PHARMACOLOGY OF THE HIGHLY SELECTIVE A(1) ADENOSINE RECEPTOR AGONIST 2-CHLORO-N6-CYCLOPENTYLADENOSINE

The pharmacological profile of 2-chloro-N6-cyclopentyladenosine (CCPA, CAS 37739-05-2), a highly selective A(1) adenosine receptor agonist, was characterized. Its effects were compared with those of the non-sel ective adenosine receptor agonist 5'-N-ethylcarboxamido-adenosine (NEC A). In binding studies on both rat and bovine brain, CCPA was highly p otent on A(1) receptors (K-i = 1.3 and 0.5 nmol/l, respectively) and d isplayed good A(1) vs A(2a) receptor selectivity (500- and 920-fold, r espectively). In functional studies, CCPA showed marked negative chron otropic activity in spontaneously beating rat atria (EC(50) = 8.2 nmol /l). This effect was antagonized dose-dependently by the A(1) selectiv e antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). In the rat La ngendorff model, in which global ischemia was induced, CCPA (3 nmol/l) prevented significantly the rise of diastolic pressure and coronary p erfusion pressure during postischemic reperfusion. In vascular prepara tions, a functional activity responsive to A(2a) adenosine receptor st imulation, CCPA did not show any vasodilating properties up to micromo lar concentrations, whereas NECA had a good relaxing activity in bovin e coronary arteries (EC(50) = 167 nmol/l). In rabbit platelets, a mode l sensitive only to A(2a)-receptor stimulation, CCPA did not elicit ar ty relevant antiaggregatory properties, whereas NECA was found to be e ffective (IC50 = 200 nmol/l). Likewise, in an in vivo model of platele t aggregation in the rabbit using a non-invasive radioisotopic techniq ue, CCPA (100 mu g/kg, 30 min i.v. infusion) did not influence platele t function, whereas NECA (10 mu g/kg, 30 min i.v. infusion) decreased peak value for platelet accumulation by 35%. In conscious spontaneousl y hypertensive rats, CCPA administered intraperitoneally caused a dose -dependent reduction in systolic blood pressure (ED(30) = 0.128 mg/kg) and marked bradycardia. Its antihypertensive effects underwent tolera nce after dosing 0.1 mg/kg i.p. twice daily for 21 days. In an in vivo model of myocardial ischemia in the rabbit, CCPA (50 mu g/kg/min for 5 min i.v. infusion) given before ischemia limited the infarct size to 28% as compared with control hearts (43%; p < 0.05). CCPA appeared to pentrate into the central nervous system as shown by its protective e ffect (PD50 = 0.11 mg/kg) against pentylentetrazole-induced convulsion s in rats. However, in electroencephalographic studies the compound (0 .03-0.3 mg/kg) did not alter sleep-waking architecture in rats. In mic e, CCPA produced changes of gross behavior at 0.1-100 mg/kg, mainly re duction of locomotor. activity and muscle tone. These findings indicat e that the pharmacologic profile of CCPA is consistent with its select ive interaction with A(1) adenosine receptors. The compound therefore merits further investigation for its potential in the treatment of arr hythmias and myocardial ischemia.