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Potent antagonists for the human adenosine A 2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM241385 with high affinity
Author(s) -
de Zwart Maarten,
Vollinga Roel C.,
Beukers Margot W.,
Sleegers Danielle F.,
von Frijtag Drabbe Künzel Jacobien K.,
de Groote Miriam,
Ijzerman Ad P.
Publication year - 1999
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199911)48:3<95::aid-ddr1>3.0.co;2-b
Subject(s) - adenosine receptor , receptor , adenosine a2b receptor , competitive antagonist , radioligand , chinese hamster ovary cell , agonist , adenosine , chemistry , adenosine a1 receptor , radioligand assay , adenosine a2a receptor , antagonist , biochemistry , stereochemistry
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 A 2B receptors. The known potent adenosine A 2A 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, K i A 2A = 1.78 nM) 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 p A 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. Drug Dev. Res. 48:95–103, 1999. © 1999 Wiley‐Liss, Inc.