Synthesis, biological properties, and molecular modeling investigation of the first potent, selective, and water-soluble human A3 adenosine receptor antagonist

被引：64

作者：

Maconi, A

Pastorin, G

Da Ros, T

Spalluto, G

Gao, ZG

Jacobson, KA

Baraldi, PG

Cacciari, B

Varani, K

Moro, S

Borea, PA

机构：

[1] Univ Trieste, Dipartimento Sci Farmaceut, I-34127 Trieste, Italy

[2] NIDDKD, NIH, Mol Recognit Sect, LBC, Bethesda, MD 20892 USA

[3] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy

[4] Univ Ferrara, Dipartimento Med Clin & Sperimentale, Sez Farmacol, I-44100 Ferrara, Italy

[5] Univ Padua, Dipartimento Sci Farmaceut, Mol Modeling Sect, I-35131 Padua, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 17期

关键词：

D O I：

10.1021/jm020974x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new, highly potent, selective, and water-soluble antagonist of the hA(3) adenosine receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo- [4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (15 mM) and the highest affinity (K-i = 0.01 nM) and selectivity for the hA(3) versus A(1), A(2A), and A(2B) receptors (>10000-fold) ever reported. A Schild analysis of the antagonism by 4 of agonist-induced inhibition of cAMP production in CHO cells expressing the hA(3) receptor indicated a K-B value of 0.20 nM.

引用

页码：3579 / 3582

页数：4

共 29 条

[1]

Abbracchio MP, 1995, MOL PHARMACOL, V48, P1038

[2]

Ali H, 1996, J PHARMACOL EXP THER, V276, P837

[3] Pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A3 adenosine receptor antagonists:: Influence of the chain at the N8 pyrazole nitrogen [J].

Baraldi, PG ;

Cacciari, B ;

Romagnoli, R ;

Spalluto, G ;

Moro, S ;

Klotz, KN ;

Leung, E ;

Varani, K ;

Gessi, S ;

Merighi, S ;

Borea, PA .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (25) :4768-4780

[4]

Baraldi PG, 2000, MED RES REV, V20, P103, DOI 10.1002/(SICI)1098-1128(200003)20:2<103::AID-MED1>3.0.CO

[5]

2-X

[6] Synthesis, biological activity, and molecular modeling investigation of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as human A3 adenosine receptor antagonists [J].

Baraldi, PG ;

Cacciari, B ;

Moro, S ;

Spalluto, G ;

Pastorin, G ;

Da Ros, T ;

Klotz, KN ;

Varani, K ;

Gessi, S ;

Borea, PA .

JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (04) :770-780

[7] Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]-pyrimidine derivatives as highly potent and selective human A3 adenosine receptor antagonists [J].

Baraldi, PG ;

Cacciari, B ;

Romagnoli, R ;

Spalluto, G ;

Klotz, KN ;

Leung, E ;

Varani, K ;

Gessi, S ;

Merighi, S ;

Borea, PA .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (22) :4473-4478

[8] Fluorosulfonyl- and bis-(β-chloroethyl)amino-phenylamino functionalized pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine derivatives:: Irreversible antagonists at the human A3 adenosine receptor and molecular modeling studies [J].

Baraldi, PG ;

Cacciari, B ;

Moro, S ;

Romagnoli, R ;

Ji, XD ;

Jacobson, KA ;

Gessi, S ;

Borea, PA ;

Spalluto, G .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (17) :2735-2742

[9] Study of lipophilic character of serotonergic ligands [J].

Biagi, GL ;

Barbaro, AM ;

Sapone, A ;

Borea, PA ;

Varani, K ;

Recanatini, M .

JOURNAL OF CHROMATOGRAPHY A, 1996, 723 (01) :135-143

[10] Activation of the A3 adenosine receptor affects cell cycle progression and cell growth [J].

Brambilla, R ;

Cattabeni, F ;

Ceruti, S ;

Barbieri, D ;

Franceschi, C ;

Kim, YC ;

Jacobson, KA ;

Klotz, KN ;

Lohse, MJ ;

Abbracchio, MP .

NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2000, 361 (03) :225-234

← 1 2 3 →