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The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A 2a selective adenosine receptor antagonist
Author(s) -
Poucher S.M.,
Keddie J.R.,
Singh P.,
Stoggall S.M.,
Caulkett P.W.R.,
Jones G.,
Collis M.G.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15923.x
Subject(s) - adenosine receptor , receptor , medicine , adenosine , pharmacology , xanthine , chinese hamster ovary cell , antagonist , biology , endocrinology , biochemistry , agonist , enzyme
1 This paper describes the in vitro pharmacology of ZM 241385 (4‐(2‐[7‐amino‐2‐(2‐furyl) [1,2,4]‐triazolo[2,3‐a][1,3,5]triazin‐5‐yl amino]ethyl) phenol), a novel non‐xanthine adenosine receptor antagonist with selectivity for the A 2a receptor subtype. 2 ZM 241385 had high affinity for A 2a receptors. In rat phaeochromocytoma cell membranes, ZM 241385 displaced binding of tritiated 5′‐N‐ethylcarboxamidoadenosine (NECA) with a pIC 50 of 9.52, (95% confidence limits, c.l., 9.02–10.02). In guinea‐pig isolated Langendorff hearts, ZM 241385 antagonized vasodilatation of the coronary bed produced by 2‐chloroadenosine (2‐CADO) and 2‐[ p ‐(2‐carboxyethyl) phenethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS21680) with pA 2 values of 8.57 (c.l., 8.45‐8.68) and 9.02 (c.l., 8.79‐9.24) respectively 3 ZM 241385 had low potency at A 2b receptors and antagonized the relaxant effects of adenosine in the guinea‐pig aorta with a pA 2 of 7.06, (c.l., 6.92‐7.19). 4 ZM 241385 had a low affinity at A 1 receptors. In rat cerebral cortex membranes it displaced tritiated R ‐phenylisopropyladenosine ( R ‐PIA) with a pIC 50 of 5.69 (c.l., 5.57‐5.81). ZM 241385 antagonized the bradycardie action of 2‐CADO in guinea‐pig atria with a pA 2 of 5.95 (c.l., 5.72‐6.18). 5 ZM 241385 had low affinity for A 3 receptors. At cloned rat A 3 receptors expressed in Chinese hamster ovary cells, it displaced iodinated aminobenzyl‐5′‐N‐methylcarboxamido adenosine (AB‐MECA) with a pIC 50 of 3.82 (c.l., 3.67‐4.06). 6 ZM 241385 had no significant additional pharmacological effects on the isolated tissues used in these studies at concentrations three orders of magnitude greater than those which block A 2a receptors. At 10 μm it displayed only minor inhibition of the bradycardic effects in guinea‐pig atria to some concentrations of carbachol. At 10 μ m , ZM 241385 had a small inhibitory effect on relaxant effects of isoprenaline in guinea‐pig aortae but no effect on sodium nitrite‐induced relaxation. ZM 241385 (100 μ m ) was without effect on phenylephrine‐induced tone in guinea‐pig aortae. 7 ZM 241385 (10 μ m ) had no inhibitory effect on rat hepatocyte phosphodiesterase types I, II, III and IV but caused a small inhibition of the calcium calmodulin‐activated type I enzyme. 8 ZM 241385 is the most selective adenosine A 2a receptor antagonist yet described and is therefore a useful tool for characterization of responses mediated by A 2 adenosine receptors.