Cyclic nucleotide phosphodiesterases: Pharmacology, biochemistry and function

doi:10.1016/0163-7258(91)90039-O

Pharmacology & Therapeutics

Volume 51, Issue 1, 1991, Pages 13-33

https://doi.org/10.1016/0163-7258(91)90039-O Get rights and content

Abstract

This article is a review of cyclic nucleotide phosphodiesterase(s) (CN PDE) from the point of view of the relationships between the newer aspects of the complex enzymology of CN PDE and recent major advances in CN PDE pharmacology. A consolidation of isozyme nomenclature to the proposed family designations is recommended. Emphasis is placed on the importance of defining the subcellular localization of isozymes expressed in a given tissue and cyclic GMP substrate and regulatory roles in CN PDE isozyme function. CN PDe inhibitors that may be useful for experimental and clinical purposes are discussed. Examples of these inhibitors include CGS 9343B, TCV-3B, KW-6, MIMAX, Dihydroisoquinolines, Trequinsin, bipyridine and dihydropyridazinone cardiotonics, Rolipram, SQ 65442, Zaprinast and Dipyridamole.

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The long and winding road of designing phosphodiesterase inhibitors for the treatment of heart failure
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
In general, PDEs are found in their dimeric form through the association of two enzymatic subunits [7]. The monomeric structure of all isoforms is composed by 3 distinct domains: a catalytic, an N-terminal, and a C-terminal domains [8–10]. The C-terminal domain is conserved in all PDE families, with the exception of PDE6, which shares 18–46% homology [11].
Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes known to play a critical role in the indirect regulation of several intracellular metabolism pathways through the selective hydrolysis of the phosphodiester bonds of specific second messenger substrates such as cAMP (3′,5′-cyclic adenosine monophosphate) and cGMP (3′,5′-cyclic guanosine monophosphate), influencing the hypertrophy, contractility, apoptosis and fibroses in the cardiovascular system. The expression and/or activity of multiple PDEs is altered during heart failure (HF), which leads to changes in levels of cyclic nucleotides and function of cardiac muscle. Within the cardiovascular system, PDEs 1–5, 8 and 9 are expressed and are interesting targets for the HF treatment. In this comprehensive review we will present a briefly description of the biochemical importance of each cardiovascular related PDE to the HF, and cover almost all the “long and winding road” of designing and discovering ligands, hits, lead compounds, clinical candidates and drugs as PDE inhibitors in the last decade.
Inhibition of type 4 cAMP-phosphodiesterases (PDE4s) in mice induces hypothermia via effects on behavioral and central autonomous thermoregulation
2020, Biochemical Pharmacology
Citation Excerpt :
As such a significant decrease in body temperature may by itself exert critical effects on immune responses, and because the role of PDE4 in body temperature regulation remains poorly understood, we have further explored this observation. Piclamilast/RP73401 [29,30], Rolipram [31], Roflumilast [32], Cilostamide [33], Chlorcyclizine [34], Spiperone [35], and Pimozide [36] were from Cayman Chemical (Ann Arbor, MI, USA). YM976 [37] was obtained from Tocris/Bio-Techne (Minneapolis, MN, USA), Naloxone [38] from MP Biomedicals (Irvine, CA), Domperidone [39] from Alfa Aesar (Haverhill, MA, USA), Ketanserin [35] from TCI America (Portland, OR, USA), Propranolol [40,41] from Millipore Sigma (St. Louis, MO, USA), and RS25344 [42] from Santa Cruz Biotech (Santa Cruz, CA, USA).
Inhibitors of Type 4 cAMP-phosphodiesterases (PDE4s) exert a number of promising therapeutic benefits, including potent anti-inflammatory, memory- and cognition-enhancing, metabolic, and antineoplastic effects. We report here that treatment with a number of distinct PDE4 inhibitors, including Rolipram, Piclamilast, Roflumilast and RS25344, but not treatment with the PDE3-selective inhibitor Cilostamide, induces a rapid (10–30 min), substantial (−5 °C) and long-lasting (up to 5 h) decrease in core body temperature of C57BL/6 mice; thus, identifying a critical role of PDE4 also in the regulation of body temperature. As little as 0.04 mg/kg of the archetypal PDE4 inhibitor Rolipram induces hypothermia. As similar or higher doses of Rolipram were used in a majority of published animal studies, most of the reported findings are likely paralleled by, or potentially impacted by hypothermia induced by these drugs. We further show that PDE4 inhibition affects central body temperature regulation and acts by lowering the cold-defense balance point of behavioral (including posture and locomotion) and autonomous (including cutaneous tail vasodilation) cold-defense mechanisms. In line with the idea of an effect on central body temperature regulation, hypothermia is induced by moderate doses of various brain-penetrant PDE4 inhibitors, but not by similar doses of YM976, a PDE4 inhibitor that does not efficiently cross the blood–brain barrier. Finally, to begin delineating the mechanism of drug-induced hypothermia, we show that blockade of D_2/3-type dopaminergic, but not β-adrenergic, H₁-histaminergic or opiate receptors, can alleviate PDE4 inhibitor-induced hypothermia. We thus propose that increased D_2/3-type dopaminergic signaling, triggered by PDE4 inhibitor-induced and cAMP-mediated dopamine release in the thermoregulatory centers of the hypothalamus, is a significant contributor to PDE4 inhibitor-induced hypothermia.
Cyclic nucleotide phosphodiesterase inhibitors: possible therapeutic drugs for female fertility regulation
2020, European Journal of Pharmacology
