Synthesis of Novel Agents for use in Addiction Treatment

用于成瘾治疗的新型药物的合成

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：吸毒成瘾是美国日益关注的一个普遍问题。与艾滋病毒呈阳性的人共用针头或注射器等注射毒品工作是黑人男性和黑人女性感染艾滋病毒的第二常见方式。对于这两个群体来说，最常见的传播方式是通过与感染艾滋病毒的男性进行无保护的性行为。由于非裔美国人中吸毒，特别是甲基苯丙胺的使用不断增加，往往与无保护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吸毒成瘾。对吸毒者的尸检研究表明，负责奖赏和愉悦感的大脑中边缘区域的 D3 受体水平升高。中边缘区域多巴胺 D3 受体的浓度明显高于多巴胺 D2 受体的浓度，这支持了以下结论：D3 受体可能是有效治疗干预的关键靶标，以协助治疗成瘾。在停止治疗的精神病患者中观察到 D3 受体的密度升高，而非 D2 受体的密度升高。此外，在长期接触可卡因的个体中也观察到类似的增加，已知可卡因会加剧和加速精神病状态。成功康复治疗的首要任务是通过药物治疗来提高认知技能、扭转损伤以及解决因毒瘾而导致的精神病。据报道，苯并氮杂卓衍生物具有抗抑郁特性，并且在治疗慢性神经系统疾病方面非常有用，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。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杂-6-12-二酮衍生物的多巴胺 D1、D2、D3、D4、D5 和血清素 5-HT 受体结合亲和力。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，用作治疗成瘾相关精神病的抗精神病药。这项工作的具体目标是 (1) 完善生产新型潜在 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和血清素5-HT受体结合亲和力； (3) 对以下各项进行功能测定：a) 对血清素 5-HT 受体表现出高至中等亲和力的配体，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。将使用伏安法对大鼠伏核中的DA清除率评估对多巴胺受体D3和/或D2表现出选择性和/或良好亲和力的配体的生理效应。该项目的长期目标是有助于更好地了解 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治疗成瘾的多巴胺 D3 受体选择性药物有关。该项目的结果将极大地促进成瘾研究和康复治疗领域的进步。总体而言，这项研究预计将有助于促进成瘾者康复中的心理健康，并降低复发的可能性。