Pharmacology of the highly selective A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine.
The pharmacological profile of 2-chloro-N6-cyclopentyladenosine (CCPA, CAS 37739-05-2), a highly selective A1 adenosine receptor agonist, was characterized. Its effects were compared with those of the non-selective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA). In binding studies on both rat and bovine brain, CCPA was highly potent on A1 receptors (Ki = 1.3 and 0.5 nmol/l, respectively) and displayed good A1 vs A2a receptor selectivity (500- and 920-fold, respectively). In functional studies, CCPA showed marked negative chronotropic activity in spontaneously beating rat atria (EC50 = 8.2 nmol/l). This effect was antagonized dose-dependently by the A1 selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). In the rat Langendorff model, in which global ischemia was induced, CCPA (3 nmol/l) prevented significantly the rise of diastolic pressure and coronary perfusion pressure during postischemic reperfusion. In vascular preparations, a functional activity responsive to A2a adenosine receptor stimulation, CCPA did not show any vasodilating properties up to micromolar concentrations, whereas NECA had a good relaxing activity in bovine coronary arteries (EC50 = 167 nmol/l). In rabbit platelets, a model sensitive only to A2a-receptor stimulation, CCPA did not elicit any relevant antiaggregatory properties, whereas NECA was found to be effective (IC50 = 200 nmol/l). Likewise, in an in vivo model of platelet aggregation in the rabbit using a non-invasive radioisotopic technique, CCPA (100 micrograms/kg, 30 min i.v. infusion) did not influence platelet function, whereas NECA (10 micrograms/kg, 30 min i.v. infusion) decreased peak value for platelet accumulation by 35%.(ABSTRACT TRUNCATED AT 250 WORDS)
Research Laboratories, Schering-Plough S.p.A., Comazzo, Milan, Italy.
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D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002417:Cattle; D003326:Coronary Circulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D014970:Xanthines / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; C058394:2-chloro-N(6)cyclopentyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine