds inhibit the activity of calmodulin is through a selective calcium-dependent binding to this protein. With the notable exception of certain stereoisomers, compounds that are clinically effective antipsychotic agents showed the greatest degree of binding to calmodulin. Other classes of pharmacological agents, including aminergic agonists and antagonists, and nonspecific central nervous system depressants and stimulants, showed little or no binding to calmodulin. In fact, the specificity with which antipsychotic drugs bind to calmodulin suggests the possibility of screening for new and clinically more effective antipsychotic agents based on their selective binding to calmodulin. Certain neuropeptides that produce behavioral effects in animals also were found to inhibit the activity of calmodulin, suggesting that there may be endogenous psychotogens or antipsychotic peptides that interact with calmodulin. Although under ordinary conditions the binding of antipsychotics to calmodulin is reversible, the binding of phenothiazine antipsychotics to calmodulin can be made irreversible either photochemically by ultraviolet irradiation, or enzymatically by a hydrogen peroxide-peroxidase system. Such a labeling technique should prove to be a useful tool to study the localization and turnover of calmodulin. These results indicate that several of the diverse biochemical actions of antipsychotic agents can be explained by a common mechanism, namely, by their binding to and inhibition of calmodulin, and raise the possibility that calmodulin may serve as one of the cellular receptors for certain antipsychotic compounds. However, further studies must be completed before we can state with any degree of certainty that these in vitro biochemical findings can explain the pharmacological and clinical actions of the antipsychotics.
许多精神药物，特别是吩噻嗪类及相关抗精神病化合物，会抑制多种钙调蛋白依赖性酶。这些化合物抑制钙调蛋白活性的机制是通过与该蛋白进行选择性钙依赖性结合。除了某些立体异构体这一显著例外，临床有效的抗精神病药物对钙调蛋白的结合程度最高。其他几类药理剂，包括胺能激动剂和拮抗剂，以及非特异性中枢神经系统抑制剂和兴奋剂，对钙调蛋白几乎没有或完全没有结合。事实上，抗精神病药物与钙调蛋白结合的特异性表明，基于它们与钙调蛋白的选择性结合来筛选新的、临床效果更佳的抗精神病药物是有可能的。某些在动物身上产生行为效应的神经肽也被发现能抑制钙调蛋白的活性，这表明可能存在与钙调蛋白相互作用的内源性致精神病原或抗精神病肽。虽然在正常情况下抗精神病药物与钙调蛋白的结合是可逆的，但吩噻嗪类抗精神病药物与钙调蛋白的结合可以通过紫外线照射进行光化学不可逆处理，或通过过氧化氢 - 过氧化物酶系统进行酶促不可逆处理。这种标记技术应被证明是研究钙调蛋白定位和周转的有用工具。这些结果表明，抗精神病药物的多种不同生化作用可以通过一种共同机制来解释，即它们与钙调蛋白结合并抑制其活性，这也增加了钙调蛋白可能作为某些抗精神病化合物的细胞受体之一的可能性。然而，在我们能够确定地说这些体外生化研究结果可以解释抗精神病药物的药理和临床作用之前，还必须完成进一步的研究。
