Platelet activation is central to the pathogenesis of hemostasis and a
rterial thrombosis. Platelet aggregation plays a major role in acute c
oronary artery diseases, myocardial infarction, unstable angina, and s
troke. ADP is the first known and an important agonist for platelet ag
gregation. ADP not only causes primary aggregation of platelets but is
also responsible for the secondary aggregation induced by ADP and oth
er agonists. ADP also induces platelet shape change, secretion from st
orage granules, influx and intracellular mobilization of Ca2+, and inh
ibition of stimulated adenylyl cyclase activity. The ADP-receptor prot
ein mediating ADP-induced platelet responses has neither been purified
nor cloned. Therefore, signal transduction mechanisms underlying ADP-
induced platelet responses either remain uncertain or less well unders
tood. Recent contributions from chemists, biochemists, cell biologists
, pharmacologists, molecular biologists, and clinical investigators ha
ve added considerably to and enhanced our knowledge of ADP-induced pla
telet responses. Although considerable efforts have been directed towa
rd identifying and cloning the ADP-receptor, these have not been compl
etely successful or without controversy. Considerable progress has bee
n made toward understanding the mechanisms of ADP-induced platelet res
ponses but disagreements persist. New drugs that do not mimic ADP have
been found to inhibit fairly selectively ADP-induced platelet activat
ion ex vivo. Drugs that mimic ADP and selectively act at the platelet
ADP-receptor have been designed, synthesized, and evaluated for their
therapeutic efficacy to block selectively ADP-induced platelet respons
es. This review examines in detail the developments that have taken pl
ace to identify the ADP-receptor protein and to better understand mech
anisms underlying ADP-induced platelet responses to develop strategies
for designing innovative drugs that block ADP-induced platelet respon
ses by acting selectively at the ADP-receptor and/or by selectively in
terfering with components of ADP-induced platelet activation mechanism
s.