Rigidized 1-aryl sulfonyl tryptamines: Synthesis and pharmacological evaluation as 5-HT6 receptor ligands

被引：21

作者：

Nirogi, Ramakrishna ^{[1
]}

Dwarampudi, Adireddy ^{[1
,2
]}

Kambhampati, Ramasastry ^{[1
]}

Bhatta, Venugopalarao ^{[1
]}

Kota, Laxman ^{[1
]}

Shinde, Anil ^{[1
]}

Badange, Rajesh ^{[1
]}

Jayarajan, Pradeep ^{[1
]}

Bhyrapuneni, Gopinadh ^{[1
]}

Dubey, P. K. ^{[2
]}

机构：

[1] Suven Life Sci Ltd, Discovery Res, Hyderabad 500034, Andhra Pradesh, India

[2] Jawaharlal Nehru Technol Univ Hyderabad, Dept Chem, Hyderabad 500085, Andhra Pradesh, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 15期

关键词：

5-HT6R antagonist; SAR; NORT; Water maze; BINDING; 5-HYDROXYTRYPTAMINE-6; AGENTS; RAT;

D O I：

10.1016/j.bmcl.2011.05.106

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of N-1-arylsulfonyl-3-(pyrrolidin-3-yl)-1H-indole and N-1-arylsulfonyl-3-(4-chloro-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole derivatives (tryptamine derivatives with rigidized side chain) have been prepared and tested for their binding affinity to 5-HT6 receptor. Several compounds displayed potent binding affinity for the 5-HT6 receptor when tested in in vitro binding assay. The primary SAR indicates that rigidification of dimethylamino alkyl chain at C-3 of indole carbon maintains the binding affinity to 5-HT6R. The lead compound N-1-benzenesulfonyl-3-(4-chloro-1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole, 10a (K-b = 0.1 nM) has shown excellent in vitro affinity and was active in animal models of cognition like NORT and water maze. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：4577 / 4580

页数：4

共 32 条

[1]

Arnt J, 2010, 2 BIENN SCHIZ INT RE

[2] 5-HT6 RECEPTOR LIGANDS AND THEIR ANTIPSYCHOTIC POTENTIAL [J].

Arnt, Jorn ;

Olsen, Christina Kurre .

PHARMACOLOGY OF 5-HT6 RECEPTORS, PT II, 2011, 96 :141-161

[3]

Batcho A.D., 1985, Org. Synth, V63, P214, DOI DOI 10.15227/orgsyn.063.0214

[4] SYNTHESIS OF ARCYRIARUBIN B AND RELATED BISINDOLYLMALEIMIDES [J].

BRENNER, M ;

REXHAUSEN, H ;

STEFFAN, B ;

STEGLICH, W .

TETRAHEDRON, 1988, 44 (10) :2887-2892

[5]

CLARK RD, 1984, HETEROCYCLES, V22, P195

[6] INHIBITORS OF PROTEIN-KINASE-C .1. 2,3-BISARYLMALEIMIDES [J].

DAVIS, PD ;

HILL, CH ;

LAWTON, G ;

NIXON, JS ;

WILKINSON, SE ;

HURST, SA ;

KEECH, E ;

TURNER, SE .

JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (01) :177-184

[7]

EDGE S, 1991, CHEM IND, V18, P130

[8] Drugs in development for the treatment of schizophrenia [J].

Emsley, Robin .

EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2009, 18 (08) :1103-1118

[9] An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function [J].

Fone, Kevin C. F. .

NEUROPHARMACOLOGY, 2008, 55 (06) :1015-1022

[10] Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease [J].

Geldenhuys, Werner J. ;

Van der Schyf, Cornelis J. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2008, 8 (12) :1035-1048

← 1 2 3 4 →