2. Academic Validation
  3. Allosteric modulators of human A2B adenosine receptor

Allosteric modulators of human A2B adenosine receptor

  • Biochim Biophys Acta. 2014 Mar;1840(3):1194-203. doi: 10.1016/j.bbagen.2013.12.021.
Maria Letizia Trincavelli 1,  Chiara Giacomelli 1,  Simona Daniele 1,  Sabrina Taliani 1,  Barbara Cosimelli 2,  Sonia Laneri 3,  Elda Severi 3,  Elisabetta Barresi 1,  Isabella Pugliesi 1,  Giovanni Greco 4,  Ettore Novellino 3,  Federico Da Settimo 1,  Claudia Martini 1
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università di Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy.
  • 2 Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: [email protected].
  • 3 Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
  • 4 Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: [email protected].
PMID: 24361612 DOI: 10.1016/j.bbagen.2013.12.021
Abstract

Background: Among adenosine receptors (ARs) the A2B subtype exhibits low affinity for the endogenous agonist compared with the A1, A2A, 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, A2B 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 A2B AR through binding and functional assays using CHO cells expressing human A1, A2A, A2B, and A3 ARs.

Results: The investigated compounds behaved as specific positive or negative allosteric modulators of human A2B 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 A2B AR.

General significance: The 1-benzyl-3-ketoindole derivatives 7-9 acting as positive or negative allosteric modulators of human A2B AR represent new pharmacological tools useful for the development of therapeutic agents to treat pathological conditions related to an altered functionality of A2B AR.

Keywords

1-Benzyl-3-ketoindole derivatives; 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide; 3′,5′-cyclic adenosine monophosphate; 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone; 4-dimethylaminopyridine; A(2B) adenosine receptor; ADA; AR; BAY 60-6583; CHO; Chinese hamster ovary; DMAP; DMEM; Dulbecco's Modified Eagle Medium; G protein-coupled receptor; GPCR; GPCR allosteric modulators; Ligand–receptor interaction; Negative allosteric modulators; Positive allosteric modulators; Ro 20-1724; [(3)H]5′-N-ethylcarboxamideadenosine; [(3)H]MRS 1754; [(3)H]N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide; [(3)H]NECA; [(35)S]GTPγS; [(35)S]guanosine 5′-O-[gamma-thio]triphosphate; adenosine deaminase; adenosine receptor; cAMP.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-131032
    98.07%, A2B AR Positive Alosteric Modulator