Allosteric modulators of human A_2B adenosine receptor

详细信息    查看全文

• 作者：Maria Letizia Trincavelli ; Chiara Giacomelli ; Simona Daniele ; Sabrina Taliani ; Barbara Cosimelli ; Sonia Laneri ; Elda Severi ; Elisabetta Barresi ; Isabella Pugliesi ; Giovanni Greco ; Ettore Novellino ; Federico Da Settimo ; Claudia Martini
• 关键词：ADA ; adenosine deaminase ; AR ; adenosine receptor ; cAMP ; 3&prime ; 5&prime ; -cyclic adenosine monophosphate ; BAY 60-6583 ; 2-[6-amino-3 ; 5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide ; CHO ; Chinese hamster ovary ; DMAP ; 4-dimethylaminopyridine ; DMEM ; Dulbecco's Modified Eagle Medium ; GPCR ; G protein-coupled receptor ; [35S]GTP纬S ; [35S]guanosine 5&prime ; -O-[gamma-thio]triphosphate ; [3H]MRS 1754 ; [3H]N-(4-cyanophenyl)-2-[4-(2 ; 3 ; 6 ; 7-tetrahydro-2 ; 6-dioxo-1 ; 3-dipropyl-1H-purin-8-y
• 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
• 出版年：March, 2014
• 年：2014
• 卷：1840
• 期：3
• 页码：1194-1203
• 全文大小：1123 K

文摘

Background

Among adenosine receptors (ARs) the A_2B subtype exhibits low affinity for the endogenous agonist compared with the A₁, A_2A, and A₃ 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 A₃ 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.