Human Trial of Allosteric Modulator Alpha7 Nicotinic Receptors in Schizophrenia

变构调节剂 Alpha7 烟碱受体治疗精神分裂症的人体试验

• 批准号: 8145800
• 负责人: Robert Freedman
• 金额: $ 223.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145800
• 关键词: Human; Trial; Allosteric; Modulator; Alpha7

DESCRIPTION (provided by applicant): The alpha 7-nicotlnic acetylcholine receptor is an investigational target for the development of new drugs to improve brain function in schizophrenia. The target is supported by (1) electrophysiological evidence for its participation in the sensory gating disturbances that are an endophenotype found in persons with schizophrenia, (2) genetic evidence for abnormalities involving CHRNA7, the gene for the a7-nicotinic receptor subunit, and (3) pharmacological evidence for possible therapeutic effects of nicotine as well as more specific a7-nicotinic agonists. The hypothesis that emerges is that persons with schizophrenia have diminished expression of the a7-nicofinic receptor on inhibitory interneurons in the hippocampus and thalamus. Increased activation of these inhibitory interneurons, by enhanced pharmacological stimulation of this diminished population of a7-nicofinic receptors, would improve patients' neurocognitive abilities, particularly their characteristic problems in sustained attention. UCI-40083, an allosteric modulator at the a7- nicotinic receptor, has unique properties as a candidate therapeutic at this site. UCI-40083 has the ability to selectively increase ion currents through the a7-nicotinic receptor channel while retaining fidelity to the agonist-induced kinetics of channel opening and closing, making it a safe and potentially effective drug to increase cholinergic neurotransmission at this receptor. It has shown promising safety and efficacy in animal models. This National Cooperative Drug Discovery Development Group will take the next step to evaluate UCI-40083 as a potential therapeutic for schizophrenia by performing a first-in-humans Phase 1 pharmacokinetics and safety trial, a Phase 1b preliminary dose-finding trial in schizophrenia, and an initial Phase 2 proof-of-principle clinical trial in schizophrenia to determine effects on neurocognition, with additional assessments involving brain imaging, pharmacogenomics, psychosocial function, and positive and negative symptoms. The drug will be synthesized through the University of California Irvine, where it was discovered, and tested at the University of Colorado Denver, which has previous experience with the clinical evaluation of agonists of the a7-nicotinic receptor for neurocognitive dysfunction in schizophrenia. Public Health Relevance: Persistent neurocognitive deficits, psychosocial disability, and negative symptoms are evidence that current neuroleptic therapies, which primarily inhibit dopamine D2 receptors, are insufficient treatment for schizophrenia. Alpha7-nicofinic receptor activation is a potential additional target for drug therapy. UCI- 40083 is the first of a new class of drug that can improve a7-nicotinic receptor function.

描述（由申请人提供）：α7-烟碱乙酰胆碱受体是开发新药以改善精神分裂症脑功能的研究靶点。该目标得到以下支持：(1) 电生理学证据证明其参与感觉门控障碍，这是精神分裂症患者中发现的一种内表型；(2) 涉及 CHRNA7（α7-烟碱受体亚基基因）异常的遗传证据；(3) 尼古丁以及更具体的 α7-烟碱激动剂可能具有治疗作用的药理学证据。出现的假设是，精神分裂症患者海马和丘脑抑制性中间神经元上α7-烟碱受体的表达减少。通过增强对α7-烟碱受体数量减少的药物刺激，增加这些抑制性中间神经元的激活，将改善患者的神经认知能力，特别是他们在持续注意力方面的特征问题。 UCI-40083 是 α7-烟碱受体的变构调节剂，作为该位点的候选治疗剂具有独特的特性。 UCI-40083 能够选择性地增加通过 a7-烟碱受体通道的离子电流，同时保持对激动剂诱导的通道打开和关闭动力学的保真度，使其成为增加该受体胆碱能神经传递的安全且潜在有效的药物。它在动物模型中显示出良好的安全性和有效性。该国家合作药物发现开发小组将采取下一步行动，通过进行首次人体 1 期药代动力学和安全性试验、精神分裂症的 1b 期初步剂量探索试验以及精神分裂症的初步 2 期原理验证临床试验来评估 UCI-40083 作为精神分裂症的潜在治疗方法，以确定对神经认知的影响，并进行涉及大脑的额外评估 影像学、药物基因组学、心理社会功能以及阳性和阴性症状。该药物将在该药物的发现地加州大学欧文分校合成，并在科罗拉多大学丹佛分校进行测试，该大学此前拥有对α7-烟碱受体激动剂治疗精神分裂症神经认知功能障碍进行临床评估的经验。 公共卫生相关性：持续的神经认知缺陷、社会心理障碍和阴性症状证明目前主要抑制多巴胺 D2 受体的精神安定疗法不足以治疗精神分裂症。 α7-烟碱受体激活是药物治疗的潜在附加靶点。 UCI-40083是第一种可以改善α7-烟碱受体功能的新药。