Analogues of AMP incorporating modifications of the adenine moiety and the phosphate function were synthesized as potential inhibitors of platelet aggregation. 2-Methoxy-, 2-ethoxy-, 2-methylthio-, 2-ethylthio-, 2-methylamino-, 2-ethylamino-, 2-trifluoromethyl-, 2-chloro-P-methyl-, and 2-methylthio-f@-methyladenosines were converted, via 2',3'-0-isopropylidene derivatives, to the 5'-monophosphates using 2-cyanoethyl phosphate and DCC. The isopropylidene derivatives of adenosine, 2-chloroadenosine, and 2-methylthioadenosine were also used to synthesize the respective 5'-0-sulfamoyladenosines by reaction with NaH and sulfamoyl chloride and subsequent deblocking. In addition, 2-chloroadenosine 5'-phosphorothioate, 2-methylthioadenosine 5'-phosphorothioate, and 2-ethylthioadenosine 5'-phosphorothioate were prepared from the unprotected nucleosides by treatment with PSC13 in triethyl phosphate. With the exception of the 5'-0-sulfamates of adenosine and 2-chloroadenosine, all the compounds tested inhibited the ADP-induced aggregation of sheep platelets. The 5'-phosphates and phosphorothioates of 8-methylthio- and 2-ethylthioadenosine were 2-13 times more potent than adenosine; the remaining 2- and N6 substituted phosphates and phosphorothioates were less potent than adenosine. 5'-O-Sulfamoyladenosine and 2-chloro-5'-0-sulfamoyladenosine potentiated ADP-mediated platelet aggregation but the three 5'-O-sulfamates inhibited serotonin-induced platelet aggregation. In contrast, all the 5'-phosphate and 5'-phosphorothioate analogues tested had negligible activity as inhibitors of serotonin-induced sheep platelet aggregation.