Structure Activity Relationships in 5-Aryl-2,3-Dihydroimidazo[2,1a]Isoquinoline PAF Antagonists

The search for substances that can antagonize PAF by a receptor-mediated mechanism has resulted in the discovery of a variety of compounds that can be classified as charged and non-charged PAF receptor antagonists. The imidazo[2,1-a]isoquinolines represent the first class of non-charged PAF receptor antagonists that were designed using the PAF molecule as a template. The primary in vitro screen used for detecting PAF antagonism activity was the inhibition of PAF-induced platelet aggregation in human platelet-rich plasma. in vivo assays involved i.v. PAF-induced hypotension in the rat and hemoconcentration and bronchoconstriction changes in the guinea pig. The most active compounds against PAF-induced aggregation and competition of [³H]PAF binding were the lipophilic alkyl, aryl, or an O- or N-linked benzyl group at position 4'- of ring D. PAF-induced hypotension in the anesthetized rat was inhibited in a dose-dependent manner both parenterally.