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: 8051558
• 负责人: Karla-Sue Camille Marriott
• 金额: $ 8.67万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051558
• 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; Health; 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; 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）：吸毒是美国日益关注的一个普遍问题。与艾滋病毒阳性的人共享注射药物，例如针头或注射器，是黑人男性和黑人妇女中艾滋病毒感染艾滋病毒的第二多数方式。两组传播的最常见方式是与患有艾滋病毒的男人的无保护性。由于使用毒品，尤其是甲基苯丙胺的使用（非裔美国人之间的增加）通常与更高的无保护性别发生率有关，因此可以认为，与HIV传播作斗争的适当策略是治疗吸毒成瘾。对吸毒者的验尸研究表明，在大脑的中唇区域中，D3受体的水平升高，负责奖励和愉悦感。多巴胺D3受体的浓度明显大于中脑旁区域中多巴胺D2受体的浓度，这支持D3受体可能是有效治疗干预以帮助治疗成瘾的结论的结论。 D3的密度，没有观察到D2受体的d2受体升高。此外，在慢性暴露于可卡因的个体中观察到了相似的增加，已知会加重和沉淀精神病状态。提高认知能力，反向障碍以及解决导致药物成瘾的导致精神病的药物是成功康复疗法的优先事项。据报道，苯唑并且中衍生物具有抗抑郁剂的特性，在治疗慢性神经系统疾病中非常有用，包括癫痫，中风，阿尔茨海默氏病，药物滥用和与艾滋病有关的痴呆引起的脑损伤。我们在该项目中的直接目标是确定新型苯甲酸苯甲酸苯甲酸苯甲胺-6-12-12-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。通常，我们希望协助开发D3受体选择性拮抗剂或部分激动剂，以用作抗成瘾相关精神病的抗精神病药。这项工作的具体目的是（1）完善生产新型D3受体选择配体的合成途径； （2）确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：a）在5-羟色胺5-HT受体上表现出高至适度亲和力的配体，b）b）配体具有选择性和/或对多巴胺受体D3和/或D2的良好亲和力。使用伏安法的大鼠伏隔核中，将评估配体具有选择性和/或对多巴胺受体D3和/或D2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理解D3受体在成瘾中的作用，并有助于开发用于中枢神经系统疾病的治疗药团。公共卫生相关性：拟议的研究与多巴胺D3受体选择性药物的发展有关，用于治疗成瘾。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恢复成瘾者的心理健康，并减少复发的可能性。

项目成果

Synthesis of N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides as new selective ligands for sigma receptors.

合成 N-苯基-N-(3-(哌啶-1-基)丙基)苯并呋喃-2-甲酰胺作为 σ 受体的新选择性配体。

• DOI: 10.1016/j.bmc.2012.09.044
• 发表时间: 2012
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Marriott,Karla-SueC;Morrison,AndrewZ;Moore,Misty;Olubajo,Olarongbe;Stewart,LeonardE
• 通讯作者: Stewart,LeonardE

Expedited Synthesis of Benzofuran-2-Carboxylic Acids via Microwave-Assisted Perkin Rearrangement Reaction.

通过微波辅助 Perkin 重排反应快速合成苯并呋喃-2-羧酸。

• DOI: 10.1016/j.tetlet.2012.04.075
• 发表时间: 2012
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Marriott,Karla-SueC;Bartee,Rena;Morrison,AndrewZ;Stewart,Leonard;Wesby,Julian
• 通讯作者: Wesby,Julian