Harfenist M, Joseph D M, Spence S C, Mcgee D P, Reeves M D, White H L
Department of Organic Chemistry, Wellcome Research Laboratories, Research Triangle Park, North Carolind 27709, USA.
J Med Chem. 1997 Aug 1;40(16):2466-73. doi: 10.1021/jm9608063.
Linear [6.6.6] tricyclic moieties whose center ring is made of two atoms of differing size (here primarily thioxanth-9-ones and phenoxathiins) monosubstituted meta to the sulfur by C(O)NHMe include potent and selective inhibitors of monoamine oxidase A. Similarities with effects on SAR of acylamide and of diazapentacyclic substitution on such rings, including positional variables, the requirement for monomethylation (primary and dialkylated amides are inactive and higher monoalkylated amides show little or no potency), and that sulfur is optimally in sulfone form, suggest that binding to the enzyme occurs similarly in each series. No significantly greater rise in blood pressure was found in rats given sufficient 8 to inhibit most brain and liver MAO A and then followed by oral tyramine than was found on administration of tyramine to controls. This is in contrast to a large blood pressure rise in rats pretreated with phenelzine followed by tyramine, and in accord with the belief that an inhibitor selective for MAO A which is reversibly bound to the enzyme and therefore displaced by any ingested tyramine will not lead to the "cheese effect" (hypertension during treatment with MAO inhibitors usually caused by ingestion of foods containing tyramine).
中心环由两个大小不同的原子构成（此处主要是硫杂蒽 -9- 酮和吩恶噻）的线性 [6.6.6] 三环部分，在硫原子间位被 C(O)NHMe 单取代，其中包括强效且具有选择性的单胺氧化酶 A 抑制剂。这些化合物在酰基酰胺的构效关系以及此类环上二氮杂五环取代（包括位置变量）的影响方面存在相似性，包括单甲基化的要求（伯酰胺和二烷基化酰胺无活性，较高的单烷基化酰胺显示出很小或没有活性），并且硫以砜形式存在时最为理想，这表明在每个系列中与酶的结合方式相似。给予足够剂量的 8 以抑制大多数脑和肝中的单胺氧化酶 A，随后口服酪胺的大鼠，其血压升高幅度并不比给予酪胺的对照组大鼠显著更大。这与先用苯乙肼预处理再给予酪胺的大鼠出现大幅血压升高形成对比，并且符合这样一种观点，即对单胺氧化酶 A 具有选择性且与酶可逆结合从而会被摄入的任何酪胺取代的抑制剂不会导致“奶酪效应”（单胺氧化酶抑制剂治疗期间的高血压通常由摄入含酪胺的食物引起）。
