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)

Despite its potent proconvulsant effects in vitro, the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) does not induce seizures when administered in vivo. This contrasts with the effects of less selective adenosine antagonists such as theophylline or cyclopentlytheophylline, and led us to reexamine the nature of DPCPX-induced epileptiform activity. In the present study, we report that proconvulsant effects of bath-applied DPCPX in rat hippocampal slices are only observed after a preceding stimulus such as NMDA receptor activation or brief tetanic stimulation. While this may be due to the absence of a basal "purinergic tone", the relatively high interstitial concentrations of adenosine present in the slice suggest that access of the drug to A1 receptors may instead be prevented by tightly coupled endogenous adenosine, with the ternary adenosine-A1 receptor-G protein complex stabilised in the high-affinity conformation by a coupling cofactor. This implies that a substantial percentage of adenosine A1 receptors are inactive under physiological conditions, but that access of adenosine A1 receptor antagonists may be facilitated under pathological conditions. Once induced, DPCPX-evoked spiking persists for long periods of time. A "kindling" effect of A1 receptor blockade is unlikely, since persistent spiking is not usually observed with less selective A1 antagonists even after prolonged application. Alternatively, endogenous adenosine released during increased neuronal activity may activate A2 receptors during selective A1 blockade. The most important factor determining the duration of DPCPX-induced spiking, however, may be a persistence of the drug in the tissue and subsequent access to the A1 receptor via a membrane-delineated pathway, since DPCPX-induced spiking could be shown to decrease markedly after a transient superfusion of theophylline. This hypothesis, which implies that the apparent affinity of adenosine antagonists for the A1 receptor is in part a function of their membrane partitioning coefficient, is supported by a close correlation between alkylxanthine logP values obtained from the literature and their Ki value at A1 receptors, but not at the enzyme phosphodiesterase, whose xanthine binding site is presented to the cytosol. The implications for the therapeutic value of purinergic drugs are discussed.
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PMID:Alkylxanthine adenosine antagonists and epileptiform activity in rat hippocampal slices in vitro. 906 16

To reverse the adverse reactions of alkylxanthines and to develop novel inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), a series of heterocycle-condensed purines were designed and synthesized. Some of these new compounds had similar or more potent and selective inhibitory activity against PDE IV than known PDE IV inhibitors. The tracheal-relaxant activity of these compounds was closely correlated with their PDE IV-inhibitory activity. Moreover, these purine analogues did not have any positive-chronotropic action or adenosine-antagonistic action on isolated heart preparations, which are the particular adverse reactions of alkylxanthines. Among them, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]-purin-5-one (1c), which was the most selective and potent PDE IV inhibitor, did not cause emesis in Suncus murinus at a dosage range of 10-100 mg/kg (po), while an imidazole analogue of 1c (4c) and known PDE IV inhibitors such as rolipram and denbufylline caused emesis even at 10 or 30 mg/kg.
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PMID:Selective inhibitors of cyclic AMP-specific phosphodiesterase: heterocycle-condensed purines. 937 44

The purpose of this experiment was to examine whether the cAMP-adenosine pathway is implicated in the autoregulatory vasodilation in response to hypotension. Suffusion with cAMP (1-100 micromol/l) or adenosine (0.01-10 micromol/l) caused a sustained vasodilation of the resting pial arteries in a concentration-dependent manner. In contrast, N6,2'-O-dibutyryl-cAMP and 8-bromo-cAMP exerted a weak dilation at high concentration (100 micromol/l). The vasodilation to cAMP (1-100 micromol/l), adenosine (0.01-10 micromol/l), and hypotension was significantly reduced by pretreatment with 3,7-dimethyl-1-propargylxanthine (1 micromol/l), an A2 receptor antagonist, as well as 3-isobutyl-1-methylxanthine (3 micromol/l), an inhibitor of endo- and ectophosphodiesterase, 1, 3-dipropyl-8-p-sulfophenylxanthine (100 micromol/l), an inhibitor of ecto-5'-phosphodiesterase, or alpha,beta-methylene-adenosine 5'-diphosphate (100 micromol/l), an inhibitor of ecto-5'-nucleotidase. However, 8-cyclopentyltheophylline (1 micromol/l), an A1 antagonist, did not elicit a similar response. The increased release of adenosine when the cortical surface was suffused with cAMP (100 micromol/l) was significantly reduced by 3-isobutyl-1-methylxanthine, 1,3-dipropyl-8-p-sulfophenylxanthine, and alpha,beta-methylene-adenosine 5'-diphosphate (each 100 micromol/l). These results indicate that the cAMP-adenosine pathway as a viable metabolic mechanism is implicated in the production of adenosine in the rat pial artery and contributes to the regulation of vasodilation in response to hypotension.
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PMID:Metabolism of cAMP to adenosine: role in vasodilation of rat pial artery in response to hypotension. 995 Aug 36

