Synthesis of Novel Agents for use in Addiction Treatment

描述(申请人提供)：在美国，吸毒成瘾是一个日益受到关注的普遍问题。在黑人男性和黑人女性中，与艾滋病毒阳性者共用针头或注射器等注射毒品是感染艾滋病毒的第二常见方式。对这两个群体来说，最常见的传播方式是与携带艾滋病毒的男子发生无保护措施的性行为。由于毒品使用，特别是在非裔美国人中日益增加的甲基苯丙胺的使用，往往与更高的无保护措施的性行为发生率有关，因此可以推断，抗击艾滋病毒传播的适当战略是治疗毒瘾。对吸毒者的尸检研究表明，负责奖赏和愉悦感觉的大脑中缘区D3受体水平升高。多巴胺D3受体在中脑边缘区域的浓度明显高于多巴胺D2受体，支持D3受体可能是有效治疗干预辅助治疗成瘾的关键靶点的结论。在非治疗精神病患者中观察到D3受体密度升高，而不是D2受体密度升高。此外，在长期接触可卡因的个人中也观察到类似的增加，已知可卡因会加剧和加速精神状态。改善认知技能、扭转损伤以及解决因吸毒成瘾而产生的精神病的药物治疗是成功康复治疗的优先事项。苯扎西平衍生物已被报道具有抗抑郁特性，并在治疗慢性神经疾病方面非常有用，包括癫痫、中风、阿尔茨海默病、药物滥用和艾滋病相关性痴呆症引起的脑损伤。我们在这个项目中的直接目标是确定新型苯并呋喃-苯扎西平-6-12-二酮衍生物的多巴胺D1、D2、D3、D4、D5和5-羟色胺5-羟色胺受体结合亲和力。总的来说，我们希望帮助开发D3受体选择性拮抗剂或部分激动剂，作为抗精神病药物用于成瘾相关精神病的治疗。这项工作的具体目标是：(1)改进合成新的潜在D3受体选择性配体的合成途径；(2)测定每个新合成的配体与多巴胺D1、D2、D3、D4、D5和5-羟色胺受体的亲和力；(3)对以下两种配体进行功能分析：a)对5-羟色胺受体表现出高到中等的亲和力，b)对多巴胺受体D3和/或D2表现出选择性和/或良好的亲和力。用伏安法研究对多巴胺受体D3和/或D2具有选择性和/或良好亲和力的配体对大鼠伏隔核DA清除的生理影响。该项目的长期目标是帮助更好地了解D3受体在成瘾中的作用，并帮助开发治疗中枢神经系统疾病的药效团。公共卫生相关性：拟议的研究与开发用于治疗成瘾的多巴胺D3受体选择性药物有关。该项目的成果将大大促进成瘾研究和康复治疗领域的进步。总体而言，这项研究有望有助于促进戒毒康复者的心理健康，并减少复发的可能性。

DESCRIPTION (provided by applicant): Drug addiction is a widespread problem of increasing concern in the United States. Sharing injection drug works such as needles or syringes with someone who is HIV positive is the second-most-common way of contracting HIV among both black men and black women. The most common way of transmission for both groups is through unprotected sex with a man who has HIV. Because drug use and particularly methamphetamine use, which is on the increase among African-Americans is often associated with higher incidence of unprotected sex, then it can be reasoned that an appropriate strategy for fighting HIV transmission is to treat drug addiction. Post-mortem studies of drug addicts indicate elevated levels of D3 receptors in the mesolimbic regions of the brain responsible for feelings of reward and pleasure. The concentration of dopamine D3 receptors is significantly greater than that of dopamine D2 receptors in the mesolimbic regions supporting the conclusion that D3 receptors may be critical targets for effective therapeutic intervention to assist in treating addiction. The density of D3, not D2 receptors was observed to be elevated in off-treatment psychotic patients. Additionally, similar increases were observed in individuals chronically exposed to cocaine, known to aggravate and precipitate psychotic states. Medication to improve cognitive skills, reverse impairments, as well as address the resultant psychosis experienced as a consequence of addiction to drugs is a priority for successful rehabilitation therapy. Benzazepine derivatives have been reported to possess anti-depressant properties and are quite useful in the treatment of chronic neurological disorders including brain damage resulting from epilepsy, stroke, Alzheimer's disease, drug abuse and AIDS-related dementia. Our immediate objective in this project is to determine dopamine D1, D2, D3, D4, D5 and serotonin 5-HT receptor binding affinities of novel benzofuro-benzazepine-6-12-dione derivatives. In general, we expect to assist in the development of D3 receptor selective antagonists or partial agonists for use as antipsychotics in the treatment of addiction-related psychosis. The specific aims of this work are to (1) refine a synthetic pathway for production of novel potential D3 receptor selective ligands; (2) determine dopamine D1, D2, D3, D4, D5 and serotonin 5-HT receptor binding affinities of each newly synthesized ligand; (3) Perform functional assays on: a) ligands exhibiting high to modest affinity at serotonin 5-HT receptors and b) ligands exhibiting selectivity and/or good affinity for dopamine receptors D3 and/or D2. The physiological effect of ligands exhibiting selectivity and/or good affinity for dopamine receptors D3 and/or D2 will be evaluated on DA clearance in the nucleus accumbens of rats using voltammetry. The long- term goal of this project is to contribute to a better understanding of the role of D3 receptors in addiction as well as to assist in the development of a therapeutic pharmacophore for central nervous system disorders. PUBLIC HEALTH RELEVANCE: The proposed studies are relevant to the development of dopamine D3 receptor selective medicinal agents for use in the treatment of addiction. The results from this project will contribute significantly to advancements in the area of addiction research and rehabilitation treatment. Overall this research is expected to assist in promoting the mental health of recovering addicts as well as reduce the possibility of relapse.