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By using tritiated 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine (3H-PAF), we have directly identified its specific binding sites on rabbit platelet plasma membranes. The equilibrium dissociation constant for 3H-PAF is 1.36 (+/- 0.05) X 10(-9) M at 0 degrees C. The number of binding sites is 1.61 (+/- 0.34) X 10(12)/mg of membrane, which corresponds to approximately 150-300 receptors/platelet (depending on membrane vesicle orientation). Binding of 3H-PAF to rabbit platelet plasma membrane is rapid (t1/2 less than 5 min at 0 degrees C) and reversible. For a series of PAF analogues, their affinity for the receptor sites parallels with their relative potency to induce platelet aggregation. PAF can cause contraction of smooth muscle of heart, parenchymal strip, trachea, and ileum. Specific PAF receptor binding was demonstrated with purified plasma membrane from several smooth muscles and from polymorphonuclear leukocytes but not from presumably PAF nonresponsive cells such as erythrocytes and alveolar macrophages. It is likely that the interaction of PAF with these binding sites initiates the specific responses of platelets, polymorphonuclear leukocytes, and smooth muscles.

Among numerous nonsteroidal anti-imflammatory agents synthesized in the past few years, various analogs of indomethacin, phenylacetic acid and heteroarylacetic acid have reached the stage of clinical evaluation. Their biochemical mechanisms of action are exemplified by the broad activity profile of indomethacin which includes inhibition of mediators and enzymes, effects on cell membranes, and, most recently, inhibition of prostaglandin biosynthesis. The importance of pharmacodynamic properties to clinical efficacy was clearly demonstrated in some cases. Several candidates were eliminated because of their side-effects. A group of amethylarylacetic acids showed a high degree of stereospecificity in their potency and metabolisms in uiuo, as well as inhibition of prostaglandin synthetase and albumin binding in uitro.Extrinsic Cotton effect provides a sensitive technique in the study of interactions of these drugs with biopolymers. Competitive binding and antagonistic interactions between nonsteroidal drugs, particularly salicylate, were observed in uitro and in uiuo. Progress in salicylate research was marked by the synthesis of flufenisal as a new derivative with enhanced potency and longer duration of action. Several fenamate analogs and new chemical types have shown promise in preliminary clinical trials. Various immunological approaches are under investigation for the treatment of rheumatoid arthritis. Newer concepts are still needed to achieve more effective control of arthritic disorders.

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5-(2,4-Difluorophenyl)salicylic acid, diflunisal (25), is the best compound, in terms of both efficacy and safety, from over 500 salicylates investigated in our laboratories. It is a chemically distinct, nonacetylating salicylic acid, more active than aspirin as an analgesic and antiinflammatory agent and superior in duration of action and therapeutic index. Some recent clinical and biochemical observations are briefly discussed.