Potent antagonists for the human adenosine A2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM241385 with high affinity
✍ Scribed by Maarten de Zwart; Roel C. Vollinga; Margot W. Beukers; Danielle F. Sleegers; Jacobien K. von Frijtag Drabbe Künzel; Miriam de Groote; Ad P. Ijzerman
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 147 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
A series of novel and known 5-substituted 7-amino-2-(2-furyl) [1,2,4]triazolo [1,5a][1,3,5]triazine derivatives were synthesized and tested for adenosine receptor antagonism in radioligand binding assays at all four adenosine receptor subtypes and for inhibition of the agonist-induced cyclic AMP response at human A 2B receptors. The known potent adenosine A 2A receptor antagonist, 7-amino-
had a K i value of 16.5 nM at A 2B receptors in radioligand binding studies on Chinese hamster ovary cells expressing A 2B receptors. A pA 2 value of 7.9 was measured for the inhibition of the cyclic AMP response by A 2B receptors induced by 5′-N-ethylcarboxamidoadenosine (NECA). In a series of 5-phenyl(alkyl)amino analogs the 5-(2-phenylethyl)amino analog LUF5452 and the 5-benzylamino analog LUF5451 were both more potent than ZM241385 in the cyclic AMP assay at A 2B receptors. Moreover, K i values of 9.9 and 7.6 nM were found in binding studies at this receptor subtype, indicating that LUF5451 and LUF5452 are more potent A 2B receptor antagonists than ZM241385. The affinity of LUF5451 for the A 2A receptor (K i value = 13 nM) showed that the selectivity for this receptor subtype was lost and that a modest A 2B receptor selectivity was achieved. The 5-(2-phenylhydrazino) derivative LUF5475 showed a high A 2B receptor affinity (K i = 7.6 nM), while it was equally active at A 2A receptors, being A 2B receptor-selective with respect to A 1 and A 3 receptors.