Investigation of Neoclerodanes as Novel Opioid Ligands

新克莱丹作为新型阿片类配体的研究

基本信息

批准号：
7424261
负责人：
THOMAS EDWARD PRISINZANO
金额：
$ 0.91万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7424261
关键词：
Absence of pain sensation Affect Affinity Agonist American Analgesics Attenuated Behavior Behavioral Biological Factors Brain Part Central Nervous System Stimulants Chemicals Chronic Cocaine Cocaine Abuse Condition Data Development Diterpenes Drug Addiction Drug Resistant Tuberculosis Drug abuse European Evaluation Event Genus Mentha Goals HIV HIV-1 Health Hepatitis B Human In Vitro Internet Investigation Knowledge Lead Ligands Literature Mediating Methamphetamine Modeling Modification Molecular Conformation Morbidity - disease rate Opioid Opioid Receptor Outcome Pain Pathology Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacology Physiological Processes Plants Property Psychological reinforcement Public Health Relapse Reporting Research Research Personnel Role Salvia Sedation procedure Self Administration Stimulus Structure System Teenagers Testing Thinking Time United States United States Food and Drug Administration Up-Regulation Ursidae Family Work analog base chemical group dependence relapse design dynorphin receptor dysphoria expectation in vivo innovation insight interest kappa opioid receptors neoclerodane neuropsychiatry nonhuman primate novel novel therapeutics programs psychostimulant receptor receptor function receptor structure function response salvinorin A stimulant abuse therapeutic target tool transmission process

项目摘要

Stimulant abuse (e.g cocaine and methamphetamine) is a major public health problem in the United States. The abuse of CMS stimulants potentiates the impact and progression of HIV-1, hepatitis B and C, and drug resistant tuberculosis. A large body of evidence indicates that kappa opioid receptors may be involved in the modulation of some abuse related effects of CNS stimulants. Thus, kappa opioid receptors offer a pharmacological target to treat stimulant abuse and its attendant pathology, as well as, various types of pain. Kappa opioid receptors have also been implicated in the actions of Salvia divinorum, a hallucinogenic mint plant that is currently unscheduled and readily available to the public over the internet. Due to the recent increase in the popularity of Salvia divinorum among both European and American teens, the DEA has recently placed it on the list of drugs to watch. It is predictable that its misuse will increase rapidly. In addition, few studies have been conducted on the pharmacological mode of action of Salvia divinorum or its active component, salvinorin A. The central hypothesis of this proposal is that structural modification of salvinorin A will lead to identification of novel kappa opioid receptor ligands with the potential to treat drug dependence and its relapse. The long-term goal of this research is to more fully understand the role of kappa opioid receptor function in treating drug dependence, as well as in hallucinogenic-like activity. The specific aims of this proposal are (1) identify novel ligands for kappa opioid receptors based on the structure of the natural product salvinorin A and (2) identify the role of structural conformation on salvinorin A's affinity and activity. The innovative approach employed in this proposal utilizes medicinal chemistry, in vitro pharmacology and in vivo pharmacology to achieve our goals. This proposal represents a new template for the study of kappa opioid receptors ligands in drug dependence and analgesia.

刺激性滥用（例如可卡因和甲基苯丙胺）是美国的主要公共卫生问题。 CMS刺激剂的滥用增强了HIV-1，乙型肝炎和C的影响和进展，药物抗性结核病。大量证据表明，卡帕阿片类药物受体可能参与调节中枢神经系统兴奋剂的某些滥用相关影响。因此，Kappa阿片类药物受体提供治疗刺激性滥用及其随之病理学的药理目标，以及各种类型疼痛。卡帕阿片受体也与幻影剂萨尔维亚神经的作用有关目前不定期的薄荷植物可以通过互联网为公众提供。由于最近在欧美青少年中，萨尔维亚神经的普及，DEA有最近将其列入了观看的毒品清单。可以预见的是，它的滥用将迅速增加。在此外，很少有关于萨尔维亚神经或ITS的药理学作用方式的研究活性成分，Salvinorin A.该提案的中心假设是萨尔维诺蛋白A将导致对新型Kappa阿片受体配体的鉴定，并具有治疗药物的潜力依赖及其复发。这项研究的长期目标是更充分了解Kappa的作用阿片受体在治疗药物依赖性以及幻觉样活性中的功能。具体该提案的目的是（1）根据基于结构的结构来确定Kappa阿片受体的新型配体天然产品salvinorin a和（2）确定结构构象对萨尔维诺蛋白A的亲和力的作用活动。该提案中采用的创新方法利用药物化学，体外药理学和体内药理学以实现我们的目标。该建议代表了一个新模板对药物依赖性和镇痛的Kappa阿片受体配体的研究。