Lipids as Drugs and Drug Design Targets

As the research area expanded, the leukotrienes were discovered next. The leukotrienes are potent lipid mediators associated with asthma and allergic reactions. In contrast to prostaglandins, leukotrienes are made predominantly in inflammatory cells, like leukocytes, macrophages, and mast cells. 

Prostaglandins, thromboxane, and the leukotrienes are lipids that are collectively called eicosanoids, since they are all derived from the C20 fatty acid, arachidonic acid [eicosa (Gr.) = twenty]. Over the past twenty years, the eicosanoids have emerged as important molecules around which to target drug design and development. 

Another and equally important substance produced from the endoperoxide is prostacyclin (8.65, PGI2), which is synthesized in the walls of blood vessels. It has an additional tetrahydrofuran ring which is easily opened and deactivated. Prostacyclin has a half-life of less than 10 minutes. 

The pharmacological effects of the prostaglandins and TXAj comprise many different activities—in fact too many. The lack of specificity of their activities implies a number of side effects which preclude the clinical application of several highly active natural prostaglandins, necessitating the development of selective synthetic compounds. The following effects of prostaglandins/eicosanoids are known and are summarized in table 8.3. 

PGEi Bronchodilatation Inhibitor of fat breakdown Inhibitor of platelet aggregation Stimulates contraction of gastrointestinal smooth muscle Vasodilation 

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