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

用于药物滥用的新型神经元 nAChR 沉默脱敏剂的设计与合成

• 批准号: 7759556
• 负责人: MIKELL PAIGE
• 金额: $ 23.25万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759556
• 关键词: Acute; Address; Affinity; Agonist; Alcohols; Animals; Area; Biological; Blood - brain barrier anatomy; Brain Diseases; Chemicals; Cholinergic Receptors; Chronic; Cocaine; Cues; Cyclic GMP; Data; Dependency; Development; Discrimination; Dopamine; Drug Addiction; Drug abuse; Electronics; Emotional; Evaluation; Event; Exposure to; Funding; Future; Health; Intake; Intervention; Ligands; Mediating; Medical; Midbrain structure; Modification; Muscle Rigidity; Neurons; Nicotine; Nucleus Accumbens; Oils; Pathway interactions; Pharmaceutical Preparations; Principal Investigator; Probability; Property; Prosencephalon; Rewards; Signal Transduction; Social Problems; Surface; Symptoms; Therapeutic Agents; Ventral Tegmental Area; addiction; analog; base; classical conditioning; clinical application; desensitization; design; dopaminergic neuron; drug candidate; drug development; drug metabolism; drug of abuse; drug synthesis; improved; in vivo; interest; meetings; melting; metabolic abnormality assessment; novel; novel therapeutics; physical property; programs; public health relevance; receptor; small molecule

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.

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以供进一步开发和最终临床应用。滥用药物具有不同的作用机制，但具有导致身体依赖的共同途径。中脑边缘多巴胺通路被广泛认为是产生成瘾药物奖赏效应的中心通路。该通路包括中脑腹侧被盖区 (VTA) 的多巴胺能神经元及其前脑边缘系统的靶标，特别是伏隔核 (NAc)。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，会促进重复吸毒。当药物被移除时，药物会产生负面情绪症状，从而加剧成瘾。对与毒品相关的环境线索的敏感性和联想学习也会强化成瘾。烟碱胆碱能受体（nAChR）可能是治疗多种成瘾的重要靶点，而不仅仅是尼古丁。研究表明，中枢 nAChR 的激活还可介导其他滥用药物（包括酒精和可卡因）的增强作用。第 1422 章 烟碱胆碱能受体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，激活和脱敏这两种模式还无法分离。 Sazetidine A 是 nAChR 的一种新型小分子配体，它可以选择性地使 1422 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 的理化性质对于进一步的药物开发来说很差。 Sazetidine A 具有相对较低的 log P 值、较高的极性表面积 (PSA) 值，并且是一种粘性油。低log P和高PSA表明sazetidine A在体内不易被吸收并且穿过血脑屏障的可能性较低。结晶度的缺乏给该化合物的进一步药物开发制造带来了问题。本提案的目的是设计和合成新型1422选择性脱敏剂，其具有以下改进的理化性质： 1. 最佳log P值在2至5之间； 2. PSA降低约60E2； 3.熔点大于150℃的结晶度。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。由于吸毒成瘾传统上被视为社会问题，而不是健康问题，因此有效的医疗选择存在差异。该提案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。