Because dinucleotides are signaling molecules that can interact with cell surface receptors and regulate the rate of mucociliary clearance in lungs, we studied their metabolism by using human airway epithelial cells. A membrane-bound enzyme was detected on the mucosal surface of polarized epithelia that metabolized dinucleotides with a broad substrate specificity (diadenosine polyphosphates and diuridine polyphosphates [Up(n)U], n = 2 to 6). The enzymatic reaction yielded nucleoside monophosphates (NMP) and Np(n)(-)(1) (N = A or U), and was inhibited by nucleoside 5'-triphosphates (alpha,betamet adenosine triphosphate [ATP] > ATP >/= uridine triphosphate > guanidine triphosphate > cytidine triphosphate). The apparent Michaelis constant (K(m,app)) and apparent maximal velocity (V(max,app)) for [(3)H]Up(4)U were 22 +/- 4 microM and 0.24 +/- 0.05 nmoles. min(-)(1). cm(-)(2), respectively. Thymidine 5'-monophosphate p-nitrophenyl ester and adenosine diphosphate (ADP)- ribose, substrates of ecto alkaline phosphodiesterase I (PDE I) activities, were also hydrolyzed by the apical surface of airway epithelia. ADP-ribose competed with [(3)H]Up(4)U, with a K(i) of 23 +/- 3 microM. The metabolism of ADP-ribose and Ap(4)A was not affected by inhibitors of cyclic nucleotide phosphodiesterases (3-isobutyl-1-methylxanthine, Ro 20-1724, and 1,3-dipropyl-8-p-sulfophenylxanthine), but similarly inhibited by fluoride and N-ethylmaleimide. These results suggest that a PDE I is responsible for the hydrolysis of extracellular dinucleotides in human airways. The wide substrate specificity of PDE I suggests that it may be involved in several signaling events on the luminal surface of airway epithelia, including purinoceptor activation and cell surface protein ribosylation.
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PMID:Biochemical evidence for an ecto alkaline phosphodiesterase I in human airways. 1091 94

The extracellular "cAMP-adenosine pathway" refers to the local production of adenosine mediated by cAMP egress into the extracellular space, conversion of cAMP to AMP by ectophosphodiesterase, and the metabolism of AMP to adenosine by ecto-5'-nucleotidase. The goal of this study was to assess whether the cAMP-adenosine pathway limits cardiac fibroblast growth. Studies were conducted in ventricular cardiac fibroblasts maintained in 3-dimensional cultures. Addition of exogenous cAMP to cardiac fibroblasts increased extracellular levels of AMP, adenosine, and inosine in a concentration-dependent and time-dependent manner. This effect was attenuated by blockade of total phosphodiesterase activity (3-isobutyl-1-methylxanthine), ectophosphodiesterase activity (high concentration of 1, 3-dipropyl-8-p-sulfophenylxanthine), or ecto-5'-nucleotidase (alpha, beta-methylene-adenosine-5'-diphosphate). Treatment with exogenous cAMP inhibited cell growth as assessed by DNA synthesis ((3)H-thymidine incorporation), cell proliferation (cell counts), and protein synthesis ((3)H-leucine incorporation). Antagonism of A(2) (KF17837) or A(1)/A(2) (low concentration of 1, 3-dipropyl-8-p-sulfophenylxanthine), but not A(1) (8-cyclopentyl-1, 3-dipropylxanthine), adenosine receptors blocked the growth-inhibitory effects of exogenous cAMP, but not the growth inhibitory effects of 8-bromo-cAMP (stable cAMP analogue). The growth-inhibitory effects of exogenous cAMP were enhanced by the combined inhibition of adenosine deaminase [erythro-9-(2-hydroxy-3-nonyl) adenine] and adenosine kinase (iodotubercidin). In conclusion, the extracellular cAMP-adenosine pathway exists in cardiac fibroblasts and attenuates cell growth. Pharmacological augmentation of this pathway could abate pathological cardiac remodeling in heart disease.
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PMID:Cardiac fibroblasts express the cAMP-adenosine pathway. 1098 61

