Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The following letter presents the synthesis and in vitro evaluation of a novel quaternary substituted series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds represent conformationally constrained analogues of the Celltech PDE IV inhibitor, CDP 840. Examples with sub-micromolar IC50's for PDE4 inhibition are reported.
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PMID:Quaternary substituted PDE4 inhibitors I: the synthesis and in vitro evaluation of a novel series of oxindoles. 987 49

Increases in the level of cAMP stimulate the secretion of GnRH from GT1 GnRH neuronal cells. We hypothesized that cyclic nucleotide phosphodiesterases (PDEs), the enzymes that hydrolyze cAMP, may constitute a negative feedback signaling mechanism for GnRH regulation by decreasing the level of cAMP. GT1 cells were shown to express three PDEs by RT-PCR analysis: the cAMP-specific PDE4B and PDE4D and the calmodulin-dependent PDE1B. A splice variant of PDE4D, PDE4D3, which is activated when phosphorylated by cAMP-dependent protein kinase (PKA), was identified in GT1 cells by Western analysis. Consistent with PDEs negatively regulating GnRH secretion, treatment with the nonselective PDE inhibitor, IBMX, stimulated GnRH secretion 137% in 30-min static cultures. Furthermore, treatment with the PDE4-specific inhibitors Rolipram and RS-25344 increased GnRH secretion 48 and 125%, while treatment with the PDE1-specific inhibitor 8-MeoM-IBMX only caused a modest increase of 28%. In perifusion studies a rapid multi-fold stimulation of GnRH secretion was observed following treatment with IBMX, Rolipram or RS-25344. In conclusion, the level of PDE activity appears to be an important negative feedback signal for GnRH secretion. We hypothesize that activation of PDE4D3 by PKA may constitute a negative feedback signaling pathway which participates in the regulation of cAMP levels.
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PMID:Role of phosphodiesterases in the regulation of gonadotropin- releasing hormone secretion in GT1 cells. 987

This communication describes the synthesis and in vitro evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. The compounds described contain an indole moiety which replaces the 'rolipram-like' 3-methoxy-4-cyclopentoxy motif. Several of the compounds presented possess low nanomolar IC50's for PDEIV inhibition. In vivo activities determined from measurement of serum TNF-alpha levels in LPS challenged mice (mouse endotoxemia model) are also reported.
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PMID:The synthesis and biological evaluation of a novel series of indole PDE4 inhibitors I. 987 49

This communication describes the synthesis and in vitro and in vivo evaluation of a novel potent series of phosphodiesterase type (IV) (PDE4) inhibitors. Several of the compounds presented possess low nanomolar IC50's for PDE4 inhibition and excellent in vivo activity for inhibition of TNF-alpha levels in LPS challenged mice (mouse endotoxemia model). Emesis studies (dog) and efficacy in a SCW arthritis model for the most potent PDE4 inhibitors are presented.
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PMID:Orally active indole N-oxide PDE4 inhibitors. 987 75

The aim of this study was to investigate the effects of selective phosphodiesterase (PDE)3 and PDE4 inhibitors on arachidonate release by alveolar macrophages from sensitized and challenged guinea-pigs. Guinea-pigs were sensitized and challenged with ovalbumin administered by aerosol. Bronchoalveolar lavage was performed 48 h later and the PDE and cyclic adenosine monophosphate (cAMP) contents of or the arachidonate release from alveolar macrophages, stimulated in vitro with N-formyl-Met-Leu-Phe (fMLP), were evaluated. PDE3 and PDE4 activities were detected in preparations of macrophage lysate from sensitized challenged and sensitized control animals. Oral pretreatment, prior to antigen challenge in sensitized guinea-pigs, with rolipram or Ro 20-1724 (PDE4 inhibitors) but not milrinone (PDE3 inhibitor) significantly reduced the arachidonate release from alveolar macrophages. In vitro incubation of alveolar macrophages from challenged guinea-pigs with Ro 20-1724 or the cAMP analogue dibutyryl cAMP (db-cAMP) but not milrinone or the cyclic guanosine monophosphate (cGMP) analogue 8-bromo-cGMP (8-br-cGMP) significantly reduced arachidonate release. Incubation of the cells with a combination of milrinone plus rolipram or Ro 20-1724 elicited a marked and significant reduction in arachidonate release by alveolar macrophages stimulated with fMLP. In conclusion, these data show that phosphodiesterase-4 isoenzyme may regulate the release of inflammatory mediators such as arachidonate from macrophages through an increase in intracellular cyclic adenosine monophosphate. This suggests that phosphodiesterase-4 inhibitors have potential in the treatment of inflammatory disorders of the lung.
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PMID:Selective phosphodiesterase inhibitors modulate the activity of alveolar macrophages from sensitized guinea-pigs. 987 87

