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Central to advancing the care for patients with malignant neoplasms are efforts to delineate how cancer cells differ from their normal counterparts, and the identification of biological targets whose activity, when normalized, corrects the cancer phenotype and re-establishes normal growth control. In this regard we and others have described the tumor promoting actions of cyclic adenosine monophos-phate (cAMP) phosphodiesterases and the antitumor effects of phosphodiesterase inhibitors. In the following chapter we will focus on the unique biology of the cAMP phosphodiesterase-4 (PDE4) family of cAMP hydrolases as it pertains to brain tumors and the experimental challenges that arise when studying patterns of PDE4 expression. [ABSTRACT FROM AUTHOR]

Nearly 10 yr have passed since the authors review "Chemistry of GABAB Modulators" appeared in the book "The GABA Receptors," 2nd edition, edited by S. J. Enna and N. G. Bowery, Humana Press, Totowa, 1997 (1). In this update the authors wish to outline only new developments not covered in the 1997 paper. Baclofen, synthesized for the first time in September 1962, is still the only γ-aminobutyric acid (GABAB)-receptor agonist marketed for the treatment of spasticity and trigeminal neuralgia. It is fascinating to learn how many highly competent chemists devised manifold and elegant synthetic procedures for either racemic or (R)-(−)-baclofen and the structurally closely related potent antidepressant (R)-(−)-Rolipram, a selective phosphodiesterase-4 inhibitor. The new syntheses published after 1996 are listed in alphabetical order (2-16). Very recently a prodrug of (R)-(−)-baclofen (Fig. 1) was described which enhanced the oral bioavailability in Cynomolgus monkeys to more than 80% (17). It is planned to test this prodrug in clinical trials for the treatment of spasticity and gastroesophageal reflux disease. [ABSTRACT FROM AUTHOR]

Selective inhibitors of cyclic nucleotide phosphodiesterases (PDEs) have been widely studied as therapeutic agents for the treatment of various human diseases. Three-dimensional structures are essential for the design of highly selective inhibitors, but their availability is limited by the speed of crystallization. We describe crystallization of the catalytic domains of the unligated PDE4B2B, rolipram-bound PDE4D2, and 3-isobutyl-1-methylxanthine-bound PDE5A1 using the methods of vapor diffusion and microdialysis. We also briefly describe general methods of protein crystallization to provide a background to readers outside of the crystallographic field. Finally, we discuss detailed procedures for and pitfalls of the crystallization of PDEs, which may be valuable for crystallization of other PDE members. [ABSTRACT FROM AUTHOR]

An encyclopedia entry for phosphodiesterases is presented. Phosphodiesterases are a class of enzymes that catalyze the hydrolysis of 3',5'-cyclic guanosine monophosphate to 5'-guanosine monophosphate. The basic characteristics of phosphodiesterases are discussed, including their substrate specificity and regulatory domains. In addition, this entry discusses the compartmentalization of phosphodiesterases.

Although antidepreβant drug treatment is a well-established therapeutic approach in manic-depreβive disorders, the mechanism by which such drugs ameliorate the depreβive syndromes remains an area of active research. The mechanism of action of antidepreβants most likely has two components. The clinical manifestation of their therapeutic effects generally is seen after a l-to 2-wk treatment, thus implying that a degree of neuronal adaptation under the effect of antidepreβants is required for clinical efficacy. The development of neuronal sub-or supersensitivity following subchronic antidepreβant treatment, however, is thought to be secondary to the direct interaction of these drugs with specific receptors and/or enzymes in the brain. To characterize this interaction of antidepreβants with such receptors and/or enzymes, radioligand binding studies using mostly 3H-labeled antidepreβants have been used extensively. Foremost among these is [3H]-imipramine, a tricyclic antidepreβant that inhibits neuronal serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (noradrenaline, NA) transport. Other radiolabeled antidepreβants whose high-affinity binding sites have been studied in the brain and peripheral tiβues include [3H]-desipramine, [3H]-nomifensine, [3H]-indalpine, [3H]-paroxetine, [3H]-cyanoimipramine, [3H]-amitriptyline, [3H]-doxepin, [3H]-mianserin, and [3H]-rolipram (Table 1 [ABSTRACT FROM AUTHOR]

The purpose of this study was to estimate effect of drugs on red blood cell (RBC) microrheological properties. Despite of simplification, mature erythrocytes retain a number of molecular components of signaling pathways and so drugs can affect on cellular function including their flow deformation and O2-transport capacity. It was found that hormones: epinephrine (10− 6 M) and insulin (70 pM) changed red blood cell deformability (RBCD) and aggregation (RBCA). It was shown that RBCD and RDCA were variable under adenylyl cyclase (AC) activation by forskolin or dibutyryl cAMP (dB-cAMP; 10− 4M), therefore one of the cellular molecular target for RBC microrheological change can be AC. It was found that all four phosphodiesterase (PDE) inhibitors: IBMX, vinpocetine, rolipram, pentoxifylline decreased RBCA significantly (by 30-50%, p<0.01) and quite the contrary they increased RBCD (by 15-24%, p<0.05). Therefore PDEs might be considered as red blood cell molecular targets for some drugs. We have obtained data showing that Ca2 +  blocker verapamil and calcium chelator EGTA decreased RBCA and increased RBCD significantly (p<0.05). Calcium ionophore (A23187), on the contrary, increased aggregation and red cell rigidity. Therefore Ca2+ channels of the red cell membrane can be also considered as molecular targets red cell microrheology modification. Of these, particular interest presents erythrocyte protein tyrosine kinases and phosphatases, because of their possible roles in the modulation of erythrocyte morphology, deformability and metabolic functions. We inhibited red cell tyrosine phosphatase activity by N-vanadat (10− 4 M) and obtained an increase of RBCD. The similar effects on the RBCD were obtained under red cell incubation with Epoetin-beta and cisplatin that can stimulate tyrosine kinase activity. The obtained data reveals evidence that some elements of erythrocyte signaling pathways can be the molecular targets for microrheological active drugs. [ABSTRACT FROM AUTHOR]