Novel 2-propynylcyclohexyl-5'-N:-ehtylcarboxamidoadenosines, trans-substituted in the 4-position of the cyclohexyl ring, were evaluated in binding assays to the four subtypes of adenosine receptors (ARs). Two esters, 4-(3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-cyclohexanecarboxylic acid methyl ester (ATL146e) and acetic acid 4-(3-[6-amino-9-(5-ethylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl] -prop-2-ynyl)-cyclohexylmethyl ester (ATL193) were >50 x more potent than 2-[4-(2-carboxyethyl)phenethylamino]-5'-N:-ethylcarboxamidoadenosine (CGS21680) for human A(2A) AR binding. Human A(2A) AR affinity for substituted cyclohexyl-propynyladenosine analogues was inversely correlated with the polarity of the cyclohexyl side chain. There was a comparable order of potency for A(2A) AR agonist stimulation of human neutrophil [cyclic AMP](i), and inhibition of the neutrophil oxidative burst. ATL146e and CGS21680 were approximately equipotent agonists of human A(3) ARs. We measured the effects of selective AR antagonists on agonist stimulated neutrophil [cyclic AMP](i) and the effect of PKA inhibition on A(2A) AR agonist activity. ATL193-stimulated neutrophil [cyclic AMP](i) was blocked by antagonists with the potency order: ZM241385 (A(2A)-selective)>MRS1220 (A(3)-selective)>>N-(4-Cyano-phenyl)-2-[4-(2,6-dioxo-1,3-dipropyl-2,3,4,5,6,7-hexahydro-1H-purin-8-yl)-phenoxy]-acetamide (MRS1754; A(2B)-selective) approximately 8-(N-methylisopropyl)amino-N(6)-(5'-endohydroxy-endonorbornyl)-9-methyladenine (WRC0571; A(1)-selective). The type IV phosphodiesterase inhibitor, rolipram (100 nM) potentiated ATL193 inhibition of the oxidative burst, and inhibition by ATL193 was counteracted by the PKA inhibitor H-89. The data indicate that activation of A(2A)ARs inhibits neutrophil oxidative activity by activating [cyclic AMP](i)/PKA.
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PMID:Cyclic AMP-dependent inhibition of human neutrophil oxidative activity by substituted 2-propynylcyclohexyl adenosine A(2A) receptor agonists. 1122 32

It is well known that bronchial asthma is defined as chronic eosinophilic inflammation of the respiratory tract and that as one of the various types of inflammatory cells, eosinophils induce the airway inflammation of chronic asthma. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to play an important role in the prolongation of the survival of eosinophils. We investigated the inhibitory effect of the selective phosphodiesterase (PDE) 4 inhibitors, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]purin-5-one (XT-611) and rolipram, and the nonselective PDE inhibitor theophylline, against GM-CSF-induced prolongation of the survival of eosinophils isolated from patients with bronchial asthma. Eosinophils (10(6) cells/ml) were incubated in the presence of GM-CSF together with or without theophylline, rolipram or XT-611 at 37 degrees C, and the viable cells were assessed up to 4d using Trypan blue dye exclusion. The presence of theophylline (10(-4) M), rolipram (10(-4)-10(-5) M) or XT-611 (10(-4)-10(-5) M) significantly reduced the GM-CSF (10 pg/ml)-induced prolongation of viability of eosinophils. These findings suggest that selective PDE 4 inhibitors, including XT-611, may effectively reduce the activities of inflammatory cells in the airway of bronchial asthma patients.
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PMID:Selective phosphodiesterase type 4 inhibitors reduce the prolonged survival of eosinophils stimulated by granulocyte-macrophage colony-stimulating factor. 1185 62

