Characterization of anandamide transport in brain

描述（由申请人提供）：大麻素受体是大麻的分子靶点，大麻是西方社会滥用最广泛的非法药物。它们在中枢神经系统（CNS）参与控制食欲、疼痛、运动和记忆的区域密集表达。这些功能受到大麻素药物的强烈影响，其后果包括食欲刺激、镇痛、欣快和记忆障碍。虽然大麻素药物的药理学现在已经很好地理解了，但大麻素受体通常参与的内源性信号系统仍然很大程度上未被探索。大麻素受体的内源性配体，如anandamide和2-花生四烯酰基甘油（2-AG），已经被描述。Anandamide在神经元去极化过程中产生并释放，并经历一个快速的生物失活过程，包括转运到细胞内和细胞内水解。Anandamide的转运是由一个高亲和力的便利载体系统介导的，其分子结构尚不清楚，而Anandamide的水解是由脂肪酸酰胺水解酶（FAAH）催化的。提出的研究的第一个目的是调查负责阿南达明转运的机制。在当前资助期间进行的实验已经揭示了阿南胺运输的几个一般性质。拟议的研究将扩展这些调查，重点关注FAAH在推动阿南达明内化中的作用。我们提出的研究的第二个目的是确定什么结构决定因素是阿南德酰胺运输。我们之前的研究已经发现了新的阿南胺转运抑制剂。我们将通过设计和合成新的anandamide反酰胺类似物，并测试它们作为选择性转运抑制剂的能力，进一步探索这一过程的结构-活性关系。我们建议的第三个目标是开发有效和选择性的FAAH活性抑制剂。我们实验室之前的研究已经确定了一类新型的氨基甲酸酯基FAAH抑制剂，它具有很强的效力和选择性。我们将在此基础上设计和合成第二代氨基甲酸酯类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和选择性阻断anandamide转运或faah催化anandamide水解的药物的开发奠定基础。总之，通过进一步阐明anandamide失活的机制，我们的研究将为大麻滥用的机制提供新的思路，并有助于制定药物滥用和精神疾病的新策略。

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.