Quinolinedione nucleus as a novel scaffold for A1 and A2A adenosine receptor antagonists

被引：0
作者：
Luisa Mosti
Paola Fossa
Giulia Menozzi
Letizia Trincavelli
Maura Floreani
机构：
[1] Università degli Studi di Genova,Dipartimento di Scienze Farmaceutiche
[2] Università degli Studi di Pisa,Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie
[3] Università degli Studi di Padova,Dipartimento di Farmacologia ed Anestesiologia
来源：
Medicinal Chemistry Research | 2008年 / 17卷
关键词：
A; and A; adenosine receptor antagonists; Molecular modeling studies; 2-Pyridones; 2,5-Quinolinediones; Synthesis;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
In the last few years, much effort has been directed towards the synthesis of selective adenosine receptor (AR) antagonists since they are attractive tools for pharmacological intervention in many pathophysiological conditions. During our studies aimed at obtaining new nonclassical adenosine antagonists devoid of phosphodiesterase (PDE) inhibition, a series of 2-pyridones and 2,5-quinolinediones (3a–f, 5a–f, 6a,c–f) has been synthesized as potential AR ligands. Binding affinities of the new compounds were determined for bovine and human adenosine A1, A2A, and A3 receptors. Compound 5f showed good affinity (Ki = 7.8 μM) towards human A1AR but no selectivity (Ki = 7.0 μM) towards human A2AAR, whereas compound 6f showed more affinity towards human A2A (Ki = 16 μM) than A1 receptor (percentage inhibition at 10 μM concentration = 11). In the 1–100 μM range, the new compounds did not inhibit cardiac PDE3 activity at all. Molecular modeling studies carried out on 5f and 6f support the pharmacological results and suggest 6f as a potential lead compound selective towards A2AAR.
引用
收藏
页码：587 / 603
页数：16
相关论文
共 140 条
[1]  
Altomare C(2000)Ionization behaviour and tautomerism-dependent lipophilicity of pyridine-2(1H)-one cardiotonic agents Bioorg Med Chem 8 909-916
[2]  
Cellamare S(2000)The SWISS-PROT protein sequence database and its supplement TrEMBL in 2000 Nucleic Acids Res 28 45-48
[3]  
Summo L(2002)Synthesis, molecular modeling studies and pharmacological activity of selective A J Med Chem 45 4875-4887
[4]  
Fossa P(1973) receptor antagonists Biochem Pharmacol 22 3099-3108
[5]  
Mosti L(2000)Relationship between the inhibition constant (K J Med Chem 43 3118-3124
[6]  
Carotti A(2007)) and the concentration of inhibitor which causes 50 per cent inhibition (I J Med Chem 50 4061-74
[7]  
Bairoch A(2003)) of an enzymatic reaction Curr Top Med Chem 3 369-385
[8]  
Apweiler R(1993)Synthesis and structure-activity relationships of a new set of 2-arylpyrazolo(3,4-c)quinoline derivatives as adenosine receptor antagonists J Med Chem 36 2475-2484
[9]  
Bondavalli F(2003)New 2-arylpyrazolo(3,4-c)quinoline derivatives as potent and selective human A Naunyn-Schmiedeberg’s Arch Pharmacol 367 109-118
[10]  
Botta M(2002) adenosine receptor antagonists. Synthesis, pharmacological evaluation, and ligand-receptor modeling studies Quant Struct-Act Relat 21 267-275
12345678910