Boger D L, Patterson J E, Guan X, Cravatt B F, Lerner R A, Gilula N B
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4810-5. doi: 10.1073/pnas.95.9.4810.
Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and has been shown to effect serotonergic systems and block gap junction communication in a structurally specific manner. Herein, the structural features of oleamide required for inhibition of the gap junction-mediated chemical and electrical transmission in rat glial cells are defined. The effective inhibitors fall into two classes of fatty acid primary amides of which oleamide and arachidonamide are the prototypical members. Of these two, oleamide constitutes the most effective, and its structural requirements for inhibition of the gap junction are well defined. It requires a chain length of 16-24 carbons of which 16-18 carbons appears optimal, a polarized terminal carbonyl group capable of accepting but not necessarily donating a hydrogen bond, a Delta9 cis double bond, and a hydrophobic methyl terminus. Within these constraints, a range of modifications are possible, many of which may be expected to improve in vivo properties. A select set of agents has been identified that serves both as oleamide agonists and as inhibitors of fatty acid amide hydrolase, which is responsible for the rapid inactivation of oleamide.
油酰胺是一种内源性脂肪酸一级酰胺，在动物体内具有诱导睡眠的特性，并且已被证明能以结构特异性的方式影响血清素能系统并阻断缝隙连接通讯。在此，确定了大鼠神经胶质细胞中抑制缝隙连接介导的化学和电传递所需的油酰胺结构特征。有效的抑制剂分为两类脂肪酸一级酰胺，其中油酰胺和花生四烯酸酰胺是典型成员。在这两者中，油酰胺是最有效的，并且其抑制缝隙连接的结构要求已明确界定。它需要16至24个碳的链长，其中16至18个碳似乎最为理想，一个能够接受但不一定提供氢键的极化末端羰基、一个Δ9顺式双键和一个疏水甲基末端。在这些限制范围内，可以进行一系列修饰，其中许多有望改善体内性质。已鉴定出一组特定的试剂，它们既是油酰胺激动剂，又是负责使油酰胺快速失活的脂肪酸酰胺水解酶的抑制剂。
