Characterization of anandamide transport in brain

大脑中 anandamide 转运的表征

• 批准号: 7261171
• 负责人: Daniele Piomelli
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-14 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261171
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Affect; Affinity; Amides; Amines; Analgesics; Arachidonic Acids; Area; Automobile Driving; Behavioral; Biological; Biological Process; Brain; Cannabinoids; Carbamates; Carrier Proteins; Cells; Class; Count; Desire for food; Development; Drug abuse; Emotions; Endocannabinoids; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Euphoria; Funding; G-Protein-Coupled Receptors; Generations; Genetic; Grant; Hydrolysis; In Vitro; Investigation; Knowledge; Ligands; Light; Marijuana; Marijuana Abuse; Mediating; Memory; Memory impairment; Mental disorders; Modeling; Molecular; Molecular Structure; Molecular Target; Movement; Mus; Neuraxis; Neurons; Pain; Pharmaceutical Preparations; Pharmacology; Play; Process; Property; Publications; Regulation; Relative (related person); Research; Role; Role playing therapy; Route; Signal Transduction; Societies; Specific qualifier value; Staging; Structure-Activity Relationship; Substance abuse problem; System; Testing; Therapeutic; Transmembrane Transport; analog; anandamide; base; cannabinoid receptor; carrier mediated transport; design; driving force; drug of abuse; fatty acid amide hydrolase; in vivo; inhibitor/antagonist; innovation; mutant; novel; novel strategies; pharmacophore; research study; response; scaffold; transport inhibitor

DESCRIPTION (provided by applicant): Cannabinoid receptors are molecular targets for marijuana, the most widespread illegal drug of abuse in Western societies. They are densely expressed in areas of the central nervous system (CNS) that participate in the control of appetite, pain, movement and memory. Such functions are strongly affected by cannabinoid drugs, with consequences that include appetite stimulation, analgesia, euphoria, and memory impairment. Although the pharmacology of cannabinoid drugs is now fairly well understood, the endogenous signaling system by which cannabinoid receptors are normally engaged remains largely unexplored. Endogenous ligands for cannabinoid receptors, such as anandamide and 2-arachidonylglycerol (2-AG), have been described. Anandamide is produced in and released from neurons on depolarization, and undergoes a rapid process of biological inactivation consisting of transport into cells and intracellular hydrolysis. Anandamide transport is mediated by a high-affinity facilitated carrier system, the molecular structure of which remains unknown, while anandamide hydrolysis is catalyzed by the enzyme fatty acid amide hydrolase (FAAH). The first aim of the proposed research is to investigate the mechanisms responsible for anandamide transport. Experiments conducted during the current funding period have revealed several general properties of anandamide transport. The proposed studies will extend these investigations, focusing on the role played by FAAH in driving anandamide internalization. The second aim of our proposed research is to determine what the structural determinants are for anandamide transport. Our previous investigations have led to the discovery of novel inhibitors of anandamide transport. We will further explore the structure-activity relationship of this process by designing and synthesizing novel reverse-amide analogs of anandamide and testing them for the ability to act as selective transport inhibitors. The third aim of our proposal is to develop potent and selective inhibitors of FAAH activity. Previous studies from our lab have identified a novel class of carbamate-based FAAH inhibitors, which are highly potent and selective. We will build on this knowledge to design and synthesize a second generation of carbamate-based FAAH inhibitors, and to investigate the molecular basis of their interaction with FAAH. These studies will set the stage for the molecular characterization of the anandamide transporter protein and for the development of agents that selective block anandamide transport or FAAH-catalyzed anandamide hydrolysis. In conclusion, by further elucidating the mechanisms of anandamide deactivation, our studies will shed new light on the mechanisms of marijuana abuse and help develop novel strategies for substance abuse and psychiatric disorders.

描述（由申请人提供）：大麻素受体是大麻的分子靶标，大麻是西方社会最广泛滥用的非法药物。它们在参与控制食欲、疼痛、运动和记忆的中枢神经系统（CNS）区域密集表达。这些功能受到大麻素药物的强烈影响，其后果包括刺激食欲、镇痛、欣快感和记忆障碍。尽管大麻素药物的药理学现已相当了解，但大麻素受体通常参与的内源信号系统仍然很大程度上未被探索。大麻素受体的内源配体，例如大麻素和 2-花生四烯酸甘油 (2-AG)，已被描述。 Anandamide 在去极化时在神经元中产生和释放，并经历快速的生物失活过程，包括转运到细胞和细胞内水解。 Anandamide 运输由高亲和力促进载体系统介导，其分子结构仍未知，而 Anandamide 水解由脂肪酸酰胺水解酶 (FAAH) 催化。拟议研究的首要目的是研究花生四烯酸乙醇胺运输的机制。在当前资助期间进行的实验揭示了大麻素运输的几个一般特性。拟议的研究将扩展这些研究，重点关注 FAAH 在驱动 anandamide 内化中所发挥的作用。我们提出的研究的第二个目标是确定 anandamide 运输的结构决定因素是什么。我们之前的研究发现了新型 anandamide 转运抑制剂。我们将通过设计和合成新型 anandamide 的反向酰胺类似物并测试它们作为选择性转运抑制剂的能力，进一步探索该过程的构效关系。我们提案的第三个目标是开发 FAAH 活性的有效和选择性抑制剂。我们实验室之前的研究已经鉴定出一类新型的基于氨基甲酸酯的 FAAH 抑制剂，它们具有高度的效力和选择性。我们将基于这些知识来设计和合成第二代基于氨基甲酸酯的 FAAH 抑制剂，并研究它们与 FAAH 相互作用的分子基础。这些研究将为 anandamide 转运蛋白的分子表征以及开发选择性阻断 anandamide 转运或 FAAH 催化的 anandamide 水解的试剂奠定基础。总之，通过进一步阐明 anandamide 失活机制，我们的研究将为大麻滥用机制提供新的线索，并有助于制定针对药物滥用和精神疾病的新策略。