Allosteric modulators of human A(2B) adenosine receptor

作者：Trincavelli Maria Letizia; Giacomelli Chiara; Daniele Simona; Taliani Sabrina; Cosimelli Barbara^*; Laneri Sonia; Severi Elda; Barresi Elisabetta; Pugliesi Isabella; Greco Giovanni; Novellino Ettore; Da Settimo Federico; Martini Claudia

来源：Biochimica et Biophysica Acta-General Subjects, 2014, 1840(3): 1194-1203.

DOI：10.1016/j.bbagen.2013.12.021

• 1-Benzyl-3-ketoindole derivatives
• A(2B) adenosine receptor
• Positive allosteric modulators
• Negative allosteric modulators
• GPCR allosteric modulators
• Ligand-receptor interaction

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.

• 出版日期2014-3