Allosteric modulators of human A2B adenosine receptor

被引：21

作者：

Trincavelli, Maria Letizia ^{[1
]}

Giacomelli, Chiara ^{[1
]}

Daniele, Simona ^{[1
]}

Taliani, Sabrina ^{[1
]}

Cosimelli, Barbara ^{[2
]}

Laneri, Sonia ^{[2
]}

Severi, Elda ^{[2
]}

Barresi, Elisabetta ^{[1
]}

Pugliesi, Isabella ^{[1
]}

Greco, Giovanni ^{[2
]}

Novellino, Ettore ^{[2
]}

Da Settimo, Federico ^{[1
]}

Martini, Claudia ^{[1
]}

机构：

[1] Univ Pisa, Dipartimento Farm, I-56126 Pisa, Italy

[2] Univ Naples Federico II, Dipartimento Farm, I-80131 Naples, Italy

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS | 2014年 / 1840卷 / 03期

关键词：

1-Benzyl-3-ketoindole derivatives; A(2B) adenosine receptor; Positive allosteric modulators; Negative allosteric modulators; GPCR allosteric modulators; Ligand-receptor interaction; INTERNATIONAL UNION; HIGH-AFFINITY; A2B RECEPTOR; PROTEIN; ANTAGONISTS; CLASSIFICATION; PHARMACOLOGY; NOMENCLATURE; DERIVATIVES; EXPRESSION;

D O I：

10.1016/j.bbagen.2013.12.021

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：

Background: Among adenosine receptors (ARs) the Am subtype exhibits low affinity for the endogenous agonist compared with the A(1), A(2A), and A(3) subtypes and is therefore activated when concentrations of adenosine increase to a large extent following tissue damages (e.g. ischemia, inflammation). For this reason, A(2B) AR represents an important pharmacological target. Methods: We evaluated seven 1-benzyl-3-ketoindole derivatives (7-9) for their ability to act as positive or negative allosteric modulators of human A(2B) AR through binding and functional assays using CHO cells expressing human A1, A(2A), A(2B), and A(3) ARs. Results: The investigated compounds behaved as specific positive or negative allosteric modulators of human A(2B) AR depending on small differences in their structures. The positive allosteric Modulators 7a,b and 8a increased agonist efficacy without any effect on agonist potency. The negative allosteric modulators 8b,c and 9a,b reduced agonist potency and efficacy. Conclusions: A number of 1-benzyl-3-ketoindole derivatives were pharmacologically characterized as selective positive (7a,b) or negative (8c, 9a,b) allosteric modulators of human A(2B) AR. General significance: The 1-benzyl-3-ketoindole derivatives 7-9 acting as positive or negative allosteric modulators of human A(2B) AR represent new pharmacological tools useful for the development of therapeutic agents to treat pathological conditions related to an altered functionality of A(2B) AR. (C) 2013 Elsevier B.V. All rights reserved.

引用

页码：1194 / 1203

页数：10

共 53 条

[1] Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis [J].