INHIBITION OF ADENYLATE-CYCLASE IN HUMAN-BLOOD PLATELETS BY 9-SUBSTITUTED ADENINE-DERIVATIVES

  • 1 January 1979
    • journal article
    • research article
    • Vol. 5  (2) , 125-134
Abstract
A series of 9-substituted adenine derivatives inhibited adenylate cyclase activity (ATP pyrophosphate-lyase (cyclizing) EC 4.6.1.1) of a particulate preparation of human blood platelets. A 3- to 6-fold elevation of adenylate cyclase activity by prostaglandin (PG)E1 was inhibited in a concentration-related manner by 9-(tetrahydro-5-methyl-2-furyl) adenine (SQ 22,538), 9-(tetrahydro-2-furyl)adenine (SQ 22,536), 9-cyclopentyladenine (SQ 22,534), 9-furfuryladenine (SQ 4647) and 9-benzyladenine (SQ 21,611). The I50 [concentration producing 50% inhibition] values ranged from 21 .mu.M for SQ 22,538 to 140 .mu.M for SQ 21,611. These same adenine derivatives reversed the inhibition by PGE1 of ADP-induced aggregation and the PGE1-stimulated elevation of cyclic[c]AMP. The reversal of platelet aggregation inhibition by SQ 22,536 and SQ 4647 was concentration-related with I50 values of 30 .mu.M in each case, whereas SQ 22,534 and SQ 21,611 reversed inhibition by 30% at 100 .mu.M. SQ 22,536, SQ 22,534 and SQ 21,611 also blocked the increase in cAMP levels in a concentration-related manner with I50 values of 1, 4 and 60 .mu.M, respectively. SQ 4647 inhibited the elevation of cAMP by more than 85% at 1000 .mu.M. The adenine derivatives had no effect on platelet aggregation or on cAMP levels in the absence of PGE1. The inhibition of platelet aggregation by PGE1 is probably mediated by cAMP.