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

基本信息

批准号：
8541885
负责人：
Robert Freedman
金额：
$ 140.98万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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

项目摘要

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.

描述（由申请人提供）：Alpha 7-Nicotlnic乙酰胆碱受体是开发新药以改善精神分裂症大脑功能的研究靶标。 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激动剂。出现的假设是，精神分裂症患者在海马和丘脑中抑制性中间神经元的α7-脱叶胶受体的表达降低了。通过增强对α7-Nicotinic受体降低的药理刺激，这些抑制性中间神经元的激活增加将提高患者的神经认知能力，尤其是他们在持续关注方面的特征问题。 UCI-40083是Alpha7-烟碱受体的变构调节剂，在该部位具有独特的特性作为候选治疗。 UCI-40083具有通过A7-Nicotinic受体通道选择性增加离子电流的能力，同时保留了对动力学诱导的通道开放和关闭动力学的保真度，使其成为一种安全有效的有效药物，以增加该受体的胆碱能神经递质。它在动物模型中显示出有希望的安全性和功效。 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成像，药物基因组学，社会心理功能以及阳性和阴性症状。该药物将通过加利福尼亚大学的尔湾分校合成，并在科罗拉多大学丹佛分校进行了测试，该药物以前曾在精神分裂症中对α7-Nicotinic受体的激动剂进行临床评估。