Dopamine receptor signaling and current and future antipsychotic drugs.
Dopamine receptor signaling and current and future antipsychotic drugs.
复制标题
DOI：
10.1007/978-3-642-25761-2_3
复制
发表时间：
2012
影响因子：
--
通讯作者：
Mailman RB
中科院分区：
文献类型：
--
作者：
Boyd KN;Mailman RB
目前所有有效的抗精神病药物都具有减弱通过多巴胺D2受体的部分或全部信号传导的能力，这是其机制的一部分。最近，多巴胺D1受体已被假设为治疗精神分裂症的负面和/或认知方面的一个有前途的目标，目前的抗精神病药物不能改善。虽然cAMP被认为是通过多巴胺受体进行信号传导的主要信使，但过去十年揭示了一种复杂性，为未来发现抗精神病药物（APD）提供了令人兴奋的途径。我们回顾了目前批准的APD在多巴胺D2受体上的信号传导机制，并注意到阿立哌唑是一种与其他批准药物明显不同的化合物。虽然阿立哌唑已被假定为引起多巴胺稳定，由于其部分D2激动剂的性质，一个机构的文献表明，替代机制，功能选择性，是最重要的。最后，我们回顾了多巴胺D1受体的信号传导，以及激活D1受体的药物可能作为APD用于改善阴性和认知症状的想法。我们讨论了D1区药物发现的现状及其与新型信号传导机制的关系。我们的结论是，虽然第一个针对多巴胺受体的APD是在半个多世纪前发现的，但最近的研究进展提供了在未来十年内出现新型和/或改进药物的可能性。
All currently efficacious antipsychotic drugs have as part of their mechanism the ability to attenuate some or all of their signaling through the dopamine D2 receptor. More recently, the dopamine D1 receptor has been hypothesized to be a promising target for the treatment of negative and/or cognitive aspects of schizophrenia that are not improved by current antipsychotics. Although cAMP has been presumed to be the primary messenger for signaling through the dopamine receptors, the last decade has unveiled a complexity that has provided exciting avenues for the future discovery of antipsychotic drugs (APDs). We review the signaling mechanisms of currently approved APDs at dopamine D2 receptors, and note that aripiprazole is a compound that is clearly differentiated from other approved drugs. Although aripiprazole has been postulated to cause dopamine stabilization due to its partial D2 agonist properties, a body of literature suggests that an alternate mechanism, functional selectivity, is of primary importance. Finally, we review the signaling at dopamine D1 receptors, and the idea that drugs that activate D1 receptors may have use as APDs for improving negative and cognitive symptoms. We address the current state of drug discovery in the D1 area, and its relationship to novel signaling mechanisms. Our conclusion is that although the first APD targeting dopamine receptors was discovered more than a half-century ago, recent research advances offer the possibility that novel and/or improved drugs will emerge in the next decade.