Synthesis and platelet antiaggregatory activity of trimetoquinol analogs as endoperoxide/thromboxane A2 antagonists

Trimetoquinol (TMQ) has activity as a beta-adrenergic agonist and as a platelet antiaggregatory agent. Recent reports from this and other laboratories have focused on the mechanism of inhibition of platelet function by TMQ and its analogs. Based on its competitive and stereoselective inhibition of thromboxane mimetic agents, TMQ was proposed as an endoperoxide/thromboxane A2 receptor antagonist; however, this mechanism has been questioned. A radiolabeled TMQ analog with high specific activity would aid in the elucidation of the actual mechanism of action. In the current research, modifications of the trimethoxy ring system of TMQ have been investigated. Replacement of one or two of the methoxy groups with iodine atoms leads to retention of platelet antiaggregatory activity and agonist blocking activity. Thus, these analogs have promise as potential radioligands since iodide exchange labeling can provide 125I-labeled compounds. Further, replacement of a methoxy group with either a nitro or amino functionality leads to decreased activity in platelet systems. These results suggest that the putative sites of interaction for the trimethoxy ring system of TMQ in platelet systems will tolerate large, lipid soluble groups but will not tolerate large changes in the electronic characteristics of the ring system.