Mechanism of Action of L THP as an Alternative Therapy for Cocaine Addiction

L THP 作为可卡因成瘾替代疗法的作用机制

• 批准号: 8369115
• 负责人: DAVID Yue-Wei LEE
• 金额: $ 45.72万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369115
• 关键词: Abstinence; Adverse effects; Affinity; Aftercare; Alcohol abuse; Alkaloids; Alternative Therapies; Amphetamines; Analgesics; Animal Model; Animals; Award; Behavior; Behavioral; Binding; Biochemical Pharmacology; Biological Factors; Brain; China; Clinical; Clinical Trials; Cocaine; Cocaine Dependence; Corydalis; Cues; Dopamine Receptor; Drug Addiction; Drug Kinetics; Drug abuse; Evaluation; Familiarity; Funding; Grant; Hepatocyte; Heroin; Heroin Dependence; In Vitro; Investigation; Ion Channel; Isoquinolines; Laboratories; Lead; Literature; Maryland; Mediating; Metabolism; Methamphetamine; Minor; Mono-S; Motor Activity; Mus; National Center for Complementary and Alternative Medicine; National Institute of Drug Abuse; Neurotransmitter Receptor; Opium; Pain; Pharmaceutical Preparations; Pharmacotherapy; Prodrugs; Property; Psychological reinforcement; Public Health; Rattus; Recording of previous events; Research; Rewards; Sedation procedure; Self Administration; Serum; Smoking; Source; Stress; Techniques; Time; United States National Institutes of Health; Universities; Withdrawal; analog L; base; behavioral sensitization; chemical synthesis; craving; drug candidate; drug development; drug discovery; drug metabolism; drug seeking behavior; hypnotic; in vivo; neurochemistry; preference; programs; receptor; receptor binding; sedative; tetrahydropalmatine

DESCRIPTION (provided by applicant): Cocaine addiction is a vexing public health problem for which no effective pharmacotherapies have been developed. Naturally derived bioactive compounds have been a rich source for modern drug development. Under our CERC program project "Alternative Therapies for Alcohol and Drug Abuse" (P01-AT- 002038) funded by NCCAM, eight isoquinoline alkaloids, including L-tetrahydropalmatine (L-THP), were isolated and characterized from tubers of Corydalis yanhuso, which is one of the five components of an herbal remedy (NPI-025) used in China to treat opium smoking for over 150 years. Interestingly, L-THP has been used clinically in China for more than 30 years as an analgesic with sedative/hypnotic properties and recently to treat heroin addiction. In animal models, L-THP reduced reinforcing property of cocaine and reinstatement of cocaine seeking following withdrawal. Importantly, L-THP itself had no rewarding effect, suggesting absence of abuse liability. Recently, Dr. Jia-Bei Wang of the University of Maryland received an NIH grant to conduct a clinical trial on L-THP for treatment of cocaine addiction in the US. Despite its long history of clinical use, the mechanisms of action of L-THP are not clear. Although some in vivo effects appear to be mediated by dopamine receptors, we found that L-THP had low or no affinity for the five subtypes (D1- D5) of DA receptors (see C.1.2). In addition, it did not bind t about 60 neurotransmitter receptors, ion channels, and transporters involved in pain modulation and drug addiction that we screened (see C.1.2). Following L-THP administration in mice or rats, we identified in serum the mono-demethylated analogs L- corypalmine (L-CP) and L-corydalmine (L-CD) to be the major metabolites and L-isocorypalmine (L-ICP) to be a minor metabolite (see C.1.3). We also found that L-ICP had moderate to high affinity for DA receptors (see C.1.4) and reduced cocaine-induced hyperlocomotion, behavioral sensitization and conditioned place preference (See C.1.5-1.8). Thus, we hypothesize that L-THP is a prodrug and its effects are due to demethylated metabolites acting on multiple DA receptors to modulate cocaine-induced behaviors. Consequently, we propose to further pharmacologically characterize L-THP and its demethylated metabolites to gain a better understanding of the mechanisms of action. Our specific aims are to (1) prepare L-THP and chemically synthesize its metabolites in sufficient quantity for pharmacological studies; (2) determine the metabolism and pharmacokinetic profiles of L-THP; (3) identify pharmacological activity of major metabolites at DA receptors and other targets; and (4) examine the effects of L-THP and its metabolites on cocaine self administration and reinstatement of drug seeking following withdrawal. The proposed research will enhance the understanding of mechanisms of action of L-THP, which may open a new avenue for mechanism-based drug discovery for cocaine addiction. As one of the major side effects of L-THP is sedation, our proposed study may yield candidate drugs with less sedation, as we have demonstrated for L-ICP. PUBLIC HEALTH RELEVANCE: The overall objective is to study the mechanism of action of the natural product L- tetrahydropalmatine (L-THP) as an alternative therapy against cocaine dependence, for which there is no satisfactory pharmacotherapy. Studies in our laboratory and others have shown that L-THP reduced cocaine self- administration, reinstatement of cocaine seeking, cocaine-induced conditioned place preference (CPP), and brain-stimulation enhancement, while having no intrinsic rewarding effect, which suggests absence of abuse liability. Consequently, we propose to further pharmacologically characterize its demethylated metabolites to gain a better understanding of the mechanism of action and to support our hypothesis that it is a prodrug and its effects are due to demethylated metabolites acting on multiple DA receptors to modulate cocaine-induced behaviors and neurochemical changes.

