Novel, subtype selective potentiators of nicotinic acetycholine receptors

描述（由申请人提供）：尼古丁受体与广泛的神经系统疾病有关，包括阿尔茨海默病（AD）、精神分裂症、自闭症、额叶癫痫、帕金森病、妥瑞特综合征和注意力缺陷障碍。鉴于人们对尼古丁受体在神经系统疾病中的作用的认识日益增加，人们对开发旨在改变这一重要受体家族的表达或功能的治疗方法产生浓厚的兴趣也就不足为奇了。一种针对nAChR亚型的新策略是识别“非常规”或变构调节剂。高选择性调节剂在研究疾病过程和作为潜在的治疗药物方面极有价值。不幸的是，目前可用的增强剂通常具有广泛的选择性（尽管最近在7种选择性增强剂方面取得了一些进展）。最近从苔藓虫中获得的一种天然产物的发现，为开发一类新的选择性调节剂提供了令人兴奋的机会。该化合物（d-甲酰基氟溴化- dFBr）是a4b2 nAChRs的高选择性正变构调节剂。与我们的合作者一起，我们合成了dFBr并评估了其对a4b2受体的作用。这种化合物显示出许多特性，使其成为理想的铅分子。我们的数据表明，dFBr可以选择性地扩增乙酰胆碱反应，而反应动力学几乎没有变化。本研究的主要目的是：1)表征dFBr类化合物与a4b2受体的相互作用；2)合成和表征新的、优化的dFBr型配体。这些独立但相互协同的目标集中在发展对dFBr作用及其与这一重要受体的相互作用的基本理解。我们已经在这两个目标上取得了重大进展。初步的诱变数据表明，在亚基界面上有一个假定的结合位点，相当于GABA受体的苯二氮杂类结合位点，我们在初步的合成研究中发现了一种改进的dFBr类似物，它保留了增强a4b2受体的能力，但没有高浓度时dFBr本身存在的抑制成分。目前的建议将我们的研究扩展到表征dFBr对a4b2受体的作用，绘制结合域和开发精炼的dFBr药效团。公共卫生相关性：该项目探索了最近发现的天然产物“d-甲酰氟虫胺”（最初从北海发现的苔藓虫或“海苔”物种中获得）作为一类新型药物的先导分子的潜力，这些药物旨在治疗中枢神经系统疾病，如阿尔茨海默病、自闭症和精神分裂症。这项研究的目标是将天然产品开发成更可用的形式，具有更高的效力和更少的潜在副作用。由于这是一种新型药物，它可能为了解和治疗这些疾病开辟新的途径。

DESCRIPTION (provided by applicant): Nicotinic receptors have been implicated in a broad range of neurological disorders including Alzheimer's disease (AD), Schizophrenia, Autism, Frontal Lobe Epilepsy, Parkinson's disease, Tourette Syndrome and Attention Deficit Disorder. Given the increasing awareness of the role of nicotinic receptors in neurological disorders, it is not surprising that there is intense interest in developing therapeutics aimed at altering the expression or function of this important receptor family. A novel strategy for targeting nAChR subtypes is the identification of "unconventional" or allosteric modulators. Highly selective modulators would be extremely valuable in investigating disease processes and as potential therapeutic drugs. Unfortunately, currently available potentiating agents typically display broad selectivity (although there have been some recent advances in 7 selective potentiators). The recent discovery of a natural product obtained from the Bryozoan, Flustra foliacea provides an exciting opportunity to develop a new class of selective modulatory agents. This compound (d-formylflustrabromide - dFBr) is a highly selective positive allosteric modulator of a4b2 nAChRs. Along with our collaborators, we have synthesized dFBr and evaluated its action on a4b2 receptors. This compound displays a number of properties that make it an ideal lead molecule. Our data suggest that dFBr would provide selective amplification of ACh responses with little change in response kinetics. The primary aims of this proposal are to: 1) Characterize the interaction of the dFBr class of compounds with the a4b2 receptor and 2) Synthesize and characterize new, optimized dFBr type ligands. These independent but mutually synergistic aims are focused on developing a fundamental understanding of dFBr action and interaction with this important receptor. We have already made significant progress in both aims. Preliminary mutagenesis data indicates a putative binding site at a subunit interface equivalent to the benzodiazepine binding site of GABA receptors and we have identified an improved dFBr analog in our preliminary synthetic studies that retains the ability to potentiate a4b2 receptors but without the inhibitory component at high concentrations that is a problem with dFBr itself. The current proposal expands our studies to characterization of dFBr's actions on the a4b2 receptor, mapping the binding domain and developing a refined dFBr pharmacophore. PUBLIC HEALTH RELEVANCE: This project explores the potential of a recently discovered natural product "d- formylflustrabomide" (obtained originally from a species of Bryozoan or "Sea Mat" found in the North Sea) as a lead molecule for a new class of drugs aimed at the treatment of CNS disorders such as Alzheimer's disease, Autism and Schizophrenia. The goal of this study is to develop the natural product into a more usable form with increased potency and less potential side effects. Since this is a new type of drug, it may open up new avenues for understanding and treating these diseases.