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5-HT^(6) 및 5-HT^(7) receptor antagonists 개발을 위한 arylsulfonamide 유도체 합성 및 활성연구

Title
5-HT^(6) 및 5-HT^(7) receptor antagonists 개발을 위한 arylsulfonamide 유도체 합성 및 활성연구
Authors
유은아
Issue Date
2009
Department/Major
대학원 생명·약학부약학전공
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
박혜영
Abstract
5-HT_(6) 및 5-HT_(7) receptor는 Alzheimer, 정신분열증, 우울증 및 불안장애와 같은 central nervous system (CNS)-mediated disease 치료를 위한 therapeutic target으로써 많은 주목을 받고 있다. 본 연구에서는 이러한 serotonin receptor subtype을 target으로 5-HT_(6) receptor antagonist로서 2-(4-methylpiperazin-1-yl)-6-Ar-sulfonamidobenzo[d]thiazol 화합물 10종과 N,N-dimethyl-N'-(5-(Ar-sulfonamido)benzo[d]isothiazol-3-yl)formimid amide 화합물 3종을 비롯해 5-HT_(7) receptor antagonist로서 N-(R₂-methyl)-4-methoxy-N-(3-(4-(R₁-phenyl)piperazin-1-yl)propyl)-Ar-sulfona mide화합물 30종과 N-(4-(4-(R-phenyl)piperazin-1-yl)butan-2-yl)-Ar-sulfon amide 화합물 8종에 이르는 총 51종의 arylsulfonamide 유도체를 합성 및 평가 하였다. Binding affinity 평가 결과 화합물들은 IC_(50)값 24-2296 nM 범위의 좋은 activity를 보였다. Methyl branch 및 cycloalkyl group의 도입은 선택성 개선에 있어서 약한 효과를 보이는 것으로 나타났다. 합성된 물질 가운데 K10은 5-HT_(7) receptor에 대해 IC_(50)값 24 nM로 가장 우수한 activity를 보였으며 O3가 5-HT₂_(A) 및 5-HT₂_(C) receptor에 비해 5-HT_(7) receptor에 선택적인 것으로 확인되었다.;5-HT_(6) and 5-HT_(7) receptors are the novel and promising therapeutic target for central nervous system (CNS)-mediated diseases such as Alzheimer, schizophrenia, depression and anxiety. In order to increase the activity and selectivity, arylsulfonamide derivatives were prepared. Thirteen compounds of 2-(4-methylpiperazin-1-yl)-6-Ar-sulfonamidobenzo[d]thiazol and N,N-dimethyl-N'-(5-(Ar-sulfonamido)benzo[d]isothiazol-3-yl)formimidamide were synthesiz -ed as 5-HT_(6) receptor antagonists. Also, thirty-eight compounds of N-(R₂-methyl)-4-methoxy-N-(3-(4-(R₁-phenyl)piperazin-1-yl)propyl)-Ar-sulfonamide and N-(4-(4-(R-phenyl)piperazin-1-yl)butan-2-yl)-Ar-sulfonamide were prepar -ed and evaluated as 5-HT_(7) receptor antagonists. The compounds showed the IC_(50) values of 24-2296 nM. Among the synthesized compounds, K10 showed the best activity on 5-HT_(7) receptors (IC_(50)= 24 nM). Compound O3 showed a good activity over 5-HT_(7) (IC_(50)= 107 nM) and good selectivity over 5-HT₂_(A) (IC_(50)= 1824 nM) and 5-HT₂C receptors (IC_(50)= 1349 nM).
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