The influence of chronic antidepressant administration on expression of the three major phosphodiesterase (PDE) 4 subtypes found in brain (PDE4A, PDE4B, and PDE4D) was examined. The treatments tested included representatives of four major classes of antidepressants: selective reuptake inhibitors of serotonin (sertraline and fluoxetine) or norepinephrine (desipramine), a monoamine oxidase inhibitor (tranylcypromine), and electroconvulsive seizure. Expression of PDE4A and PDE4B, but not PDE4D, mRNA and immunoreactivity were significantly increased in rat frontal cortex by chronic administration of each of the four classes of antidepressants. We also found that antidepressant administration significantly increased the expression of PDE4B mRNA in the nucleus accumbens, a brain region thought to mediate pleasure and reward that could also contribute to the anhedonia often observed in depressed patients. In contrast, expression of PDE4A and PDE4B were not influenced by short-term treatment (1 or 7 d) and were not influenced by chronic administration of nonantidepressant psychotropic drugs (cocaine or haloperidol), demonstrating the time dependence and pharmacological specificity of these effects. Upregulation of PDE4A and PDE4B may represent a compensatory response to antidepressant treatment and activation of the cAMP system. The possibility that targeted inhibition of these PDE4 subtypes may produce an antidepressant effect is discussed.
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PMID:Chronic antidepressant administration increases the expression of cAMP-specific phosphodiesterase 4A and 4B isoforms. 988 May 81

1. Visnagin relaxed aortae previously contracted by noradrenaline. This effect was unalterated by endothelium removal and potentiated, at high concentrations, by the previous incubation with sodium nitroprusside. 2. Visnagin weakly inhibited the hydrolytic activity of the cyclic nucleotide phosphodiesterase (PDE) isozymes (PDE5, PDE4, PDE3, cyclic GMP activated PDE2 and PDE1). 3. The present results indicate an involvement of PDE inhibition in the relaxant effect of visnagin at high concentration (>5x10(-5) M).
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PMID:Effects of visnagin on cyclic nucleotide phosphodiesterases and their role in its inhibitory effects on vascular smooth muscle contraction. 988 57

