Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse
Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse
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DOI：
10.1016/j.bmc.2010.08.049
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发表时间：
2010-11-01
影响因子：
3.5
通讯作者：
Cook, James M.
中科院分区：
文献类型：
--
作者：
Yin, Wenyuan;Majumder, Samarpan;Cook, James M.
合成了一系列3，6-二取代的β-咔啉，并通过放射性配体结合试验评价了它们对α（x）β（3）γ（2）GABA（A）/苯二氮卓受体亚型的体外亲和力，以寻找治疗酒精滥用的α（1）亚型选择性配体。β-咔啉-3-羧酸叔丁酯（β CCt，1）的类似物通过CDI介导的方法合成，并且相关的6-取代的β-咔啉-3-羧酸酯6（包括WYS 8（7））通过Sonogashira或Stille偶联方法从6-碘-β CCt（5）合成。bCCt的二价配体（32和33）也通过钯催化的同偶联过程设计和制备，以将结构-活性关系（SAR）扩展到更大的配体。基于药效团/受体模型，对34个类似物的初步SAR研究表明，在6位的b-咔啉的大取代基耐受良好。正如所预期的，这些基团被提议投射到GABA（A）/Bz受体的细胞外结构域（L-Di区）中（参见32和33）。此外，位于β-咔啉核-3位的取代基在亲脂口袋L-1中表现出保守的立体相互作用，而N（2）可能与H-1发生氢键相互作用。三种新的b-咔啉配体（bCCt，3 PBC和WYS 8），优先结合α 1 BzR亚型允许与一系列经典的BzR拮抗剂（氟马西尼，ZK 93426）从几个不同的结构组的药理学效果进行比较，并表明这些b-咔啉是“近GABA中性拮抗剂”。基于SAR，最有效的（体外）α 1选择性配体是6-取代的乙炔基bCCt（WYS 8，7）。早期bCCt和3 PBC都显示出减少酒精偏好（P）和高度饮酒（HAD）大鼠的酒精自我给药，但对蔗糖自我给药几乎没有影响。1-3此外，这两个b-咔啉口服活性，此外，抗焦虑的P大鼠，但只有弱抗焦虑的啮齿类动物。这些数据促进了本文所述的bcarbolines的合成。爱思唯尔有限公司出版
A series of 3,6-disubstituted beta-carbolines was synthesized and evaluated for their in vitro affinities at alpha(x)beta(3)gamma(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of alpha(1) subtype selective ligands to treat alcohol abuse. Analogues of beta-carboline-3-carboxylate-t-butyl ester (beta CCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted beta-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-beta CCt (5). The bivalent ligands of bCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the b-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L-Di region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the beta-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L-1, while N(2) presumably underwent a hydrogen bonding interaction with H-1. Three novel b-carboline ligands (bCCt, 3PBC and WYS8), which preferentially bound to alpha 1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these b-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) a1 selective ligand was the 6-substituted acetylenyl bCCt (WYS8, 7). Earlier both bCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration. 1-3 Moreover, these two b-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the bcarbolines presented here. Published by Elsevier Ltd.