Synthesis of Novel Agents for use in Addiction Treatment

描述（由申请人提供）：吸毒成瘾在美国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，与艾滋病毒阳性的人共用针头或注射器等注射药物是感染艾滋病毒的第二常见方式。这两种人群最常见的传播方式是与携带艾滋病毒的男性发生无保护的性行为。因为毒品的使用，尤其是在非裔美国人中不断增加的甲基苯丙胺的使用，通常与无保护的性行为的发生率较高有关，因此可以推断，对抗艾滋病毒传播的适当策略是治疗毒瘾。对吸毒成瘾者的死后研究表明，在负责奖赏和愉悦感觉的大脑中边缘区域，D3受体水平升高。中脑边缘区多巴胺D3受体的浓度显著高于多巴胺D2受体的浓度，支持D3受体可能是有效治疗干预的关键靶点，以协助治疗成瘾。在未接受治疗的精神病患者中，D3受体而非D2受体的密度升高。此外，在长期暴露于可卡因的个体中也观察到类似的增加，已知可卡因会加重和沉淀精神状态。通过药物治疗提高认知能力，逆转损伤，以及解决药物成瘾导致的精神病是成功康复治疗的优先事项。据报道，苯扎平衍生物具有抗抑郁特性，在治疗慢性神经系统疾病方面非常有用，包括癫痫、中风、阿尔茨海默病、药物滥用和与艾滋病有关的痴呆症造成的脑损伤。我们在这个项目中的直接目标是确定新型苯并呋喃-苯并氮-6-12-二酮衍生物的多巴胺D1， D2, D3, D4， D5和5-羟色胺5-HT受体的结合亲和力。总的来说，我们希望协助开发D3受体选择性拮抗剂或部分激动剂，用于治疗成瘾相关精神病的抗精神病药物。这项工作的具体目的是：(1)完善一种新的潜在D3受体选择性配体的合成途径；(2)测定各新合成配体的多巴胺D1、D2、D3、D4、D5和5-羟色胺5-HT受体结合亲和力；(3)进行功能分析：a)对5-羟色胺5-羟色胺受体具有高至中等亲和力的配体；b)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。对多巴胺受体D3和/或D2具有选择性和/或良好亲和力的配体的生理效应将通过伏安法对大鼠伏隔核的DA清除进行评估。该项目的长期目标是有助于更好地理解D3受体在成瘾中的作用，并协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成瘾治疗的多巴胺D3受体选择性药物有关。该项目的成果将对成瘾研究和康复治疗领域的进步作出重大贡献。总的来说，这项研究预计将有助于促进康复成瘾者的心理健康，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.