Kunovac J L, Stahl S M
Clinical Neuroscience Research Center, University of California, San Diego, USA.
Psychiatr Clin North Am. 1995 Dec;18(4):895-909.
It seems that psychopharmacology may be well on its way toward the goal of developing new anxiolytic drug(s) that are fast acting and free from the unwanted effects associated with the traditional benzodiazepines. Several specific candidates exist, based upon rational targeting of neurotransmitter receptors shown to be linked to the neurobiology of anxiety. Thus, partial agonists at the benzodiazepine receptor, such as alpidem, abecarnil, and bretazenil, have highly promising preclinical profiles, and some useful preliminary results in clinical testing of anxiety disorder subjects. Neurosteroids are another interesting set of pharmacologic agents that target the benzodiazepine receptor, have a preclinical anxiolytic profile, and now need to be tested in clinical populations. Targeting of various serotonin (5HT) receptor subtypes is a very active area of current research for novel anxiolytic agents. 5HT3 antagonists may have an anxiolytic profile, but clinical results are still preliminary and need more validation. Of considerable interest is the idea of developing new drugs that act at 5HT1A, 5HT2A, or 5HT2C receptors. It has even been proposed that simultaneous targeting of both 5HT2A and 5HT1A receptors could result in robust anxiolytic agents that will have more immediate onset of action than currently available 5HT1A receptor acting drugs. Neuropeptide receptor agonists and antagonists with anxiolytic properties may represent one of the most striking new classes of potential anxiolytic drugs, but this is an emerging field that still requires considerably more systematic clinical testing. Nevertheless, preclinical studies as well as early clinical studies suggest that at least three neuropeptide receptors are provocative targets for novel anxiolytic agents: namely antagonists for CCK-B receptors, antagonists for CRF receptors, and agonists for neuropeptide Y receptors. Rational development of new pharmacologic agents based upon targeting receptors for those neurotransmitters that regulate the neurobiology of anxiety promises to bring forth a number of exciting therapeutic agents for the treatment of anxiety disorders in the future.
看来，精神药理学可能正朝着开发新型抗焦虑药物的目标稳步迈进，这些药物起效迅速，且没有传统苯二氮䓬类药物的不良副作用。基于对已证明与焦虑神经生物学相关的神经递质受体的合理靶向，有几种特定的候选药物。因此，苯二氮䓬受体的部分激动剂，如阿吡坦、阿贝卡尼和布雷替奈，具有非常有前景的临床前特征，并且在焦虑症患者的临床试验中取得了一些有用的初步结果。神经甾体是另一类有趣的药理剂，它们靶向苯二氮䓬受体，具有临床前抗焦虑特征，现在需要在临床人群中进行测试。针对各种5-羟色胺（5HT）受体亚型是目前新型抗焦虑药物研究非常活跃的领域。5HT3拮抗剂可能具有抗焦虑特征，但临床结果仍处于初步阶段，需要更多验证。开发作用于5HT1A、5HT2A或5HT2C受体的新药的想法备受关注。甚至有人提出，同时靶向5HT2A和5HT1A受体可能会产生强效抗焦虑药物，其起效速度将比目前可用的作用于5HT1A受体的药物更快。具有抗焦虑特性的神经肽受体激动剂和拮抗剂可能代表了最引人注目的新型潜在抗焦虑药物类别之一，但这是一个新兴领域，仍需要进行大量更系统的临床试验。然而，临床前研究以及早期临床研究表明，至少有三种神经肽受体是新型抗焦虑药物的有吸引力的靶点：即CCK-B受体拮抗剂、CRF受体拮抗剂和神经肽Y受体激动剂。基于针对调节焦虑神经生物学的神经递质受体来合理开发新的药理剂，有望在未来带来许多令人兴奋的治疗焦虑症的药物。
