The inhibitory effects of several adenosine analogues, including the new A2-selective agonists 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenosi ne (CGS 21680) and 2-hexynyl-5'-N-ethylcarbox-amidoadenosine (2-hexynyl-NECA), were investigated in vitro on human and rabbit platelet aggregation. The compounds examined inhibited ADP-induced platelet aggregation over a wide range of potency. The rank order of activity was similar between the two species thus showing that the rabbit is a useful animal model for studying the effects of adenosine derivatives on platelet aggregation. 2-Hexynyl-NECA was found to be the most potent adenosine compound of those currently available, having IC50 values of 0.10 and 0.07 microM in human and rabbit platelets, respectively. Conversely, the A1 agonists R(-)-N6-(2-phenylisopropyl) adenosine (R-PIA), S(+)-N6-(2-phenylisopropyl) adenosine (S-PIA) and 2-chloro-N6-cyclopentyladenosine (CCPA) were the least potent compounds with IC50 values in the micromolar range. The potency of the compounds in inhibiting platelet aggregation was found to be highly correlated with their affinity for A2 receptors as measured using 3H-CGS 21680 binding in rat brain striatum.