8-Substituted 2-alkynyl-N9-propargyladenines as A2A adenosine receptor antagonists

被引：16

作者：

Endo, Kazuki ^{[1
]}

Deguchi, Kazuki ^{[1
]}

Matsunaga, Hirokazu ^{[1
]}

Tomaya, Kota ^{[1
]}

Yamada, Kohei ^{[1
]}

机构：

[1] Yamasa Corp, Biochem Div, Choshi, Chiba 2880056, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 12期

关键词：

Adenosine receptor; Agonist; Antagonist; Parkinson's disease; Structure-activity relationship; PARKINSONS-DISEASE; POTENT; AGONISTS; DERIVATIVES; DRUGS; NUCLEOTIDES; NUCLEOSIDES; 2-ALKYNYLADENOSINES; PHARMACOLOGY; MEMBRANES;

D O I：

10.1016/j.bmc.2014.04.041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Structure-activity relationships of 2-alkynyladenine derivatives were explored by varying substituents at the 9-, 8- and 2-positions of the purine moiety in order to optimize A(2A) adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A2A antagonist activity, and the introduction of a halogen, aryl, or heteroaryl at the 8-position further enhanced activity. A series of 8-substituted 2-alkynyl-N-9-propargyladenine derivatives exhibited potent antagonist activity, with IC50 values in the low nM range. Compound 4a from this series was found to be orally active at a dose of 3 mg/kg in a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model of Parkinson's disease. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：3072 / 3082

页数：11

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