Cyclic nucleotide phosphodiesterases (PDEs) are group of enzymes responsible for the hydrolysis of cyclic adenosine 3′, 5′ monophosphate (cAMP) and cyclic guanosine 3′, 5′ monophosphate (cGMP) levels in wide variety of cell types. These PDEs are detected in encircling granulosa cells or in oocyte with in follicular microenvironment and responsible for the decrease of cAMP and cGMP levels in mammalian oocytes. A transient decrease of cAMP level initiates downstream pathways to cause spontaneous meiotic resumption from diplotene arrest and induces oocyte maturation. The nonspecific PDE inhibitors (caffeine, pentoxifylline, theophylline, IBMX etc.) as well as specific PDE inhibitors (cilostamide, milrinone, org 9935, cilostazol etc.) have been used to elevate cAMP level and inhibit meiotic resumption from diplotene arrest and oocyte maturation, ovulation, fertilization and pregnancy rates both in vivo as well as under in vitro culture conditions. The PDEs inhibitors are used as powerful experimental tools to demonstrate cyclic nucleotide mediated changes in ovarian functions and thereby fertility. Indeed, non-hormonal nature and reversible effects of nonspecific as well as specific PDE inhibitors hold promise for the development of novel therapeutic drugs for female fertility regulation.
Negative inotropic effects of diadenosine tetraphosphate are mediated by protein kinase C and phosphodiesterases stimulation in the rat heart
2018, European Journal of Pharmacology
Citation Excerpt :
This assumption allows suggesting that Ap4A-induced PDE stimulation in the rat heart is PKC dependent. It is known that N-terminal domain of PDE4 contain specific phosphorylation sites for protein kinases, while PDE3 represents several sites for phosphorylation by PKC (Hunter et al., 2009; Thompson, 1991). There have been demonstrated PKC mediated phosphorylation of PDE3 and PDE4 in various tissues including heart (Bian et al., 2000; Hunter et al., 2009).
Extracellular diadenosine polyphosphates (Ap_nA) are recently considered as an endogenous signaling compounds with transmitter-like activity which present in numerous tissues, including heart. It has been demonstrated previously that extracellular Ap_nA cause alteration of the heart functioning via purine receptors in different mammalian species. Nevertheless, principal intracellular pathways which underlie Ap_nA action in the heart remain unknown. In the present study the role of the P2Y-associated intracellular regulatory pathway in the mediation of diadenosine tetraphosphate (Ap₄A) effects in the rat heart has been investigated for the first time.
Extracellular Ap₄A caused significant decreasing of the ventricular inotropy. Ap₄A evoked reduction of the left ventricle contractility in the isolated Langendorff-perfused rat hearts, decreasing of the Ca²⁺ transients in the enzymatically isolated ventricular cardiomyocytes and induced shortening of action potentials in the ventricle multicellular preparations. The inhibitory effects of Ap₄A in the rat heart were significantly attenuated by protein kinase C (PKC) inhibitor chelerythrine but these effects were not affected by NO-synthase inhibitor L-NAME and guanylyl cyclase (sGC) inhibitor ODQ. In addition, substantial attenuation of Ap₄A-caused negative inotropy in the left ventricle was produced by nonselective phsophodiesterase (PDE) inhibitor IBMX, while PDE type 2 inhibitor EHNA was ineffective.
In conclusion, our results allow suggesting that Ap₄A-induced inhibitory effects in the rat heart are mediated by PKC, but not by NO/sGC/PKG-related signaling pathway. In addition, PDE stimulation may contribute to Ap₄A-caused inhibition of the rat heart contractility.
Inhibition of mitochondrial pyruvate transport by Zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina
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Transport of pyruvate into mitochondria by the mitochondrial pyruvate carrier is crucial for complete oxidation of glucose and for biosynthesis of amino acids and lipids. Zaprinast is a well known phosphodiesterase inhibitor and lead compound for sildenafil. We found Zaprinast alters the metabolomic profile of mitochondrial intermediates and amino acids in retina and brain. This metabolic effect of Zaprinast does not depend on inhibition of phosphodiesterase activity. By providing ¹³C-labeled glucose and glutamine as fuels, we found that the metabolic profile of the Zaprinast effect is nearly identical to that of inhibitors of the mitochondrial pyruvate carrier. Both stimulate oxidation of glutamate and massive accumulation of aspartate. Moreover, Zaprinast inhibits pyruvate-driven O₂ consumption in brain mitochondria and blocks mitochondrial pyruvate carrier in liver mitochondria. Inactivation of the aspartate glutamate carrier in retina does not attenuate the metabolic effect of Zaprinast. Our results show that Zaprinast is a potent inhibitor of mitochondrial pyruvate carrier activity, and this action causes aspartate to accumulate at the expense of glutamate. Our findings show that Zaprinast is a specific mitochondrial pyruvate carrier (MPC) inhibitor and may help to elucidate the roles of MPC in amino acid metabolism and hypoglycemia.
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We previously demonstrated that parotid saliva cAMP and cGMP were lower in patients with taste and smell dysfunction than in normal subjects. We subsequently demonstrated parotid saliva cAMP and cGMP were inversely correlated with smell loss degree such that as smell loss severity increased parotid saliva cAMP and cGMP decreased proportionately. To learn more about these relationships we studied parotid saliva cAMP and cGMP with respect to aetiology of sensory loss in these patients.
Parotid saliva cAMP and cGMP in patients with smell loss (hyposmia) who participated in an open label fixed design controlled clinical trial with treatment with oral theophylline were evaluated with respect to their initial etiological diagnosis. Levels of cyclic nucleotides in each etiological category were compared to each other, to the entire patient group and to normal subjects.
Mean cAMP and cGMP in all patients combined were below those in normals, as previously described. However, categorized by aetiology, there was a stratification of levels of both cyclic nucleotides; some levels were below the normal mean and some were at or above the normal mean.
Parotid saliva cyclic nucleotides characterised in hyposmic patients by aetiology indicate (1) there are differential alterations in these nucleotides related to aetiology of sensory dysfunction and (2) these moieties measured prior to treatment indicate which patient groups may benefit from treatment with phosphodiesterase (PDE) inhibitors which increase levels of these moieties and thereby correct their sensory dysfunction.

