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

描述（由申请人提供）：为了解决药物成瘾的破坏性影响，该项目旨在提供三种潜在的候选药物，用于进一步开发和最终的临床应用。药物滥用有不同的作用机制，但有一个共同的途径，以身体依赖。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心通路。这条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，特别是丘脑核（NAc）的靶点。所有滥用药物，无论其作用机制如何，都集中在VTA-NAc途径上。急性暴露于成瘾性药物导致多巴胺水平升高，这是一种奖励信号事件，促进了重复的药物摄入。当药物被移除时，药物会产生负面的情绪症状，从而加强成瘾。对与毒品有关的环境线索的敏感化和联想学习也会加强成瘾。烟碱胆碱能受体（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nAChR的激活也被证明介导其他滥用药物（包括酒精和可卡因）的强化作用。烟碱胆碱能受体的1422亚型与尼古丁的成瘾特性有关。尼古丁是nAChR的激动剂，并且具有激活和脱敏的双重模式。直到最近，这两种模式的激活和脱敏不能解耦。氮杂环丁烷A是一种新型的nAChR小分子配体，它可以选择性地使1422种受体脱敏，而不首先激活它们。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，sazetidine A的物理化学性质差，无法进一步开发药物。氮杂环丁烷A具有相对低的log P值、高的极性表面积（PSA）值，并且是粘性油。低log P和高PSA表明沙泽替丁A在体内不易吸收，穿过血脑屏障的可能性较低。结晶度的缺乏在制造用于进一步药物开发的该化合物中造成问题。本论文的目标是设计合成具有以下物理化学性质的新型1422选择性脱敏剂：1。最佳log P值在2和5之间; 2. PSA降低约60 E2;和3.熔点大于150 ℃的结晶度。公共卫生相关性：药物成瘾是一种慢性脑部疾病，具有破坏性的社会影响。由于吸毒成瘾传统上被视为一个社会问题，而不是一个健康问题，因此在有效的医疗选择方面存在差异。该提案旨在通过提供用于药物滥用的医学干预的新治疗剂来解决这种差异。

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.