Novel lead molecule optimization targeting nicotinic receptor subtypes

描述（由申请人提供）：本R21申请的重点是通过结构引导、计算机辅助合成药物化学方法对新型先导分子进行优化。我们的目标是神经元烟碱乙酰胆碱受体（nAChR）。基于结构的药物设计作为一种“理性”的方法已经相当成功，为50种化合物进入临床试验和许多药物批准做出了贡献。nachr及其许多亚型与许多神经系统疾病有关，如精神分裂症、注意力缺陷多动障碍、阿尔茨海默病、妥瑞氏综合征、帕金森氏病、自闭症和某些类型的癫痫。此外，尼古丁是美国使用最频繁的成瘾性药物之一。考虑到1)它们在生理/病理生理上的重要性，2)过去二十年来在该领域投入的药物发现的时间和精力（和资源），3)该领域的大多数药物发现项目都是针对正位位点[内源性激动剂（乙酰胆碱）结合位点]，以及4)选择性靶向特定亚型nAChR的药物被发现，nAChR药物发现领域需要寻求新的方法。在过去的几年里，我们的实验室研究了一类作为负变构调节剂的新分子。利用计算方法，我们最近在nAChR上发现了一个新的位点，这些分子可能在这里结合。最近，我们发现了一种新的铅分子，可以选择性地抑制42个nachr。这一发现的重要性在于，该分子是通过分子动力学模拟和虚拟筛选确定的，使用我们的人类42 nachr变构位点的计算模型，从而验证了我们的模型并支持了我们提出的方法。我们的假设是，对nAChRs特定亚型上这些变构位点的分子表征和计算建模将导致发现针对nAChRs特定亚型的分子。我们的观点是，变构位点比正构位点存在更大的结构多样性，一旦这些位点被识别和表征，nAChR亚型选择性药物的开发将随之而来。作为概念证明，本R21提案侧重于人类42 nachr的负变构结合位点以及选择性结合该位点的药物（负变构调节剂，NAMs）的发现。我们的目标是1)表征人类42 nachr的变抗结合位点，2)通过结合计算和合成药物化学方法来提高我们的先导分子的效力和选择性。成功将被定义为a)对42个nachr的选择性为1000倍，b)效价增加100至1000倍。

DESCRIPTION (provided by applicant): The focus of this R21 application is novel lead molecule optimization through structure-guided, computer-aided synthetic medicinal chemistry approaches. Our target is the neuronal nicotinic acetylcholine receptor (nAChR). Structure-based drug design as a "rational" method has been quite successful, contributing to the introduction of ~50 compounds into clinical trials and to numerous drug approvals. nAChRs and their many subtypes are linked to a number of neurological diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, autism, and some types of epilepsy. In addition nicotine is one of the most heavily used addictive drugs in the United States. Considering 1) their physisological/pathophysiological importance, 2) the time and effort (and resources) devoted to drug discovery in this area over the past twenty years, 3) most drug discovery programs in this area targeting orthosteric sites [endogenous agonist (acetylcholine) binding sites], and 4) few drugs that are selectively targeting specific subtypes of nAChRs being identified, new approaches in the area of nAChR drug discovery need to be pursued. For the past several years our laboratories have investigated a novel class of molecules that act as negative allosteric modulators. Using computational approaches we have recently identified a novel site on nAChR where these molecules likely bind. Most recently we have identified a novel lead molecule that selectively inhibits 42 nAChRs. The importance of this discovery is that this molecule was identified via molecular dynamics simulation and virtual screening using our computational model of the allosteric site on human 42 nAChRs, thus validating our model and supporting our proposed approaches. Our hypothesis is that molecular characterization and computational modeling of these allosteric sites on specific subtypes of nAChRs will lead to the discovery of molecules that target specific subtypes of nAChRs. Our contention is that greater structural diversity exists in allosteric sites than in orthosteric sites and, once these sites are identified and characterized, the development of nAChR subtype-selective agents will follow. As proof of concept, this R21 proposal focuses on a negative allosteric binding site on human 42 nAChRs and the discovery of drugs that selectively bind this site (negative allosteric modulators, NAMs). Our goals are 1) to characterize the allosteric binding sites on human 42 nAChRs and 2) to improve the potency and selectivity of our lead molecule through combined computational and synthetic medicinal chemistry approaches. Success will be defined as a) selectivity toward 42 nAChRs of 1000 fold, and b) a 100- to 1000-fold increase in potency. PUBLIC HEALTH RELEVANCE: Historically, receptors were identified through the use of specific drugs that altered functional processes mediated by these receptors. From Sir Henry Dale's work with muscarine and nicotine to R.P. Ahlquist's sub- classification of adrenergic receptors, pharmacological identification was the norm. These approaches led 1) to the discovery of the physiological importance of specific receptors, 2) to the identification of new therapeutic targets, and 3) to novel strategies that treat disease. Over the past 25 to 30 years, molecular biological approaches have now identified a host of new receptors and new receptor subtypes. Since these approaches are not linked to receptor-specific drugs, the shear numbers of new receptor subtypes have outstretched the availability of receptor-specific drugs. Nicotinic receptors and their many subtypes are linked to a number of neurological diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, autism, and some types of epilepsy. In addition, nicotine is one of the most heavily used and addictive drugs in the United States; it is estimated that 70 million people 12 and older (or 29 percent of the U.S. population) use cigarettes, cigars and or chewing tobacco products, resulting in ~ 440,000 premature deaths each year with an annual cost of more than $75 billion in direct medical charges. Taking into consideration the importance of these receptors as well as considering the time and effort (and resources) devoted to the discovery of selective molecules over the past twenty years, few drugs that target specific subtypes of nicotinic receptors have been identified. New approaches in the area of nicotinic receptor drug discovery need to be pursued. Our novel target (an allosteric site recently identified by our laboratory), our promising lead molecule (recently identified via virtual screening), and our rational drug design approach (involving computer-aided drug design), provide a promising approach for the discovery of molecules that selectively target specific subtypes of nicotinic receptors.