Boger D L, Patterson J E, Jin Q
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4102-7. doi: 10.1073/pnas.95.8.4102.
Oleamide is an endogenous fatty acid primary amide that possesses sleep-inducing properties in animals and that has been shown to effect serotonergic receptor responses and block gap junction communication. Herein, the potentiation of the 5-HT1A receptor response is disclosed, and a study of the structural features of oleamide required for potentiation of the 5-HT2A and 5-HT1A response to serotonin (5-HT) is described. Of the naturally occurring fatty acids, the primary amide of oleic acid (oleamide) is the most effective at potentiating the 5-HT2A receptor response. The structural features required for activity were found to be highly selective. The presence, position, and stereochemistry of the delta9-cis double bond is required, and even subtle structural variations reduce or eliminate activity. Secondary or tertiary amides may replace the primary amide but follow a well defined relationship requiring small amide substituents, suggesting that the carboxamide serves as a hydrogen bond acceptor but not donor. Alternative modifications at the carboxamide as well as modifications of the methyl terminus or the hydrocarbon region spanning the carboxamide and double bond typically eliminate activity. A less extensive study of the 5-HT1A potentiation revealed that it is more tolerant and accommodates a wider range of structural modifications. An interesting set of analogs was identified that inhibit rather than potentiate the 5-HT2A, but not the 5-HT1A, receptor response, further suggesting that such analogs may permit the selective modulation of serotonin receptor subtypes and even have opposing effects on the different subtypes.
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，并且已被证明会影响血清素能受体反应并阻断间隙连接通讯。本文公开了5-HT1A受体反应的增强作用，并描述了对5-HT2A和5-HT1A对血清素（5-HT）反应增强所需的油酰胺结构特征的研究。在天然存在的脂肪酸中，油酸的一级酰胺（油酰胺）在增强5-HT2A受体反应方面最为有效。发现活性所需的结构特征具有高度选择性。需要δ9-顺式双键的存在、位置和立体化学，即使是细微的结构变化也会降低或消除活性。二级或三级酰胺可以取代一级酰胺，但遵循明确的关系，需要小的酰胺取代基，这表明羧酰胺作为氢键受体而非供体。羧酰胺处的替代修饰以及甲基末端或跨越羧酰胺和双键的烃区域的修饰通常会消除活性。对5-HT1A增强作用的一项不太广泛的研究表明，它更具耐受性，能适应更广泛的结构修饰。鉴定出一组有趣的类似物，它们抑制而非增强5-HT2A受体反应，但不抑制5-HT1A受体反应，这进一步表明此类类似物可能允许对血清素受体亚型进行选择性调节，甚至对不同亚型产生相反的作用。