描述（由申请人提供）：可卡因成瘾是一个令人烦恼的公共卫生问题，尚未开发出有效的药物治疗。天然衍生的生物活性化合物已成为现代药物开发的丰富来源。在我们的CERC计划项目“酒精和药物滥用的替代疗法”（P01-AT- 002038）由NCCAM资助，八个异喹啉生物碱，包括L-四氢巴马汀（L-THP），分离和表征从Cordyanhuso的块茎，这是中国用于治疗鸦片吸烟超过150年的草药（NPI-025）的五个成分之一。有趣的是，L-THP作为具有镇静/催眠特性的镇痛药在中国临床使用已有30多年，最近用于治疗海洛因成瘾。在动物模型中，L-THP降低可卡因的增强特性和戒断后可卡因寻求的恢复。重要的是，L-THP本身没有奖励效应，表明没有滥用责任。最近，马里兰州大学的王佳蓓博士获得了美国国立卫生研究院的资助，在美国进行了一项关于L-THP治疗可卡因成瘾的临床试验。尽管L-THP的临床应用历史悠久，但其作用机制尚不清楚。尽管一些体内效应似乎是由多巴胺受体介导的，但我们发现L-THP对DA受体的五种亚型（D1- D5）具有低亲和力或没有亲和力（见C.1.2）。此外，它不结合我们筛选的约60种参与疼痛调节和药物成瘾的神经递质受体、离子通道和转运蛋白（见C.1.2）。在小鼠或大鼠中给予L-THP后，我们在血清中鉴定出单脱甲基类似物L-紫堇碱（L-CP）和L-紫堇达明（L-CD）为主要代谢产物，L-异紫堇碱（L-ICP）为次要代谢产物（见C.1.3）。我们还发现L-ICP对DA受体具有中等至高亲和力（见C.1.4），并减少可卡因诱导的过度运动、行为敏化和条件性位置偏爱（见C.1.5-1.8）。因此，我们假设L-THP是一种前药，其作用是由于去甲基代谢物作用于多种DA受体来调节可卡因诱导的行为。因此，我们建议进一步研究L-THP及其脱甲基代谢产物的特性，以更好地了解其作用机制。我们的具体目标是（1）制备足够量的L-THP并化学合成其代谢产物用于药理学研究;（2）确定L-THP的代谢和药代动力学特征;（3）鉴定主要代谢产物对DA受体和其他靶点的药理活性;（4）研究L-THP及其代谢产物对可卡因自我给药和戒断后复吸的影响。拟议的研究将增进对L-THP作用机制的理解，这可能为基于机制的可卡因成瘾药物发现开辟新途径。由于L-THP的主要副作用之一是镇静，我们提出的研究可能会产生镇静作用较小的候选药物，正如我们已经证明的L-ICP。 公共卫生相关性：总体目标是研究天然产物L-四氢巴马汀（L-THP）作为对抗可卡因依赖的替代疗法的作用机制，对于可卡因依赖没有令人满意的药物疗法。我们实验室和其他实验室的研究表明，L-THP减少了可卡因自我给药、可卡因寻求的恢复、可卡因诱导的条件性位置偏好（CPP）和脑刺激增强，同时没有内在的奖励效应，这表明没有滥用倾向。因此，我们建议进一步研究其去甲基化代谢产物，以更好地了解其作用机制，并支持我们的假设，即它是一种前药，其作用是由于去甲基化代谢产物作用于多种DA受体，以调节可卡因诱导的行为和神经化学变化。