Selective Antagonism of A2a Adenosine Receptors: The Profile of ZM 241385 In Vitro

This study presents the in vitro pharmacological profile of ZM 241385, a novel non-xanthine adenosine receptor antagonist with a high degree of selectivity for the A2a receptor subtype. The compound exhibited strong affinity for A2a receptors, as evidenced by its displacement of tritiated NECA in rat phaeochromocytoma cell membranes and its antagonism of vasodilation induced by adenosine analogs in guinea-pig hearts.

ZM 241385 demonstrated significantly lower potency at A2b receptors and showed a weak antagonistic effect on the relaxant effects of adenosine in guinea-pig aorta. The affinity for A1 receptors was also low, with the compound displacing tritiated R-PIA in rat cerebral cortex membranes and antagonizing the bradycardic action of 2-CADO in guinea-pig atria.

Furthermore, ZM 241385 had minimal affinity for A3 receptors, as shown by its displacement of iodinated AB-MECA at cloned rat A3 receptors expressed in Chinese hamster ovary cells. The compound did not exhibit any substantial additional pharmacological effects on the isolated tissues at concentrations significantly higher than those required to block A2a receptors.

In terms of other pharmacological activities, ZM 241385 showed no significant inhibition of rat hepatocyte phosphodiesterase types I, II, III, and IV, except for a minor inhibition of the calcium calmodulin-activated type I enzyme. Importantly, ZM 241385 stands out as the most selective adenosine A2a receptor antagonist reported to date, making it a valuable tool for studying responses mediated by A2 adenosine receptors.