The Influence of Some 1-Substituted 6-Methoxy-1,2,3,4-tetrahydro-β-carbolines on the Metabolism and Activity of 5-Hydroxytryptamine
The Influence of Some 1-Substituted 6-Methoxy-1,2,3,4-tetrahydro-β-carbolines on the Metabolism and Activity of 5-Hydroxytryptamine
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一些1-取代的6-甲氧基-1,2,3,4-四氢-β-咔啉对5-羟色胺代谢和活性的影响
DOI：
10.1021/jm00322a005
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发表时间：
1966
影响因子：
7.3
通讯作者：
B. Panczenko
中科院分区：
文献类型：
--
作者：
R. Gryglewski;S. Misztal;J. Spławiński;B. Panczenko
1-（2-吡啶基）-、1-（3-吡啶基）-和1-（4-吡啶基）-6-甲氧基-1，2，3，4-四氢-β-咔啉由5-甲氧基色胺和相应的吡啶醛制备。在体外和体内测试了这三种化合物和先前获得的六种其他的Maryl-和1-烷基-6-甲氧基-1，2，3，4-四氢-β-咔啉作为5-羟色胺（5-HT）的生物合成和失活的拮抗剂，以及它们与色胺受体的相互作用。化合物不改变5-羟色氨酸脱羧酶（5-HTP-D）的活性。在9个测试化合物中，只有1-（4-吡啶基）-取代的衍生物似乎抑制单胺氧化酶（MAO）的活性。测试的所有β-咔啉都是5-HT的竞争性拮抗剂，竞争肌营养性色胺受体。就Schild的pA 2值而言，最具活性的是1-（4-吡啶基）-取代的衍生物。其pA 2 = 6.50，而标准化合物（LSD）的pA 2 = 7.52。活性最低的是1-烷基取代的衍生物。1-（4-吡啶基）-6-甲氧基-1，2，3，4-四氢-β-咔啉拮抗大鼠中的色胺惊厥。与LSD不同的是，所测试的β-咔啉类药物都不会收缩平滑肌。化学部分β-咔啉是许多生物活性剂所共有的。1最近的研究表明，1，2，3，4-四氢-/3-咔啉的衍生物与5-羟色胺（5-HT）和5-甲氧基-N/S-乙酰色胺（褪黑激素）沿着存在于哺乳动物的松果体中。2从松果体组织中分离出1-甲基-6-甲氧基-1，2，3，4-四氢-β-咔啉，由于其可能的生理作用，提出它是一种醛固酮释放因子，并命名为肾上腺肾小球促肾上腺素。2a较新的实验质疑这种化合物对肾上腺皮质激素活性的影响，345因此“肾上腺-肾小球促素”这个名称不应作为这种特殊β-咔啉的同义词。然而，1-甲基-6-甲氧基-1，2，3，4-四氢-β-咔啉以及1-苄基-1，2，3，4-四氢-β-咔啉和许多其它β-咔啉存在于松果体组织中，2b肯定起某些生理作用，可能作为5-HT活性和代谢的调节剂。20，4 5-HT和松果体/3-咔啉的类似生物发生途径使这一假设更有可能。此外，植物/3-咔啉对5-HT代谢的影响似乎已经确立。20，4 The
l-(2-Pyridyl)-, l-(3-pyridyl)-, and l-(4-pyridyl)-6-methoxy-l, 2, 3, 4-tetrahydro-/3-carbolines were prepared from 5-methoxytrypfamine and the corresponding pyridinealdehydes. These three compounds and six other Maryl-and l-alkyl-6-methoxy-l, 2, 3, 4-tetrahydro-/3-carbolines previously obtained were tested in vitro and in vivo as antagonists of the biosynthesis and inactivation of 5-hydroxytryptamine (5-HT), and for their interaction with tryptamine receptors. The compounds did not change the activity of 5-hydroxytryptophan decarboxylase (5-HTP-D). Out of nine tested compounds only the l-(4-pyridyl)-substituted derivative seems to inhibit the activity of monoamine oxidase (MAO). All/3-carbolines tested are competitive antagonists of 5-HT, competing for a myotropic tryptamine receptor. In terms of Schild’s pA2 values the most active was the l-(4-pyridyl)-substituted derivative. Its pA2= 6.50 compares with pA2= 7.52 of the standard compound (LSD). The least active were the 1-alkyl-substituted derivatives. l-(4-Pyridyl)-6-methoxy-l, 2, 3, 4-tetrahydro-/3-carboline antagonized tryptamine convulsions in the rat. Unlike LSD none of/3-carbolines tested contracted smooth muscles.The chemical moiety,/3-carboline, is common to many biologically active agents. 1 Recently evidence has been found that derivativesof 1, 2, 3, 4-t etrahy dro-/3-carboline are present in the mammalian pineal gland along with 5-hydroxytryptamine (5-HT) and 5-methoxy-N/s-acetyltryptamine (melatonin). 2 As a possible physiological role of 1-methyl-6-methoxy-1, 2, 3, 4-tetrahydro-/3-carboline, a substance isolatedfrom pineal tissue, it was proposed that it acted as an aldosteronereleasing factor and the name“adrenoglomerulotro-pine” was coined. 2a Newer experiments questioned the influence of this compound on the hormonal ac-tivity of adrenal cortex, 3 45and so the name“adreno-glomerulotropine” should not beused as the synonym of this particular/3-carboline. Nevertheless, 1-methyl-6-methoxy-1, 2, 3, 4-tetrahydro-/3-carboline, as well as l-benzyl-l, 2, 3, 4-tetrahydro-/3-carboline and a number of other/3-carbolines present in pineal tissue, 2b cer-tainly plays some physiological role, probably as moderators of 5-HT activity and metabolism. 20, 4 The similar pathway of biogenesis for 5-HT and for pineal/3-carbolines makes this assumption even more prob-able. 20 Moreover, the influence of plant/3-carbolines on 5-HT metabolism seems to be established. 20, 4 The