Zaprinast

IC50: 0.15, 0.76, 12.0 and 29.0 μM for PDE6, 5, 11 and 9 respectively.

Zaprinast is a phosphodiesterase inhibitor with selection for PDE6, 5, 11 and 9[1].

Several isoforms of phosphodiesterases (PDEs) can mediate their action of the diverse cellular and behavioral responses to these second messengers. Accordingly, these responses are modulated by the rates of synthesis of cyclic nucleotides by cyclases as well as their degradation by PDEs to biologically inactive 59 monophosphate nucleosides.

In vitro: Zaprinast is a PDE5 and PDE6 inhibitor with inhibiting PDE9 at moderately high concentrations (29 mM) [1]. Indeed, it showed that inhibition of cGMP hydrolysis by infusion of zaprinast increases the effect of ANP on natriuresis with no causing deleterious drops in blood pressure. Because it was known that ANP receptors is localized within the glomerulus and inner medullary collecting ducts, to determine the cellular localization of PDE9 enzyme in kidney will be interesting. [2]. The enzyme displayed a high specificity for cGMP with binding sites for cGMP, and a sensitivity to zaprinast similar to smooth muscle PDE5, resulting in both enzymes were named cGMP-PDE. However, retinal cGMP-PDE was first distinguished as photoreceptor cGMP-PDE with being specifically distributed in the retina and having a higher Vmax and Km values than other cGMP-PDEs and being modulated by G protein. [3].

In vivo: So far, no study in vivo has been conducted.

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Christensen and Torphy (1994) Isozyme-selective phosphodiesterase inhibitors as antiasthmatic agents.  Annu.Rep.Med.Chem. 29 185.
[2] Soderling SH, Bayuga SJ, Beavo JA.  Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem. 1998 Jun 19; 273(25):15553-8.
[3].  Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther. 2006 Mar; 109 (3):366-98. Epub 2005 Aug 15.

Kynurenic acid and zaprinast induce analgesia by modulating HCN channels through GPR35 activation.[Pubmed:27131920]

Neuropharmacology. 2016 Sep;108:136-43.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have a key role in the control of cellular excitability. HCN2, a subgroup of the HCN family channels, are heavily expressed in small dorsal root ganglia (DRG) neurons and their activation seems to be important in the determination of pain intensity. Intracellular elevation of cAMP levels activates HCN-mediated current (Ih) and small DRG neurons excitability. GPR35, a Gi/o coupled receptor, is highly expressed in small DRG neurons, and we hypothesized that its activation, mediated by endogenous or exogenous ligands, could lead to pain control trough a reduction of Ih current. Patch clamp recordings were carried out in primary cultures of rat DRG neurons and the effects of GPR35 activation on Ih current and neuronal excitability were studied in control conditions and after adenylate cyclase activation with either forskolin or prostaglandin E2 (PGE2). We found that both kynurenic acid (KYNA) and Zaprinast, the endogenous and synthetic GPR35 agonist respectively, were able to antagonize the forskolin-induced depolarization of resting membrane potential by reducing Ih-mediated depolarization. Similar results were obtained when PGE2 was used to activate adenylate cyclase and to increase Ih current and the overall neuronal excitability. Finally, we tested the analgesic effect of both GPR35 agonists in an in vivo model of PGE2-induced thermal hyperalgesia. In accord with the hypothesis, both KYNA and Zaprinast showed a dose dependent analgesic effect. In conclusion, GPR35 activation leads to a reduced excitability of small DRG neurons in vitro and causes a dose-dependent analgesia in vivo. GPR35 agonists, by reducing adenylate cyclase activity and inhibiting Ih in DRG neurons may represent a promising new group of analgesic drugs.

Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus.[Pubmed:25281278]

Behav Brain Res. 2015 Feb 1;278:129-36.

In this work, we report the effect of post-training intraperitoneal administration of Zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30 min after the Zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30 min after the Zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of Zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors.

Comparative Relaxant Effects of Ataciguat and Zaprinast on Sheep Sphincter of Oddi.[Pubmed:27606143]

Balkan Med J. 2016 Jul;33(4):453-7.

BACKGROUND: Relaxing the sphincter of Oddi (SO) is an important process during endoscopic retrograde cholangiopancreatography (ERCP) procedures. This issue suggests that the easier the sphincterotomy and cannulation, the more post-ERCP complications decrease. AIMS: To compare the relaxant effects of ataciguat (a novel soluble guanylyl cyclase activator) and Zaprinast (an inhibitor of phosphodiesterase 5) on sheep SO in vitro, thus testing whether they can be used during ERCP. STUDY DESIGN: Animal experimentation. METHODS: Sheep SO rings were placed in tissue baths and their isometric tension to ataciguat and Zaprinast were tested. We also tested their isometric tension against ataciguat in the presence of 1H-(1,2,4) oxadiazole (4,3-a) quinoxalin-1-one (ODQ) which is a soluble guanylyl cyclase inhibitor. RESULTS: Ataciguat and Zaprinast both triggered concentration addicted relaxation on sheep SO rings (p=0.0018, p=0.0025 respectively) but the relaxation of the ataciguat was significantly greater than that of Zaprinast at all concentrations (p=0.0024). It was observed that decreased relaxation responses were initiated by ataciguat in the presence of ODQ (p=0.0012). CONCLUSION: Ataciguat and Zaprinast both have relaxing effects on sphincter of Oddi, although that of Zaprinast is lower. We believe that ataciguat and Zaprinast can be used in ERCP procedures in order to relax the sphincter of Oddi and thus can be used locally in order to decrease complications.