Investigations of recent years revealed that isozymes of cyclic-3', 5'-nucleotide phosphodiesterase (PDE) are a critically important component of the cyclic-3',5'-adenosine monophosphate (cAMP) protein kinase A (PKA) signaling pathway. The superfamily of cyclic-3', 5'-phosphodiesterase (PDE) isozymes consists of at least nine gene families (types): PDE1 to PDE9. Some PDE families are very diverse and consist of several subtypes and numerous PDE isoform-splice variants. PDE isozymes differ in molecular structure, catalytic properties, intracellular regulation and location, and sensitivity to selective inhibitors, as well as differential expression in various cell types. A number of type-specific "second-generation" PDE inhibitors have been developed. Current evidence indicates that PDE isozymes play a role in several pathobiologic processes in kidney cells. In rat mesangial cells, PDE3 and PDE4 compartmentalize cAMP signaling to the PDE3-linked cAMP-PKA pathway that modulates mitogenesis and PDE4-linked cAMP-PKA pathway that modulates generation of reactive oxygen species. Administration of selective PDE isozyme inhibitors in vivo suppresses proteinuria and pathologic changes in experimental anti-Thy-1.1 mesangial proliferative glomerulonephritis in rats. Increased activity of PDE5 (and perhaps also PDE9) in glomeruli and in cells of collecting ducts in sodium-retaining states, such as nephrotic syndrome, accounts for renal resistance to atriopeptin; diminished ability to excrete sodium can be corrected by administration of the selective PDE5 inhibitor zaprinast. Anomalously high PDE4 activity in collecting ducts is a basis of unresponsiveness to vasopressin in mice with hereditary nephrogenic diabetes insipidus. Apparently, PDE isozymes apparently also play an important role in the pathogenesis of acute renal failure of different origins. Administration of PDE isozyme-selective inhibitors suppresses some components of immune responses to allograft transplant and improves preservation and survival of transplanted organ. PDE isozymes are a target for action of numerous novel selective PDE inhibitors, which are key components in the design of novel "signal transduction" pharmacotherapies of kidney diseases.
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PMID:Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. 989 13

Epithelial cells actively participate in inflammatory airway disease by liberating mediators such as arachidonate metabolites and cytokines. Inhibition of phosphodiesterases (PDEs) may be a useful anti-inflammatory approach. The PDE isoenzyme pattern and the effects of PDE inhibition on mediator generation were analyzed in primary cultures of human and porcine airway epithelial cells (AEC) and in the bronchial epithelial cell line BEAS-2B. PDE4 and PDE5 were detected in lysates of all cell types studied. In primary cultures of human AEC, the PDE4 variants PDE4A5, PDE4C1, PDE4D2, and PDE4D3 were identified by polymerase chain reaction analysis. Evidence of the recently described PDE7 was obtained by rolipram- insensitive cyclic adenosine monophosphate (cAMP) degradation, and its presence was verified by the demonstration of PDE7 messenger RNA. Primary cultures of human airway epithelium also expressed PDE1. Enhanced epithelial cAMP levels, induced by forskolin and PDE4 inhibition, increased formation of prostaglandin E2 (PGE2), but not of interleukin (IL)-8 or 15-hydroxyeicosatetraenoic acid (15-HETE) in airway epithelial cells. Increased cyclic guanosine monophosphate levels in these cells provoked by sodium nitroprusside and the PDE5 inhibitor zaprinast reduced the PGE2 synthesis, whereas 15-HETE and IL-8 formation were unchanged. The data suggest that PDE isoenzymes are important in airway inflammation and that PDE inhibitors exert anti-inflammatory effects by acting on AEC.
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PMID:Identification and function of cyclic nucleotide phosphodiesterase isoenzymes in airway epithelial cells. 992 21

The postnatal development of rolipram-sensitive, low-K(m), cyclic AMP-specific phosphodiesterase (PDE4) was investigated in discrete regions of rat brain using a PDE4 activity assay and immunoblot analyses with K116, a PDE4 antibody. The Vmax for cyclic AMP hydrolysis by PDE4 was lower at birth when compared to adult levels in cerebral cortex, cerebellum, and neostriatum. K(m) values for cyclic AMP hydrolysis by PDE4, in contrast, did not change throughout the observed period in any brain region tested. The developmental patterns for PDE4 were significantly different among the examined brain regions. PDE4 activity in olfactory bulb and hippocampus also was found to be lower at birth in comparison to adult levels. Immunoblot analyses showed that developmental patterns of PDE4 were significantly different for the various subtypes, and also varied substantially across brain regions. The results suggest that PDE4 might be differentially regulated by different ontogenetic events.
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PMID:Ontogeny of rolipram-sensitive, low-K(m), cyclic AMP-specific phosphodiesterase in rat brain. 997 55


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