Fezza Filomena, De Simone Chiara, Amadio Daniele, Maccarrone Mauro
Department of Experimental Medicine and Biochemical Sciences, University of Rome, Rome, Italy.
Subcell Biochem. 2008;49:101-32. doi: 10.1007/978-1-4020-8831-5_4.
The family of endocannabinoids contains several polyunsaturated fatty acid amides such as anandamide (AEA), but also esters such as 2-arachidonoylglycerol (2-AG). These compounds are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of Delta9-tetrahydrocannabinol (Delta9-THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA at its receptors is limited by cellular uptake, through a putative membrane transporter, followed by intracellular degradation by fatty acid amide hydrolase (FAAH). Growing evidence demonstrates that FAAH is the critical regulator of the endogenous levels of AEA, suggesting that it may serve as an attractive therapeutic target for the treatment of human disorders. In particular, FAAH inhibitors may be next generation therapeutics of potential value for the treatment of pathologies of the central nervous system, and of peripheral tissues. Investigations into the structure and function of FAAH, its biological and therapeutic implications, as well as a description of different families of FAAH inhibitors, are the topic of this chapter.
内源性大麻素家族包含几种多不饱和脂肪酸酰胺，如花生四烯乙醇胺（AEA），也包含酯类，如2-花生四烯酸甘油酯（2-AG）。这些化合物是大麻素受体的主要内源性激动剂，能够模拟Δ9-四氢大麻酚（Δ9-THC）的多种药理作用，Δ9-THC是大麻制剂（如哈希什和大麻）的活性成分。AEA在其受体上的活性受细胞摄取限制，通过一种假定的膜转运蛋白，随后被脂肪酸酰胺水解酶（FAAH）进行细胞内降解。越来越多的证据表明，FAAH是AEA内源性水平的关键调节因子，这表明它可能是治疗人类疾病的一个有吸引力的治疗靶点。特别是，FAAH抑制剂可能是治疗中枢神经系统和外周组织疾病的具有潜在价值的下一代治疗药物。本章的主题是对FAAH的结构和功能、其生物学和治疗意义以及不同家族的FAAH抑制剂进行研究。
