GABA uptake inhibitors containing mono- and diarylmethoxyalkyl N-substituents.

Drug design and delivery Pub Date : 1989-05-01
E Falch, P Krogsgaard-Larsen
{"title":"GABA uptake inhibitors containing mono- and diarylmethoxyalkyl N-substituents.","authors":"E Falch,&nbsp;P Krogsgaard-Larsen","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>Analogues of GABA and the GABA uptake inhibitors, nipecotic acid and guvacine, carrying N-(mono)- or N-(diarylmethoxy)alkyl substituents were synthesized and tested in vitro as inhibitors of synaptosomal GABA uptake and GABAA receptor binding. Whereas the N-(diphenylmethoxy)ethyl derivative GABA (compound 23) (see Figures 1 and Scheme 1 for structures) was only a moderately potent inhibitor of GABA uptake, corresponding derivatives of nipecotic acid and guvacine compounds 7e and 16, respectively) were potent inhibitors having IC50 values in the low micromolar range. In the case of 7e, (a) the (R)-isomer (10) was three times more potent than the (S)-isomer (13), (b) the bis-4-chlorophenyl analogue (compound 7g) was more potent than 7e, (c) the introduction of an additional methylene group into the linkage between the nipecotic acid and benzhydryl ether moiety (to give 7f) did not significantly affect in vitro biological activity, and (d) removal of one of the phenyl groups, or replacement of the benzhydryl ether group by the conformationally restrained fluorenyloxy group (to give 7i), resulted in substantial loss of activity. None of the compounds synthesized showed detectable affinity for GABAA receptor sites.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"4 3","pages":"205-15"},"PeriodicalIF":0.0000,"publicationDate":"1989-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug design and delivery","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Analogues of GABA and the GABA uptake inhibitors, nipecotic acid and guvacine, carrying N-(mono)- or N-(diarylmethoxy)alkyl substituents were synthesized and tested in vitro as inhibitors of synaptosomal GABA uptake and GABAA receptor binding. Whereas the N-(diphenylmethoxy)ethyl derivative GABA (compound 23) (see Figures 1 and Scheme 1 for structures) was only a moderately potent inhibitor of GABA uptake, corresponding derivatives of nipecotic acid and guvacine compounds 7e and 16, respectively) were potent inhibitors having IC50 values in the low micromolar range. In the case of 7e, (a) the (R)-isomer (10) was three times more potent than the (S)-isomer (13), (b) the bis-4-chlorophenyl analogue (compound 7g) was more potent than 7e, (c) the introduction of an additional methylene group into the linkage between the nipecotic acid and benzhydryl ether moiety (to give 7f) did not significantly affect in vitro biological activity, and (d) removal of one of the phenyl groups, or replacement of the benzhydryl ether group by the conformationally restrained fluorenyloxy group (to give 7i), resulted in substantial loss of activity. None of the compounds synthesized showed detectable affinity for GABAA receptor sites.

分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
含有单酰基甲氧基烷基和二酰基甲氧基烷基n取代基的GABA摄取抑制剂。
合成了GABA的类似物和GABA摄取抑制剂,nipecotic酸和guvacine,携带N-(单)或N-(二芳基甲氧基)烷基取代基,并在体外测试了它们作为突触体GABA摄取和GABAA受体结合的抑制剂。而N-(二苯基甲氧基)乙基衍生物GABA(化合物23)(结构见图1和方案1)仅是GABA摄取的中等有效抑制剂,相应的nipecotic酸和guvacine化合物7e和16的衍生物分别是有效抑制剂,IC50值在低微摩尔范围内。在7e的情况下,(a) (R)-异构体(10)的效力是(S)-异构体(13)的三倍,(b)双-4-氯苯类似物(化合物7g)比7e的效力更强,(c)在nipecotic酸和苯并羟基醚部分之间的连接中引入额外的亚甲基(给出7f)没有显著影响体外生物活性,(d)去除一个苯基。或者苯并羟基被构象受限的氟酰氧基取代(得到7i),导致活性的大量损失。合成的化合物均未显示出对GABAA受体位点的可检测亲和力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
In-silico drug design: An approach which revolutionarised the drug discovery process Insoluble drug delivery technologies: review of health benefits and business potentials Microscopy characterisation of micro- and nanosystems for pharmaceutical use Synthesis and anticonvulsant activity of 3-(3'-trifluoromethylphenoxy)-pyridines and -dihydropyridines. Synthesis of the diastereomers of 5-(2,2-dichlorocyclopropyl)- and 5-(2-chlorocyclopropyl)-2'-deoxyuridine, and the antiviral and cytotoxic activity of these and bromo analogues.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1