Studies on the Coronary Dilator Actions of Some Adenosine Analogues

Abstract

1 The cardiovascular actions of 23 adenosine analogues have been examined in anaesthetized open thorax dogs; the analogues were substituted in the 2-position of the purine ring, or in the exocyclic amino group, or were modified in the imidazole or sugar rings. 2 The effects of these compounds on coronary blood flow, peripheral blood pressure, and heart rate were compared with those of adenosine.3 9-0-D-Arabinofuranosyladenine had no cardiovascular action; the other analogues on intra-atrial administration caused an immediate increase in coronary blood flow, the magnitude and duration of which varied with the structures of the analogues. 4 2-Fluoro-, 2-bromo-, 2-isobutylthio-, 2-ethylamino-, and 5'-deoxy-5'-chloro-adenosines had coronary dilator potencies equal to or greater than that of adenosine. No relationship was found between the dilator potency of the adenosine analogues and their duration of coronary dilator action.5 The coronary dilator action of adenosine was potentiated by inosine, 9-0-D-arabinofuranosyladenine, tubercidin, N6 -methyladenosine and 2-trifluoromethyl-N6-methyladenosine. 6 There was no correlation between the substrate specificities of the shorter-acting analogues for adenosine deaminase or adenosine kinase and their duration of coronary dilator action. 7 It is proposed that in the anaesthetized dog, uptake into tissues is a more important mode of removal of adenosine and adenosine analogues from the vascular system than inactivation by adenosine deaminase, that the duration of coronary dilator action of the analogues is related primarily to their specificity for the carrier which mediates adenosine uptake, and that the adenosine carrier is not associated with kinase action.

Structure and function of adenosine receptors and their genes

“…After the discovery by Drury and Szent-Györgyi (1929) that adenosine can influence several bodily functions the pronounced cardiovascular effects of adenosine were particularly well investigated. Several adenosine analogues were synthesized and examination of the dose-response relationships suggested the presence of specific adenosine receptors (Cobbin et al 1974). The essentially competitive nature of the antagonism by methylxanthines of adenosine effects in the heart (De Gubareff and Sleator 1965) and also in the brain (Sattin and Rall 1970) also supported the idea of adenosine receptors.…”

5′‐n‐ethylcarboxamidoadenosine: A Potent Inhibitor of Human Platelet Aggregation

“…Certain analogues of adenosine, generally those substituted at the C`or N6 positions, retain activity as vasodilators (Dietmann, Birkenheier & Schaumann, 1970;Cobbin, Einstein & Maguire, 1974) and also inhibit platelet aggregation by raising levels of cyclic AMP (Kikugawa, lizuka & Ichino, 1973a;Kikugawa, Suehiro & Ichino, 1973b;Haslam, Davidson & Desjardins, 1978).…”

The resurgence of A2B adenosine receptor signaling

“…The dose–response effects observed with adenosine and synthetic adenosine analogues [10] in conjunction with the competitive antagonism by methylxanthines of adenosine’s biological effects supported the idea of specific adenosine receptors [2,11,12]. Categorization of ‘purinergic’ receptors into adenosine activated ‘P 1 -purinoreceptors’ and nucleotide activated ‘P 2 -purinoreceptors’ was formally recognized by Burnstock in 1978 [13].…”