Potent antagonists for the human adenosine A2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM241385 with high affinity

Abstract

A series of novel and known 5-substituted 7-amino-2-(2-furyl)[1,2,4]triazolo[1,5-a][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 A2B receptors. The known potent adenosine A2A receptor antagonist, 7-amino-2-(2-furyl)-5-[2-(4-hydroxyphenyl)ethyl]amino[1,2,4]triazolo[1,5-a][1,3,5]triazine (ZM241385, KiA2A = 1.78 nM) had a Ki value of 16.5 nM at A2B receptors in radioligand binding studies on Chinese hamster ovary cells expressing A2B receptors. A pA2 value of 7.9 was measured for the inhibition of the cyclic AMP response by A2B 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 A2B receptors. Moreover, Ki 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 A2B receptor antagonists than ZM241385. The affinity of LUF5451 for the A2A receptor (Ki value = 13 nM) showed that the selectivity for this receptor subtype was lost and that a modest A2B receptor selectivity was achieved. The 5-(2-phenylhydrazino) derivative LUF5475 showed a high A2B receptor affinity (Ki = 7.6 nM), while it was equally active at A2A receptors, being A2B receptor-selective with respect to A1 and A3 receptors. Drug Dev. Res. 48:95–103, 1999. © 1999 Wiley-Liss, Inc.