Molecular Pharmacology, Vol 8, 170-177, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Analogues of Adenosine 5'-Diphosphate—New Platelet Aggregators

Influence of Purine Ring and Phosphate Chain Substitutions on the Platelet-Aggregating Potency of Adenosine 5'-Diphosphate

¹ Department of Pharmacology, University of Sydney, Sydney, New South Wales 2006, Australia

A number of previously unreported analogues of adenosine 5'-diphosphate have been synthesized in order to evaluate their effects as aggregators of mammalian blood platelets. These compounds include 2-methoxyadenosine 5'-diphosphate, 2-methylthioadenosine 5'-diphosphate, and 2-ethylaminoadenosine 5'-diphosphate, which are shown to be more powerful aggregating agents than ADP, 2-chloro-N⁶-methyladenosine 5'-diphosphate (which is less potent than the unsubstituted nucleotide), and 2-chloroadenosine 5'-methylenediphosphonate (which is inactive). The 2-methylthio analogue proved to be exceptionally active and aggregated sheep platelets at concentrations 30 times less than equieffective concentrations of ADP. Evidence is presented that all these substances act at the same receptor site. On the basis of calculated analogue-receptor affinity constants and the observed lack of activity of the two analogues of ADP in which the anhydride oxygen is replaced by a methylene group, namely, adenosine 5'-methylenediphosphonate and 2-chloroadenosine 5'-methylenediphosphonate, some speculations concerning the requirements of the platelet ADP receptor have been made.

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ACKNOWLEDGMENTS The authors wish to thank Professor R. H. Thorp for his interest and encouragemenut, and to express their gratitude to Dr. J. Fildes and Mrs. R. Bergman of the Australian National University, who performed the elemental micro-analyses.