The in vitro pharmacology of ZM 241385, a potent, non‐xanthine, A_2aselective adenosine receptor antagonist

<jats:p><jats:list list-type="explicit-label"><jats:list-item><jats:p>This paper describes the<jats:italic>in vitro</jats:italic>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<jats:sub>2a</jats:sub>receptor subtype.</jats:p></jats:list-item><jats:list-item><jats:p>ZM 241385 had high affinity for A<jats:sub>2a</jats:sub>receptors. In rat phaeochromocytoma cell membranes, ZM 241385 displaced binding of tritiated 5′‐N‐ethylcarboxamidoadenosine (NECA) with a pIC<jats:sub>50</jats:sub>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‐[<jats:italic>p</jats:italic>‐(2‐carboxyethyl) phenethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS21680) with pA<jats:sub>2</jats:sub>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<jats:sub>2b</jats:sub>receptors and antagonized the relaxant effects of adenosine in the guinea‐pig aorta with a pA<jats:sub>2</jats:sub>of 7.06, (c.l., 6.92‐7.19).</jats:p></jats:list-item><jats:list-item><jats:p>ZM 241385 had a low affinity at A<jats:sub>1</jats:sub>receptors. In rat cerebral cortex membranes it displaced tritiated<jats:bold>R</jats:bold>‐phenylisopropyladenosine (<jats:bold>R</jats:bold>‐PIA) with a pIC<jats:sub>50</jats:sub>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<jats:sub>2</jats:sub>of 5.95 (c.l., 5.72‐6.18).</jats:p></jats:list-item><jats:list-item><jats:p>ZM 241385 had low affinity for A<jats:sub>3</jats:sub>receptors. At cloned rat A<jats:sub>3</jats:sub>receptors expressed in Chinese hamster ovary cells, it displaced iodinated aminobenzyl‐5′‐N‐methylcarboxamido adenosine (AB‐MECA) with a pIC<jats:sub>50</jats:sub>of 3.82 (c.l., 3.67‐4.06).</jats:p></jats:list-item><jats:list-item><jats:p>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<jats:sub>2a</jats:sub>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<jats:sc>m</jats:sc>, 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<jats:sc>m</jats:sc>) was without effect on phenylephrine‐induced tone in guinea‐pig aortae.</jats:p></jats:list-item><jats:list-item><jats:p>ZM 241385 (10 μ<jats:sc>m</jats:sc>) 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.</jats:p></jats:list-item><jats:list-item><jats:p>ZM 241385 is the most selective adenosine A<jats:sub>2a</jats:sub>receptor antagonist yet described and is therefore a useful tool for characterization of responses mediated by A<jats:sub>2</jats:sub>adenosine receptors.</jats:p></jats:list-item></jats:list></jats:p>