Infliximab reduces Zaprinast-induced retinal degeneration in cultures of porcine retina.[Pubmed:25301432]

J Neuroinflammation. 2014 Oct 10;11:172.

BACKGROUND: cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4 to 5% of retinitis pigmentosa (RP), a rare form of retinal dystrophy. Growing evidence suggests that inflammation is involved in the progression of RP. The aims of this study were to corroborate the presence of high TNFalpha concentration in the eyes of RP patients and to evaluate whether the blockade of TNFalpha with Infliximab, a monoclonal anti-TNFalpha antibody, prevented retinal degeneration induced by PDE6 inhibition in cultures of porcine retina. METHODS: Aqueous humor from 30 patients with RP and 13 healthy controls were used to quantify the inflammatory mediators IL-6, TNFalpha, IL-1beta, IL-10 by a multiplex enzyme-linked immunosorbent assay (ELISA) system. Retinal explants from pig were exposed to Zaprinast, a PDE6 inhibitor, for 24 hours in the absence or the presence of Infliximab. Cell death was evaluated by TUNEL assay. The number and distribution of caspase-3 positive cells, indirect poly(ADP)ribose polymerase (PARP) activation and glial fibrillary acidic protein (GFAP) content were visualized by immunolabeling. Antioxidant total capacity, nitrites and thiobarbituric acid reactive substances (TBARS) formation were determined to evaluate antioxidant-oxidant status. RESULTS: IL-6 and TNFalpha concentrations were higher in the aqueous humor of RP patients than in controls. Infliximab prevented retinal degeneration, as judging by the reduced presence of TUNEL-positive cells, the reduction of caspase-3 activation and also reduction of glial activation, in an ex vivo model of porcine retina. Additionally, Infliximab partially reduced oxidative stress in retinal explants exposed to Zaprinast. CONCLUSIONS: Inflammatory mediators IL-6 and TNFalpha were elevated in the aqueous humor of RP patients corroborating previous studies suggesting sustained chronic inflammation. Our study suggests that TNFalpha is playing an important role in cell death in an ex vivo model of retinal degeneration by activating different cell pathways at different cell layers of the retina that should be further studied.

Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.[Pubmed:16102838]

Pharmacol Ther. 2006 Mar;109(3):366-98.

Cyclic nucleotide phosphodiesterases (PDEs), which are ubiquitously distributed in mammalian tissues, play a major role in cell signaling by hydrolyzing cAMP and cGMP. Due to their diversity, which allows specific distribution at cellular and subcellular levels, PDEs can selectively regulate various cellular functions. Their critical role in intracellular signaling has recently designated them as new therapeutic targets for inflammation. The PDE superfamily represents 11 gene families (PDE1 to PDE11). Each family encompasses 1 to 4 distinct genes, to give more than 20 genes in mammals encoding the more than 50 different PDE proteins probably produced in mammalian cells. Although PDE1 to PDE6 were the first well-characterized isoforms because of their predominance in various tissues and cells, their specific contribution to tissue function and their regulation in pathophysiology remain open research fields. This concerns particularly the newly discovered families, PDE7 to PDE11, for which roles are not yet established. In many pathologies, such as inflammation, neurodegeneration, and cancer, alterations in intracellular signaling related to PDE deregulation may explain the difficulties observed in the prevention and treatment of these pathologies. By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.

Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35.[Pubmed:16934253]

FEBS Lett. 2006 Sep 18;580(21):5003-8.

We found that Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, acted as an agonist for a G protein-coupled receptor, GPR35. In our intracellular calcium mobilization assay, Zaprinast activated rat GPR35 strongly (geometric mean EC(50) value of 16nM), whereas it activated human GPR35 moderately (geometric mean EC(50) value of 840nM). We also demonstrated that GPR35 acted as a Galpha(i/o)- and Galpha(16)-coupled receptor for Zaprinast when heterologously expressed in human embryonic kidney 293 (HEK 293) cells. These findings will facilitate the research on GPR35 and the drug discovery of the GPR35 modulators.

Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases.[Pubmed:9624145]

J Biol Chem. 1998 Jun 19;273(25):15553-8.

We report the cloning, expression, and characterization of a new family of cyclic nucleotide phosphodiesterase (PDE) that has unique kinetic and inhibitor specificities. A clone corresponding to the C terminus of this PDE was initially identified by a bioinformatic approach and used to isolate a cDNA that is likely full-length. This novel PDE, designated as MMPDE9A1, shows highest mRNA expression in kidney with lower levels in liver, lung, and brain. The mRNA size by Northern blot analysis is approximately 2.0 kilobases, and the cDNA encoding PDE9A1 is 1929 base pairs in length. The largest open reading frame predicts a protein of 534 amino acids with a molecular mass of 62,000 Da. When expressed in COS-7 cells, PDE9A1 activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methyl-xanthine or the new selective PDE5 inhibitor, sildenafil, but it is inhibited by the PDE1/5 inhibitor (+)-cis-5,6a, 7,8,9 hyl] phenylmethyl]-5-methyl-cylopent[4,5]imidao[2, 1-b]purin-49(3H)one (SCH51866) with an IC50 of 1.55 microM. This new phosphodiesterase is highly specific for cGMP. Its Km of approximately 0.07 microM for cGMP is the lowest yet reported for a PDE, being at least 40-170 times lower than that of PDE5 and PDE6, respectively.

Zaprinast (M&B 22948) is an inhibitor of cGMP-selective Phosphodiesterases(PDEs). Zaprinast is a G protein-coupled receptor (GPR) 35 agonist which activates rat GPR35 strongly and activates human GPR35 moderately. Zaprinast reduces vessel remodeling through antiproliferative and proapoptotic effects.

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