Division of Pharmacotherapies and Medical Consequences of Drug Abuse, National Institute on Drug Abuse, National Institutes of Health, 6001 Executive Boulevard, Suite 4123, Bethesda, MD 20892, USA.
Trends Pharmacol Sci. 2012 Nov;33(11):611-20. doi: 10.1016/j.tips.2012.08.003. Epub 2012 Sep 14.
The discovery of benzodiazepine receptors provided the impetus to discover and develop anxioselective anxiolytics ('Valium without the side effects'). The market potential for an anxioselective based on the γ-aminobutyric acid A (GABA(A)) receptor resulted in clinical trials of multiple compounds. In contrast to the anxioselective profile displayed in preclinical models, compounds such as bretazenil, TPA023, and MRK 409 produced benzodiazepine-like side effects (sedation, dizziness) in Phase I studies, whereas alpidem and ocinaplon exhibited many of the characteristics of an anxioselective in the clinic. Alpidem was briefly marketed for the treatment of anxiety, but was withdrawn because of liver toxicity. Reversible elevations in liver enzymes halted development of ocinaplon in Phase III. The clinical profiles of these two molecules demonstrate that it is possible to develop GABA(A) receptor-based anxioselectives. However, despite the formidable molecular toolbox at our disposal, we are no better informed about the GABA(A) receptors responsible for an anxioselective profile in the clinic. Here, I discuss the evolution of a quest, spanning four decades, for molecules that retain the rapid and robust anti-anxiety actions of benzodiazepines without the side effects that limit their usefulness.
苯二氮䓬受体的发现为发现和开发具有抗焦虑选择性的抗焦虑药（“没有副作用的安定”）提供了动力。基于γ-氨基丁酸 A (GABA(A))受体的抗焦虑选择性的市场潜力导致了多种化合物的临床试验。与临床前模型中显示的抗焦虑选择性特征相反，布瑞他唑仑、TPA023 和 MRK 409 等化合物在 I 期研究中产生了苯二氮䓬样副作用（镇静、头晕），而阿普唑仑和奥沙普仑则在临床上表现出许多抗焦虑选择性的特征。阿普唑仑曾短暂上市用于治疗焦虑症，但因肝毒性而被撤回。奥沙普仑在 III 期因肝酶可逆性升高而停止开发。这两个分子的临床特征表明，开发基于 GABA(A)受体的抗焦虑选择性是可能的。然而，尽管我们拥有强大的分子工具包，但对于在临床上具有抗焦虑选择性的 GABA(A)受体，我们仍然知之甚少。在这里，我讨论了一个长达四十年的探索，旨在寻找既能保留苯二氮䓬类药物的快速而强大的抗焦虑作用，又能避免限制其用途的副作用的分子。
