Human Trial of Allosteric Modulator Alpha7 Nicotinic Receptors in Schizophrenia

描述（由申请人提供）：α 7-尼古丁乙酰胆碱受体是开发改善精神分裂症脑功能新药的研究靶点。该靶点得到了以下方面的支持：(1)电生理证据表明其参与了精神分裂症患者中发现的一种内表型感觉门控障碍；(2)基因证据表明CHRNA7 （α 7-尼古丁受体亚基基因）异常；(3)药理学证据表明尼古丁以及更特异性的α 7-尼古丁激动剂可能具有治疗作用。出现的假设是，精神分裂症患者在海马和丘脑的抑制性中间神经元上α 7-尼古丁受体的表达减少。通过加强对α 7-尼古丁受体群体的药理刺激，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性问题。UCI-40083是一种α - 7-尼古丁受体的变构调节剂，作为该位点的候选治疗药物具有独特的特性。UCI-40083能够选择性地增加通过a7-尼古丁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，使其成为一种安全且潜在有效的药物，可以增加该受体的胆碱能神经传递。在动物模型中显示出良好的安全性和有效性。下一步，国家合作药物研发小组将对UCI-40083作为一种潜在的精神分裂症治疗药物进行评估，包括进行首次人体i期药代动力学和安全性试验、1b期初步剂量发现试验和ii期初步原理验证临床试验，以确定其对神经认知的影响，并进行额外的评估，包括脑成像、药物基因组学、社会心理功能。阳性和阴性症状该药物将通过加州大学欧文分校（University of California Irvine）进行合成，并在科罗拉多大学丹佛分校（University of Colorado Denver）进行测试，该大学此前在阿尔法7-尼古丁受体激动剂治疗精神分裂症神经认知功能障碍的临床评估方面有经验。

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 alpha7-nicotinic receptor subunit, and (3) pharmacological evidence for possible therapeutic effects of nicotine as well as more specific alpha7-nicotinic agonists. The hypothesis that emerges is that persons with schizophrenia have diminished expression of the alpha7-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 alpha7-nicotinic receptors, would improve patients' neurocognitive abilities, particularly their characteristic problems in sustained attention. UCI-40083, an allosteric modulator at the alpha7- 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 alpha7-nicotinic receptor for neurocognitive dysfunction in schizophrenia.