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Cyclic nucleotide phosphodiesterases: Pharmacology, biochemistry and function

Abstract

J. Pharmac. Sci.

TIPS

J. biol. Chem.

Biochem. Pharmac.

J. biol. Chem.

J. biol. Chem.

TIPS

Biochim. biophys. Acta

Biochem. Pharmac.

J. biol. Chem.

Archs Biochem. Biophys.

Molec. cell. Endocr.

Life Sci.

J. biol. Chem.

TIPS

Cell. Sig.

Am. J. Cardiol.

Biochem. Pharmac.

J. biol. Chem.

Biochem. Pharmac.

Biochem. Pharmac.

J. biol. Chem.

J. Molec. cell. Cardiol.

Thromb. Res.

A potent and selective inhibitor of cyclic AMP phosphodiesterase with potential cardiotonic and antithromotic properties

Molec. Pharmac.

Analysis of the binding sites for the cardiotonic phosphodiesterase inhibitor [3H]-LY186126 in ventricular myocardium

Molec. Pharmac.

Cyclic AMP turnover in response to prostaglandins in intact platelets: evidence for separate stimulatory and inhibitory prostaglandin receptors

Sec. Mess. Phos.

Role of high affinity cAMP phosphodiesterase activities in the response of S49 Cells to agonists

Molec. Pharmac.

The role of cyclic nucleotides in atrial natriuretic peptide-mediated inhibition of aldosterone secretion

Endocrinology

Multiple isozymes of cyclic nucleotide phosphodiesterase

Adv. Sec. Mess. Phos. Res.

Multiple phosphodiesterase isozymes: background, nomenclature and implications

Rat mast cell high affinity cyclic nucleotide phosphodiesterases: separation and inhibitory effects of two antiallergic agents

Molec. Pharmac.

Mechanism of action and cardiotonic activity of a new phosphodiesterase inhibitor, the benzimidazole derivative adibendan (BM 14,478), in Guinea-Pig Hearts

Naunyn-S-chmidebergs Arch. Pharmac.

Inhibition of gastric acid secretion in vivo and in vitro by new calmodulin antagonist, CGS 9343B

J. Pharmac. exp. Ther.

Resolution of soluble rat cardiac phosphodiesterase by high performance liquid chromatography

Sec. Mess. Phos.

Retinal degeneration in the RD mouse is caused by a defect in the beta subunit

Nature

Purification of an insulin-sensitive cyclic AMP phosphodiesterase from rat liver

Eur. J. Biochem.

Selective inhibition of cAMP phosphodiesterase III Activity by the cardiotonic agent saterinone in guinea pig myocardium

A.F. Drug Res.

Phosphodiesterase after twenty years: an introduction

Adv. cyc. Nucl. Prot. Phos. Res.

Defect in Cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophilia Melanogaster

Nature

Effects of selective phosphodiesterase inhibition on cyclic AMP hydrolysis in rat cerebral cortical slices

Br. J. Pharmac.

Structure-function relationships among cyclic nucleotide phosphodiesterases

Identification of a conserved domain among cyclic nucleotide phosphodiesterases from diverse species

Identification of a noncatalytic cGMP-binding domain conserved in both the cGMP stimulated and photoreceptor cyclic nucleotide phosphodiesterase

Inhibitors and activators of cyclic nucleotide phosphodiesterase

Adv. cycl. Nucl. Res.

Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce + gene, the structural gene for cAMP phosphodiesterase

Isolation and characterization of a mammalian gene encoding a high affinity cAMP phosphodiesterase

New positive inotropic agents in the treatment of congestive heart failure

New Engl. J. Med.