Cardiovascular Effects of Nucleoside Analogs

Abstract

Short-chain aliphatic esters and amides of adenosine-5'-carboxylic acid caused marked increases in coronary sinus oxygen tension (PO2) in the dog; the amides were generally more potent, causing additionally marked hypotension and tachycardia. The hypotensive effect was observed also in the spontaneously hypertensive rat. That the increase in coronary sinus PO2 paralleled an increase in coronary flow was verified with ethyl adenosine-5'-carboxylate hydrochloride. This compound also increased the reactive hyperemic response. Aminophylline blocked the increase in coronary flow. A representative amide and ester were very poor substrates for adenosine and adenylate deaminase in vitro; the amide exhibited a weak inhibitor effect on the enzymic activities while the ester was inactive. The observations that the compounds (1) cause marked pharmacological effects within seconds after intravenous administration, (2) are blocked by aminophylline like adenosine, (3) are not deaminated significantly in vitro by either adenosine or adenylate deaminase, and (4) cannot be phosphorylated at the 5' terminus because the 5'-OH has been removed chemically, support the hypothesis that they are acting directly on an "adenosine receptor" and have a prolonged duration of action because they are not metabolized significantly by the normal physiological pathways of adenosine degradation.

Subclasses of external adenosine receptors.

“…Amidated 5'-carboxyl analogs of adenosine have been shown to possess much greater coronary vasodilatory activity than adenosine (16,17). However, the extent to which these enhanced activities reflected retarded degradation rather than increased intrinsic potency was not clear.…”

“…Thus, it can be concluded that activation of adenylate cyclase in liver and Leydig cell membranes and inhibition of cyclase in fat cell membranes are mediated by functionally distinct subclasses of adenosine receptors with agonist recognition sites characteristic for each. Nevertheless, both subclasses share common characteristics, such as antagonism of nucleoside action by the methylxanthines theophylline and 3-isobutyll-methylxanthine (1, 3-7, 9, 11) and an absolute dependence on the presence of GTP (3, 7, 9) as would be expected for receptor-mediated modulations of adenylate cyclase (14, 15).Amidated 5'-carboxyl analogs of adenosine have been shown to possess much greater coronary vasodilatory activity than adenosine (16,17). However, the extent to which these enhanced activities reflected retarded degradation rather than increased intrinsic potency was not clear.…”

Highlights on the Development of A2A Adenosine Receptor Agonists and Antagonists

“…From the whole series, which includes 2-amino-, [80] 2-hydrazino-, [32,45,81] 2-alkoxy-, [82] 2-alkylthio-, [83][84][85] and 2-alkynyl-derivatives, [37,38,77,79] the compounds showing the highest A 2A affinity bore a phenylethyl (or cyclohexylethyl) group directly linked to the heteroatom or triple bond (see Table 1 compounds 4-9).…”

Conformational basis for the activation of adenylate cyclase by adenosine

“…Adenosine stimulation of adenosine 3':5'-cyclic monophosphate (cAMP) production is attributed to the interaction of adenosine with a receptor for adenosine on the external cell surface (15,(17)(18)(19)(20)(21)(22)(23)(24). Immunodeficiency diseases have been associated with the loss of adenosine deaminase activity (5, 25-32).The coronary vasodilator activity of adenosine has recently been reviewed (33,34). The cardiovascular effects of adenosine are potentiated by inhibitors of either adenosine deaminase or the uptake of adenosine by the heart (35-42), both of which increase extracellular adenosine concentrations which stimulates adenylate cyclase.…”

“…The coronary vasodilator activity of adenosine has recently been reviewed (33,34). The cardiovascular effects of adenosine are potentiated by inhibitors of either adenosine deaminase or the uptake of adenosine by the heart (35-42), both of which increase extracellular adenosine concentrations which stimulates adenylate cyclase.…”