Design and Synthesis of New Neuronal nAChR Silent Desensitizers for Drug Abuse

描述(由申请者提供)：为了解决毒瘾的破坏性影响，该项目旨在提供三种潜在的候选药物，以供进一步开发和最终临床应用。滥用药物有不同的作用机制，但有一个共同的途径，导致身体依赖。中脑边缘多巴胺通路被广泛认为是成瘾药物产生奖赏效应的中枢通路。该通路包括中脑腹侧被盖区(VTA)的多巴胺能神经元及其在边缘前脑，特别是伏隔核(NAC)的靶点。所有滥用药物，无论其作用机制如何，都汇聚在VTA-NAC途径上。急性接触成瘾药物会导致多巴胺水平升高，这是一种奖励信号事件，可以促进反复吸食药物。然后，当药物被移除时，产生负面情绪症状的药物会加强成瘾。对与药物有关的环境线索的敏感化和联想学习也会增强成瘾。尼古丁胆碱能受体(NAChRs)可能是治疗多种成瘾的重要靶点，而不仅仅是尼古丁。中枢nAChRs的激活也被证明调节了包括酒精和可卡因在内的其他滥用药物的强化效应。尼古丁胆碱能受体的1422亚型与尼古丁的成瘾特性有关。尼古丁是nAChRs的激动剂，具有激活和脱敏的双重模式。直到最近，这两种激活和脱敏模式还无法脱钩。沙替丁A，一种新的nAChR小分子配体，就是这样做的，在没有首先激活1422受体的情况下选择性地使它们脱敏。初步数据表明，这种分子确实可能被证明是一种治疗成瘾的有趣药物。不幸的是，沙泽替丁A的物理化学性质很差，不能用于进一步的药物开发。沙滋替丁A的对数P值相对较低，极表面积(PSA)值较高，是一种粘性油。低对数P和高PSA表明沙泽替丁A在体内不容易被吸收，并且通过血脑屏障的可能性很低。结晶度的缺乏给进一步的药物开发制造这种化合物带来了问题。本建议的目的是设计和合成具有以下物理化学性质的新的1422选择性脱敏剂：1.最佳的logP值在2到5之间；2.降低PSA约60E_2；以及3.结晶度与熔点大于150℃。公共卫生相关性：吸毒成瘾是一种慢性脑部疾病，具有毁灭性的社会影响。由于毒瘾传统上被视为一个社会问题，而不是一个健康问题，有效的医疗选择存在差异。这项提议旨在通过为药物滥用的医疗干预提供新的治疗剂来解决这一差距。

DESCRIPTION (provided by applicant): To address the devastating effects of drug addiction, this project aims to deliver three potential drug candidates for further development and eventual clinical application. Drugs of abuse have differing mechanisms of action, but share a common pathway toward physical dependency. The mesolimbic dopamine pathway is widely accepted as a central pathway in producing the rewarding effects of addictive drugs. This pathway includes the dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAc). All drugs of abuse, regardless of their mechanisms of actions, converge on the VTA-NAc pathway. Acute exposure to addictive drugs results in the elevation of dopamine levels, a reward signaling event, which promotes repeated drug intake. Addiction is then reinforced by the drugs producing a negative emotional symptom when the drug is removed. Sensitization and associative learning toward drug-related environmental cues also reinforce addiction. The nicotinic cholinergic receptors (nAChRs) may be an important target for the treatment of multiple addictions, not just nicotine. Activation of the central nAChRs has been shown to also mediate the reinforcing effects of other drugs of abuse including alcohol and cocaine. The 1422 subtype of nicotinic cholinergic receptors are implicated in the addictive properties of nicotine. Nicotine is an agonist of nAChRs, and has a dual mode of activation and desensitization. Until recently, these two modes of activation and desensitization could not be decoupled. Sazetidine A, a novel small molecule ligand of nAChR, does just this, selectively desensitizes 1422 receptors without first activating them. Preliminary data suggest that this molecule may indeed prove to be an interesting drug for treating addiction. Unfortunately, sazetidine A has poor physicochemical properties for further drug development. Sazetidine A has a relatively low log P value, a high polar surface area (PSA) value, and is a viscous oil. The low log P and high PSA suggest sazetidine A will not be readily absorbed in vivo and will have a low probability of crossing the blood-brain barrier. The lack of crystallinity poses problems in manufacturing this compound for further drug development. The aims of this proposal are to design and synthesize new 1422-selective desensitizers with the following improved physicochemical properties: 1. optimal log P value between 2 and 5; 2. reduced PSA of approximately 60 E2; and 3. crystallinity with a melting point greater than 150 0C. PUBLIC HEALTH RELEVANCE: Drug addiction is a chronic brain disease with devastating societal impact. Since drug addiction has traditionally been viewed as a social problem, not a health problem, there is a disparity in effective medical treatment options. This proposal is directed at addressing this disparity by providing new therapeutic agents for medical intervention of drug abuse.