In 1886 the activity of PDEs was actually first described as it was noted that ► caffeine had bronchodilator properties. Later on, this effect was attributed to cyclic nucleo-tide cAMP and that caffeine-inhibited cAMP-specific PDEs. In 1970 PDEs were identified in rat and bovine tissue and it was demonstrated that PDEs hydrolyze the phosphodiesteric bond of cAMP and cGMP (Bender and Beavo 2006). From then on more PDEs were identified and characterized. Until now 21 classes of genes for PDEs in humans, rats, and mice have been identified.
PDEs have been classified into 11 families (PDE1-PDE11) based on several criteria such as subcellular distributions, mechanisms of regulation, and enzymatic and kinetic properties. Most of these families have more than one gene product (e.g., PDE4A, PDE4B, PDE4C, PDE4D). In addition, each gene product may have multiple splice variants (e.g., PDE4D1-PDE4D9). In total, there are more than 100 specific PDEs (Bender and Beavo 2006).
Caffeine is a nonselective PDE inhibitor and it also inhibits cGMP-specific PDEs such as PDE5. cGMP causes vasodilatation in blood vessels by regulating their smooth muscle physiology. In addition, PDE5 also has an action on smooth muscles of contractile organs such as the penis. The most widely known PDE5 inhibitor is ► sildenafil. It was initially developed for the treatment of arterial hypertension and angina pectoris (Puzzo et al. 2008). In 1998 sildenafil was approved by the US Food and Drug Administration (FDA) for the treatment of erectile dysfunction and marketed under the name Viagra. Under the name of Revatio it was also approved for the therapy of pulmonary artery hypertension in 2005.
The discovery of sildenafil started the research and development of numerous inhibitors of PDE5. At the same time, it stimulated researchers to explore other classes of PDEs for their therapeutic potential in different disorders. In addition, the previously explored PDEs, such as PDE4 were reevaluated after first being dismissed as a fruitful target due to side effects and a lack of specificity or efficacy of the developed PDE inhibitors (Esposito et al. 2009). For instance, in 1984 the PDE4 inhibitor ► roli-pram was developed as a putative antidepressant, but it never made it to the market due to severe emetic side effects (e.g., nausea, vomiting).
PDEs hydrolyze the second messengers cAMP and/or cGMP, which are synthesized by adenylate and guanylate cyclase, respectively. However, the intracellular concentrations of both cyclic nucleotides are especially regulated by the PDE activity as its hydrolysis capacity far exceeds the capacity for synthesis. Besides this absolute and temporal regulation of cyclic nucleotides, PDEs contribute to their compartmentalized signaling as different PDEs are localized at some specific sites in the cell such as the plasma or nuclear membrane, or cytosol. Thus, PDEs play a key role in the intracellular, signal transduction pathways in various biological systems as is illustrated in Fig. 1. cAMP and cGMP transfer an extracellular signal
(e.g., neurotransmitter or hormone) to their effector proteins, protein kinase A and protein kinase G, respectively. Both kinases phosphorylate other enzymes or transcription factors, thus influencing the signal trans-duction. In addition, both cyclic nucleotides regulate their corresponding cyclic nucleotide-gated ion channels, which depolarizes synaptic terminals and thus influences signaling pathways. For instance, cGMP regulates cGMP-gated ion channels and thus directly regulates the ion flux, which depolarizes the presynaptic terminal and influences glutamate release. Eventually, changes in signal transduc-tion are translated into a biological system-dependent physiological and cellular response (Halene and Siegel 2007; Menniti et al. 2006; Puzzo et al. 2008; Reneerkens et al. 2009).
Phosphodiesterase Inhibitors. Fig. 1. Intracellular, signal transduction pathways. An extracellular signal (e.g., neurotransmitter or hormone) activates adenylate cyclase (AC) and guanylate cyclase (GC), which produce their corresponding cyclic nucleotides out of ATP and GTP, respectively. cAMP activates protein kinase A (PKA) and cGMP activates protein kinase G (PKG). Both PKA and PKG can phosphorylate other enzymes or transcription factors such as CREB in the nucleus. Besides gene expression, cAMP and cGMP also regulate cAMP- and cGMP-gated ion channels, respectively, which depolarizes the synaptic terminals. Eventually, these processes will result in a cellular response. Phosphodiesterases (PDEs) hydrolyse cAMP and/or cGMP leading to the formation of the inactive 5'-cAMP and 5'-cGMP, respectively. PDE inhibitors are selective for cAMP and/or cGMP degrading PDEs. In this way, a selective PDE inhibitor can specifically influence the cellular response of a biological system. (Adapted from Puzzo et al. 2008.)
PDEs itself are regulated by intracellular cyclic nucle-otide concentrations, phosphorylation (e.g., protein kinase G), interaction with regulatory proteins, subcellu-lar compartmentalization, and binding of Ca2+/calmodu-lin (Cheng and Grande 2007).
The specific localization of the different PDEs in the brain and the body will predict which certain physiological function may be influenced by some PDE inhibitors, but not by others. Table 1 gives an overview of the distribution of the different PDEs. Obviously, the PDE5-inhibitor sildenafil can be used for the treatment of erectile dysfunction since PDE5 is expressed in human cavernosal smooth muscle. Since PDE10A is highly expressed in the striatum where it regulates signal trans-duction in the corticostriatothalamic circuit, it is, therefore, an interesting target for schizophrenia and related disorders of basal ganglia function. In contrast, PDE4 is highly expressed in the ► hippocampus, which is a key structure in the limbic system, and is, therefore, considered as a useful target for treatment of mood disorders or cognitive deficits.
Only the ► pharmacokinetics of compounds that have been approved by the FDA and are also being evaluated for CNS applications are described.
The PDE3-inhibitor cilostazol is given orally and has a half-life of about 11-13 h. Cilostazol is metabolized and eliminated by CYP3A4 and CYP2C19, two isoenzymes of the cytochrome P450 system in the liver, after which it is predominantly excreted via the kidneys (Chapman and Goa 2003).
Sildenafil, vardenafil, and tadalafil are rapidly absorbed in the gastrointestinal tract at the level of the small intestine. The ► half-life of sildenafil and vardenafil is about 34 h. In contrast, tadalafil has a long half-life of about 18 h. All three compounds are metabolized and eliminated in the liver by CYP3A4. For sildenafil CYP2C9 is also partly involved. All three metabolized PDE5 inhibitors are excreted predominantly via the liver into the feces but also via the kidneys into the urine (Puzzo et al. 2008).
If a compound can be used to target central nervous system-related disorders it is vital that it crosses the
Phosphodiesterase Inhibitors. Table 1. Localization of different phosphodiesterases (PDEs) and PDE isoforms in the body and brain of rodents and humans in adulthood.
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