Small-molecule phosphodiesterase probes: discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1

Humphrey, John M.; Yang, Eddie; Ende, Christopher W. am; Arnold, Eric P.; Head, Jenna L.; Jenkinson, Stephen; Lebel, Lorraine A.; Liras, Spiros; Pandit, Jayvardhan; Samas, Brian; Vajdos, F.F.; Simons, Samuel P.; Evdokimov, A.G.; Mansour, Mahmoud N.; Menniti, Frank S.

doi:10.1039/c4md00113c

Cited by 33 publications

(37 citation statements)

References 26 publications

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“…To measure the Ca 2+ /calmodulin-independent component of the PDE activity, we performed assays in the presence of EGTA and without added Ca 2+ /calmodulin. Addition of the PDE1 inhibitor PF-04822163 [ 43 ] to the assay mixture reduced the basal cGMP-hydrolyzing activity in the follicle lysates by ∼45%, but did not inhibit the increase in cGMP hydrolysis in response to LH ( Fig. 2 A).…”

Section: Resultsmentioning

confidence: 99%

“…2 A). PF-04822163 was used at 100 nM, a concentration that is specific for PDE1 [ 43 ]. These results indicated that Ca 2+ /calmodulin-independent PDE1 activity accounts for ∼45% of the basal cGMP-hydrolytic activity.…”

Section: Resultsmentioning

confidence: 99%

“…S3, B–D), 100 nM sildenafil could be used as a specific inhibitor of PDE5. At 3 μM, PF-04822163 has little effect on other cyclic nucleotide phosphodiesterases except for PDE10 [ 43 ], which is not expressed at a detectable level (Supplemental Figs. S3A and S4).…”

Section: Resultsmentioning

confidence: 99%

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Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis1

Egbert

Uliasz

Shuhaibar

et al. 2016

Biology of Reproduction

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The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis1

Egbert

Uliasz

Shuhaibar

et al. 2016

Biology of Reproduction

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“…We tested a new PDE1 inhibitor, PF1 at 1 µM, a concentration chosen to be 10-times higher than its IC 50 for PDE1, 30-times lower than its IC 50 for PDE3, PDE4 or PDE9 and 10-times lower than its IC 50 for PDE5 (Humphrey et al, 2014). In this condition, PF1 totally abolished the Ca 2+ /CaM-stimulated cAMP-and cGMP-PDE activities measured in the lysates of the RASMCs, strongly supporting a PDE1 inhibitory action of PF1.…”

Section: Role Of Pde1 Pde5 and Pde9 In The Control Of Rasmcs Prolifementioning

confidence: 99%

“…Thus, the aim of the present study was to investigate the role of PDE1 in cyclic nucleotide compartmentation in synthetic VSMCs. We took advantage of a new quinazoline-based compound, PF-04471141 (named PF1), described as a potent inhibitor of PDE1 family (with IC 50 of 35-118 nM for human PDE1 subtypes) with more than 30-to 100-fold selectivity over other PDE families (Humphrey et al, 2014). To monitor intracellular cyclic nucleotide concentrations, fluorescence live cell imaging was conducted in cultured rat aortic SMCs (RASMCs) using Förster resonance energy transfer (FRET)-based sensors, an approach that has been widely used to evaluate the real-time dynamics of cAMP-or cGMP-dependent signals (Sprenger and Nikolaev, 2013).…”

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Cyclic nucleotide signalling compartmentation by PDEs in cultured vascular smooth muscle cells

Zhang

Bouadjel

Manoury

et al. 2019

British J Pharmacology

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Role of Cyclic Nucleotide Phosphodiesterases During Meiotic Resumption From Diplotene Arrest in Mammalian Oocytes

et al. 2016

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Cyclic nucleotide phosphodiesterases (PDEs) are group of enzymes that hydrolyze cyclic nucleotides in wide variety of cell types including encircling granulosa cells as well as associated oocytes. One group of PDEs are located in encircling granulosa cells and another group get expressed in the oocyte, while few other PDEs are expressed in both compartments. The PDE1A, PDE4D, PDE5A, PDE8A, and PDE8B are granulosa cell specific PDEs that hydrolyze adenosine 3',5'-cyclic monophosphate (cAMP) as well as guanosine 3',5'-cyclic monophosphate (cGMP) with different affinities. PDE3A, PDE8A as well as PDE9A are expressed in oocyte and specifically responsible for the cyclic nucleotide hydrolysis in the oocyte itself. Few other PDEs such as PDE7B, PDE10A, and PDE11A are either detected in granulosa cells or oocytes. Activation of these PDEs either in encircling granulosa cells or in oocyte directly or indirectly reduces intraoocyte cAMP level. Reduction of intraoocyte cAMP level modulates phosphorylation status of cyclin-dependent kinase 1 (Cdk1) and triggers cyclin B1 degradation that destabilizes maturation promoting factor (MPF) and/or increases Cdk1 activity. The destabilized MPF and/or increased Cdk1 activity leads to resumption of meiosis, which initiates the achievement of meiotic competency in preovulatory follicles of several mammalian species. Use of specific PDEs inhibitors block cyclic nucleotides hydrolysis that results in increase of intraoocyte cyclic nucleotides level, which leads to maintenance of meiotic arrest at diplotene stage in vivo as well as in vitro. Thus, cyclic nucleotide PDEs play important role in the achievement of meiotic competency by reducing intraoocyte cyclic nucleotides level in mammalian oocytes. J. Cell. Biochem. 118: 446-452, 2017. © 2016 Wiley Periodicals, Inc.

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Small-molecule phosphodiesterase probes: discovery of potent and selective CNS-penetrable quinazoline inhibitors of PDE1

Abstract: We describe the discovery of potent, selective, brain penetrable quinazoline inhibitors of PDE1 that represent valuable new tools for the dissection of related biological events.

Cited by 33 publications

References 26 publications

Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis1

Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis1

Cyclic nucleotide signalling compartmentation by PDEs in cultured vascular smooth muscle cells

Role of Cyclic Nucleotide Phosphodiesterases During Meiotic Resumption From Diplotene Arrest in Mammalian Oocytes

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