Human Trial of Allosteric Modulator Alpha7 Nicotinic Receptors in Schizophrenia

描述（由申请人提供）：α 7-烟碱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。该靶标得到以下方面的支持：（1）其参与感觉门控障碍的电生理学证据，感觉门控障碍是在精神分裂症患者中发现的内表型，（2）涉及CHRNA 7（α 7-烟碱受体亚基的基因）的异常的遗传学证据，和（3）尼古丁以及更特异性的α 7-烟碱激动剂的可能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中抑制性中间神经元上的α 7-烟碱受体表达减少。通过增强对这种减少的α 7-烟碱受体群体的药理学刺激，这些抑制性中间神经元的激活增加，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α 7-烟碱受体的变构调节剂，具有作为该位点的候选治疗剂的独特性质。UCI-40083具有选择性地增加通过α 7-烟碱受体通道的离子电流的能力，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处的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。这个国家合作药物发现开发小组将采取下一步措施，通过进行首次人体1期药代动力学和安全性试验，1b期初步剂量探索试验，以及初步的2期精神分裂症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药物，以确定对神经认知的影响，其他评估包括脑成像、药物基因组学、心理社会功能以及阳性和阴性症状。该药物将由发现该药物的加州尔湾大学合成，并在科罗拉多丹佛大学进行测试，该大学先前在精神分裂症神经认知功能障碍的α 7-烟碱受体激动剂的临床评估方面有经验。 公共卫生相关性：持续的神经认知缺陷、心理社会残疾和阴性症状是目前主要抑制多巴胺D2受体的精神抑制剂疗法不足以治疗精神分裂症的证据。α 7-烟碱受体活化是药物治疗的潜在额外靶标。UCI- 40083是第一个能改善α 7-烟碱受体功能的新药。

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.