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Cardiovascular pharmacology of SCH 59761, a highly potent, non‐selective, adenosine receptor agonist
Author(s) -
Casati Carlo,
Lozza Gianluca,
Conti Annamaria,
Ongini Ennio,
Monopoli Angela
Publication year - 1996
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(19960901)39:1<1::aid-ddr1>3.0.co;2-j
Subject(s) - agonist , adenosine , chronotropic , vasodilation , pharmacology , chemistry , ed50 , coronary perfusion pressure , adenosine receptor , adenosine a2a receptor , potency , medicine , endocrinology , blood pressure , receptor , heart rate , anesthesia , in vitro , biochemistry , cardiopulmonary resuscitation , resuscitation
The therapeutic application of selective adenosine agonists is hampered by the difficulty of separating desirable actions from side effects. A non‐selective agent, combining A 1 and A 2A properties, might have advantages in this regard. In the present study, the pharmacological properties of N‐ethyl‐1′‐deoxy‐1′{6‐amino‐2‐[1‐(3‐hydroxy‐3‐phenyl)‐propynyl]‐9H‐purin‐9‐yl} ‐β‐D‐ribofuran‐5′‐uronamide (SCH 59761), a potent, non‐selective adenosine agonist, were evaluated. The drug SCH 59761 showed high affinity at both A 1 (K i = 2.5 nM) and A 2A (K i = 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 1 [negative chronotropic activity in the rat atria, EC 50 = 110 (35–345) nM] or A 2A receptor stimulation [vasodilation in rat aorta, EC 50 = 123 (50–301) nM; vasodilation in bovine coronary arteries, EC 50 = 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 50 = 0.001 (0.0002–0.003) 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 μmol/kg ip), respectively. In normotensive rats, SCH 59761 lowered blood pressure at doses 10‐fold higher than those used in hypertensive rats [ED 50 = 0.010 (0.002–0.040) mg/kg ip; i.e., 21.91 (4.38–87.62) nmol/kg ip]. SCH 59761 proved to be a highly potent, non‐selective adenosine agonist, inducing blood pressure decrease, accompanied by slight reflex tachycardia, compared with A 2A selective agents. Moreover, probably due to a different balance between A 1 and A 2A 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 1 ‐ and A 2A ‐mediated responses, can show a more favorable hemodynamic profile compared with selective compounds. Drug Dev. Res. 39:1–11 © 1997 Wiley‐Liss, Inc.