含 α5的 GABAA受体的选择性调节剂及其治疗意义

Title:Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

Volume: 16 Issue: 7

Author(s): Ming Shiuan Soh and Joseph W. Lynch

Affiliation:

关键词: 变构调节剂，α5GABAA受体，老年痴呆，健忘症，唐氏综合症，记忆损伤，益智药，中风。

摘要: GABA_A receptors containing the α₅ subunit (α₅GABA_ARs) are found mainly in the hippocampus where they mediate a tonic chloride leak current and contribute a slow component to GABAergic inhibitory synaptic currents. Their inhibitory effect on the excitability of hippocampal neurons at least partly explains why changes in the level of activity of α₅GABA_ARs affect cognition, learning and memory. These receptors have been implicated as potential therapeutic targets for a range of clinical conditions including age-related dementia, stroke, schizophrenia, Down syndrome and anesthetic- induced amnesia. Accordingly, a range of pharmacological modulators that selectively target α₅GABA_ARs, as either inhibitors or allosteric enhancers, have been developed. Although many of these compounds show therapeutic effects in animal models of the above clinical disorders, none has been marketed yet due to unsuccessful clinical trials and toxicity in humans. These experiments have also revealed paradoxical effects of α₅GABA_AR modulation (e.g., cognitive impairments can be reversed by both positive and negative modulation), suggesting that our knowledge of the physiological roles of α₅GABA_ARs is incomplete. This review highlights the various positive and negative modulators for α₅GABA_ARs that have been developed, key findings concerning their effects in behavioral studies, and their importance across a number of therapeutic fields. It also highlights some of the gaps in our knowledge of the physiological and pathological roles of α5GABAARs.

Cite this article as:

Ming Shiuan Soh and Joseph W. Lynch , Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance, Current Drug Targets 2015; 16 (7) . https://dx.doi.org/10.2174/1389450116666150309120235