The therapeutic application of selective adenosine agonists i s hampered by the difficulty of separating desirable actions from side effects. A non-selective agent, combining A, and A , properties, might have advantages in this regard. In the present study, the pharmacological properties of N-ethyl-1 '-deoxy-l'{6-amino-2-[1-(3-hydroxy-3-phenyl)-propynyl]-9H-pu rin-9-yl} +-Dribofuran-5'-uronamide (SCH 59761), a potent, non-selective adenosine agonist, were evaluated.
The drug SCH 59761 showed high affinity at both A, (Ki = 2.5 nM) and A , , (Ki = 0.9 nM) adenosine receptors, as measured in rat brain cortex or striatal membranes. In functional studies, the drug showed similar potency in assays involving A, [negative chronotropic activity in the rat atria, E C , , = 110 (35-345) nM] or A , , receptor stimulation [vasodilation in rat aorta, EC, , = 123 (50-301) nM; vasodilation in bovine coronary arteries, EC, , = 49 (20-122) nM]. In isolated rat hearts, SCH 59761, at 100 nM, prevented ischemia-induced hemodynamic changes and creatine phosphokinase release. Given at very low doses in spontaneously hypertensive rats, SCH 59761 caused marked dose-related reductions in blood pressure [ ED, , = 0.001 (0.00024.003) mg/kg ip; i.e., 2.19 (0.43-6.57) nmol/kg ip], accompanied by reflex increase in heart rate. It was also active by oral route, decreasing blood pressure by 44 and 58 mmHg, at 1 and 5 mg/kg (2.19 and 10.95 pnol/kg ip), respectively. In normotensive rats, SCH 59761 lowered blood pressure at doses 10-fold higher than those used in hypertensive rats [ ED, , = 0.010 (0.0024.040) mg/kg ip; i.e., 21.91 (4.3847.62) nmol/kg ipl. SCH 59761 proved to be a highly potent, non-selective adenosine agonist, inducing blood pressure decrease, accompanied by slight reflex tachycardia, compared with A , , selective agents. Moreover, probably due t o a different balance between A, and A , , receptor activation, SCH 59761 did not show the adverse effects which have been reported with the non-selective agent 5'-N-ethylcarboxamidoadenosine (NECA). Therefore, a non-selective agent, with an optimal balance between A, -and A,,-mediated responses, can show a more favorable hemodynamic profile compared with selective compounds. Drug Dev. Res.