Synthesis of Novel Agents for use in Addiction Treatment

用于成瘾治疗的新型药物的合成

• 批准号: 7895391
• 负责人: Karla-Sue Camille Marriott
• 金额: $ 13.9万
• 依托单位: SAVANNAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895391
• 关键词: AIDS Dementia Complex; Accounting; Acquired Immunodeficiency Syndrome; Address; Adult; Adverse effects; Affect; Affinity; African American; Age; Agonist; Alcohol or Other Drugs use; Alcohols; Alzheimer' s Disease; Amphetamines; Antipsychotic Agents; Area; Benzazepines; Binding; Biological Assay; Bisexual; Brain; Brain Injuries; Brain region; Cannabis; Case Study; Cause of Death; Centers for Disease Control and Prevention (U.S.); Central Nervous System Diseases; Chronic; Cities; Cocaine; Cognitive; Communicable Diseases; Communities; Contracts; County; Crack Cocaine; Data; Dependence; Development; Dopamine; Dopamine D2 Receptor; Drug Addiction; Drug abuse; Drug usage; Epilepsy; Exhibits; Feeling; Gays; Goals; HIV; HIV Infections; HIV Seropositivity; Hispanics; Homelessness; Impairment; Incidence; Individual; Infection; Injection of therapeutic agent; Investigation; Ligands; Literature; Major Depressive Disorder; Maps; Mediating; Mental Health; Mental disorders; Methamphetamine; Minority; Modification; National Institute of Allergy and Infectious Disease; National Institute of Mental Health; Needles; New York; Nucleus Accumbens; Pathway interactions; Patients; Personality Disorders; Persons; Pharmaceutical Preparations; Physicians; Physiological; Population; Preclinical Drug Evaluation; Prevalence; Process; Production; Property; Psychotic Disorders; Rattus; Rehabilitation Research; Rehabilitation therapy; Relapse; Reporting; Research; Rewards; Risk; Role; Route; Serotonin; Stroke; Syringes; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; United States; United States National Center for Health Statistics; Universities; Unsafe Sex; Woman; Work; addiction; cocaine exposure; density; dopamine D3 receptor; drug addict; experience; fighting; improved; man; medical schools; men; methamphetamine abuse; nervous system disorder; novel; pharmacophore; pleasure; programs; public health relevance; receptor; receptor binding; research study; serotonin receptor; skills; success; transmission process

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.

描述（由申请人提供）：药物成瘾是美国日益关注的一个普遍问题。与艾滋病毒阳性者共用针头或注射器等注射毒品是黑人男性和黑人女性感染艾滋病毒的第二种最常见方式。这两个群体最常见的传播方式是通过与感染艾滋病毒的男子发生无保护措施的性行为。由于吸毒，特别是甲基苯丙胺的使用，这是在非洲裔美国人中的增加往往与无保护性行为的发生率较高，那么可以推理，一个适当的战略，打击艾滋病毒的传播是治疗吸毒成瘾。对吸毒者的尸检研究表明，负责奖励和快乐感觉的大脑中脑边缘区域的D3受体水平升高。中脑边缘区多巴胺D3受体的浓度显著大于多巴胺D2受体的浓度，这支持了D3受体可能是有效治疗干预以帮助治疗成瘾的关键靶标的结论。在停止治疗的精神病患者中，观察到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观察到类似的增加，已知可卡因会加重和沉淀精神病状态。改善认知技能、逆转损伤以及解决因药物成瘾而导致的精神病的药物治疗是成功康复治疗的优先事项。苯并氮杂衍生物已被报道具有抗癫痫性质，并且在治疗慢性神经系统疾病中非常有用，包括由癫痫、中风、阿尔茨海默病、药物滥用和艾滋病相关痴呆引起的脑损伤。本项目的近期目标是确定新型苯并呋喃并苯并氮杂卓-6-12-二酮衍生物的多巴胺D1、D2、D3、D4、D5和5-羟色胺5-HT受体结合亲和力。总的来说，我们希望有助于开发D3受体选择性拮抗剂或部分激动剂，用作治疗成瘾相关精神病的抗精神病药。本工作的具体目的是（1）改进用于生产新的潜在D3受体选择性配体的合成途径;（2）测定每种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）对以下进行功能测定：a）对5-羟色胺5-HT受体表现出高至中等亲和力的配体和B）对多巴胺受体D3和/或D2表现出选择性和/或良好亲和力的配体。将使用伏安法评价对多巴胺受体D3和/或D2表现出选择性和/或良好亲和力的配体对大鼠延髓核中DA清除的生理作用。该项目的长期目标是促进更好地理解D3受体在成瘾中的作用，并协助开发中枢神经系统疾病的治疗药效团。公共卫生关系：所提出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，以及减少复发的可能性。