The Influence of Benzamidine Derivatives on Human Platelet Function

Abstract

SummaryThe influence of derivatives of benzamidine, benzylamine and phenylguanidine on platelet function was investigated in vitro. Among the compounds tested 4-nitro-benzoic acid 4’-amidinoanilide, 4-aminobenzoic acid 4’-amidinoanilide, 4-amidino-benzoic acid anilide and 4-amidinobenzoic acid 3’,4’-dimethoxyanilide were found to be potent inhibitors of platelet aggregation induced by ADP, collagen and thrombin. Other platelet functions, such as the thrombin-induced amine liberation, serotonin and adenosine uptake, retraction and phosphodiesterase activity, were not influenced. The action of the benzamidine derivatives, known to be thrombin inhibitors, is not caused by an inhibition of the clotting enzyme, but it seems to be mainly due to the prevention of the ADP effect on platelets.

Specific Inhibition of Platelet Agglutination and Aggregation by Aromatic Amidino Compounds

“…This enzyme also may have been the actual point of intervention for our ami dines in the ADP-dependent aggregation system. Its involvement would riot suffice to explain our results with the collagen-induced aggregation process, however, because several of our compounds blocked the release reaction very effectively and thus differed significantly from the inhibitors of Glusa et al (1974). Instead, one might wonder whether binding of platelets to the collagen fibers could have been interfered with, as has, for example, been noted with amitriptyline and imipramine (Mohammad and Mason 1974); whether thromboxane synthesis might have been suppressed; or whether the compounds could have exerted a stabilizing effect on the platelet granules.…”

“…In their study of aromatic monoamidines Glusa et a!. (1974) noted that the compounds blocked equally well aggregation produced by ADP, collagen or thrombin, but they found the release reaction unimpeded.…”

Inhibition of the Thrombin-Platelet Reaction by Hirudin

“…The release of serotonin from suspensions of washed platelets proved to be a suitable method for investigating the activation of platelets [4,5,12].…”

Pharmacologic Aspects of the Development of Selective Synthetic Thrombin Inhibitors as Anticoagulants

“…Since the anticoagulant action of selective thrombin inhibitors is based solely on their effect on the enzymatic activity of thrombin, its blockade not only prevents plasmatic coagulation processes, but also the activation of blood platelets. 11,[67][68][69][70][71][72][73][74][75] This is also true for tumor cellmediated aggregation of platelets. 76 Inhibition of thrombin-induced platelet reactions, however, requires higher inhibitor concentrations than are necessary for preventing the reaction of thrombin with its substrate fibrinogen.…”