Synthesis of 7,12-dihydropyrido[3,4-b:5,4-b']diindoles. A novel class of rigid, planar benzodiazepine receptor ligands.
Synthesis of 7,12-dihydropyrido[3,4-b:5,4-b']diindoles. A novel class of rigid, planar benzodiazepine receptor ligands.
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7,12-二氢吡啶并[3,4-b:5,4-b]二吲哚的合成。
DOI：
10.1021/jm00386a003
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发表时间：
1987
影响因子：
7.3
通讯作者：
Cook,JM
中科院分区：
文献类型：
--
作者：
Trudell,ML;Basile,AS;Shannon,HE;Skolnick,P;Cook,JM
将生物功能性结合到刚性框架中以增强活性或选择性作用的做法决不是新的。Bentley等人在吗啡领域的早期工作就是一个很好的例子。虽然构效关系研究23 -1表明，配体与苯二氮卓类受体（Bz R）高亲和力结合的一个必要标准是这些分子呈现平面或假平面拓扑结构的能力，但据我们所知，23-1没有具有平面几何结构的完全刚性化合物显示出与Bz R高亲和力结合。我们现在报告的BZ R，起源于针对这一目标的研究的高亲和力配体的合成。这些分子基于7，12-二氢吡啶并[3，2-6：5，4-6]二吲哚系统2，并已显示对Bz R具有高亲和力（5-15 nM，见表I）。此外，在吡啶并二吲哚的E环上的取代对这些化合物的体外结合亲和力和药理学活性具有显著影响：2的2位上的氢或甲氧基被氯原子取代导致活性从反向激动剂变为拮抗剂。高亲和力，目前认为哺乳动物中枢神经系统中苯并二氮杂卓的立体选择性结合位点介导苯并二氮杂卓的主要药理学作用。[3]自1977年发现这些受体以来，至少有六种独特的化合物被证明与这些位点结合。这些化合物已被证明产生广泛的药理作用，从几乎无法与苯二氮卓类（如佐匹克隆）4区分的药理作用到在灵长类动物中产生惊厥、5减少睡眠、6并产生类似恐惧或焦虑综合征的“反向激动剂”。7其他化合物，如吡唑并喹啉酮8 CGS-9896、CGS-9895和CGS-8216
The practice of incorporating biofunctionality into a rigid framework to enhance activity or selectivity of action is by no means new. The early work of Bentley et al. 1 2in the morphine area serves as an excellent example. While structure-activity relationship studies23-1 suggest that one necessary criteria for high-affinity binding of ligands to benzodiazepine receptors (Bz R) is the ability of these molecules to assume a planar or pseudoplanar topogra-phy, 23-1 to our knowledge no completely rigid compounds with a planar geometry havebeen shown to bind with high affinity to Bz R. We now report the synthesis of high-affinity ligands of the Bz R that originated from studies directed toward this goal. These molecules are based on the 7, 12-dihydropyrido [3, 2-6: 5, 4-6 d diindole system 2 and have been shown to possess high affinity (5-15 nM, see Table I) for Bz R. Moreover, substitution on the E ring of the pyridodiindoles has a marked effect on both the in vitro binding affinity and the pharmacological activity of these compounds: replacement of eitherhydrogen or methoxyl at position 2 of 2 by a chlorine atom results in a change in the activity from an inverse agonist to an antagonist.High-affinity, stereoselective binding sites for benzodiazepines in the mammalian central nervous system are currently thought to mediate the principal pharmacological actions of the benzodiazepines. 3 Since the discovery of these receptors in 1977, at least one-half dozen unique classes of compounds have been shown to bind to these sites. Such compounds have been shown to produce a wide range of pharmacologic actions that vary from those that are virtually indistinguishable from benzodiazepines (eg, zopiclone) 4 to “inverse agonists” that produce convulsions, 5 reduce sleep, 6 and produce a syndrome resembling fear or anxiety in primates. 7 Other compounds, such as the pyrazoloquinolinones8 CGS-9896, CGS-9895, and CGS-8216