Pdes As Targets For Pharmacological Intervention

Inhibition of PDE is one of the most ancient pharmacological treatments used by mankind. It is believed that stone-age man discovered the stimulating properties of extracts of leaves and seeds from

Thea sinensis, Coffea arabica, and Theobroma cacao, and mention of the stimulating properties of these extracts is found in records of the most ancient civilizations. The active principles in these extracts are alkaloids called xanthines, the most potent being the-ophylline and caffeine. The effect of caffeine and theophylline on PDE activity was discovered soon after the discovery of cAMP. It was actually adopted as a diagnostic tool of activation of the cAMP-dependent pathway. Those cell functions that are potentiated by xanthines are most likely mediated by activation of the cyclic nucleotide pathway. More comprehensive studies have demonstrated that xanthines have additional effects on Ca2+ sequestration and on the adenosine pathway, but it is still accepted that a good portion of their stimulatory activity is due to the increase in cAMP that follows inhibition of the PDE activity. Treatment with xanthines produces a wide range of pharmacological effects, including stimulation of the central nervous system (CNS), increased urine production by the kidney, increased cardiac functions, and relaxation of the bronchi and vascular smooth muscle. Theophylline is still the most prescribed antiasthma drug and is used for cardiovascular disorders (Torphy, 1998). While PDE inhibition is regarded as an effective strategy to manipulate intracellular cyclic nucleotide concentration and therefore cell responses, the use of xanthines is limited by the fact that they inhibit all PDEs present in the body. Because of this lack of selectivity, xanthines produce a large array of effects, restricting the useful therapeutic margin to a narrow window. The development of a second generation of inhibitors selective for different PDE families has confirmed the concept that increased selectivity can be obtained by targeting different PDE families (Thompson, 1991). For instance, inhibitors of PDE3 have useful cardiovascular effects but produce little stimulation of the CNS, while PDE4 inhibitors are largely devoid of cardiovascular effects, while retaining the CNS and pulmonary effects of theophyl-line. The potency of these inhibitors has also been greatly improved. While xanthines inhibit most PDEs in the millimolar range of concentration, there are now inhibitors selective for PDE3 or PDE4 that are effective in the nanomolar range. Here we will briefly review the most relevant pharmacological application of PDE inhibitors.

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