Platelet-activating factor (PAF) antagonistic actions of two new analogs of tetrahydrofurans

Platelet-activating factor (PAF) has been implicated as a mediator involved in the pathogenesis of several types of inflammatory and shock states. The following group of experiments were designed to examine the effects of two new PAF receptor antagonists termed JS-1 and JS-3. The chemical structures of the two compounds were synthesized based on computer modeling of PAF and previously reported PAF receptor antagonists (e.g., tetrahydrofurans). Both JS-1 (1.3 mumols/kg) and JS-3 (9.5 mumols/kg) were found to significantly reverse PAF-induced (0.3 microgram/kg) hypotension in the rat when compared to their respective vehicles. In washed rabbit platelets, pretreatment with JS-1 (10 microM) and JS-3 (60 microM) inhibited aggregation induced by PAF at concentrations from 185 pM to 18.5 nM. These data indicate that both JS-1 and JS-3 are effective receptor antagonists of platelet-activating factor, and that computer modeling of molecular structures can be an important tool in developing analogs of known mediators of circulatory disease.