We examined the effect of a phosphodiesterase 4 (PDE4) inhibitor, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]-purin-5-one (XT-611) on osteoclast formation in three different mouse bone-marrow cell (BMC) culture systems. We confirmed that selective inhibitors of PDE4, including XT-611, among several PDE inhibitors decreased osteoclast formation in the BMC culture system. XT-611 also inhibited osteoclast formation in co-culture of mouse bone-marrow stromal cell line ST2 and adherent cell-depleted (ACD)-BMCs. However, it did not inhibit osteoclastogenesis in culture of ACD-BMCs alone in the presence of macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of NF-kappaB ligand (sRANKL). XT-611 significantly increased prostaglandin E(2) (PGE(2)) production from ST2 cells and, in combination with PGE(2), synergistically increased cAMP concentration in osteoclast progenitors. In the ST2 co-culture system, XT-611 did not influence the expression of RANKL, osteoprotegerin and RANK mRNAs. By combined treatment with XT-611 and PGE(2) of ACD-BMCs, osteoclast multinucleation was clearly inhibited with decrease in the expression of calcitonin receptor mRNA, while the expression of RANK and c-fms (an M-CSF receptor) mRNAs was unchanged. These results indicate that the PDE4 inhibitor inhibits osteoclastogenesis by acting on osteoclast progenitors synergistically with PGE(2) secreted from stromal cells, but not by influencing the cell-to-cell interaction between stromal cells and osteoclast progenitors.
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PMID:Inhibition of osteoclastogenesis by a phosphodiesterase 4 inhibitor XT-611 through synergistic action with endogenous prostaglandin E2. 1294 61

Adenosine regulates tubular transport in collecting ducts (CDs); however, the sources of adenosine that modulate ion transport in CDs are unknown. The extracellular cAMP-adenosine pathway refers to the conversion of cAMP to AMP by ectophosphodiesterase, followed by metabolism of AMP to adenosine by ecto-5'-nucleotidase, with all steps occurring in the extracellular compartment. The goal of this study was to assess whether the extracellular cAMP-adenosine pathway exists in CDs. Studies were conducted in both freshly isolated CDs and in CD cells in culture (first passage) that were derived from isolated CDs. Purity of CDs was confirmed by microscopy, by Western blotting for aquaporin-1, aquaporin-2, bumetanide-sensitive cotransporter type 1, and thiazide-sensitive cotransporter; and by reverse transcription-polymerase chain reaction for adenosine receptors. Both freshly isolated CDs and CD cells in culture converted exogenous cAMP to AMP and adenosine. In both freshly isolated CDs and CD cells in culture, conversion of cAMP to AMP and adenosine was affected by a broad-spectrum phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine), an ectophosphodiesterase inhibitor (1,3-dipropyl-8-p-sulfophenylxanthine), and a blocker of ecto-5'-nucleotidase (alpha,beta-methylene-adenosine-5'-diphosphate) in a manner consistent with exogenous cAMP being processed by the extracellular cAMP-adenosine pathway. In CD cells in culture, stimulation of adenylyl cyclase increased extracellular concentrations of cAMP, AMP, and adenosine, and these changes were also modulated by the aforementioned inhibitors in a manner consistent with the extracellular cAMP-adenosine pathway. In conclusion, the extracellular cAMP-adenosine pathway is an important source of adenosine in CDs.
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PMID:Adenosine biosynthesis in the collecting duct. 1456 43

We investigated the structure-activity relationship of the (R)- and (S)-isomer of 7-methyl- and 8-alkyl-tetrahydroimidazo[2,1-i]purines for phosphodiesterase 4 (PDE4) inhibitors. (S)-8-Isopropyl-3,4-dipropyl-imizazo[2,1-i]purine (S)-2c exhibited both potent and selective PDE4 inhibitory activity.
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PMID:Cyclic AMP phosphodiesterase 4 isoenzyme inhibitory activity of (R)- and (S)-isomer of 7-methyl- or 8-alkyl-4,5,7,8-tetrahydroimidazo[2,1-i]- purin-5-one. 1499 2


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