Selective Phosphodiesterase 4B Inhibitors: A Review

Azam, Mohammed Afzal

doi:10.3797/scipharm.1404-08

Cited by 44 publications

(31 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Various studies indicate that increased cAMP signaling is associated with an anxiety-like phenotype and suggest that elevated cAMP activity is associated with abnormal reactivity to novel environments [11, 12], stress-coping responses [13, 14], and an overall increased anxiety [15-18]. Thus, therapeutic manipulation of PKA activation, such as decreasing phosphorylation of cAMP–CREB might lead to new treatment strategies for anxiety, addiction, or psychiatric disorders [3, 19-21]. …”

Section: Introductionmentioning

confidence: 99%

Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA’s catalytic subunits in anxiety

Briassoulis

Keil²,

Naved³

et al. 2016

Behavioural Brain Research

View full text Add to dashboard Cite

Cyclic adenosine mono-phosphate-dependent protein kinase (PKA) is critically involved in the regulation of behavioral responses. Previous studies showed that PKA's main regulatory subunit, R1α, is involved in anxiety-like behaviors. The purpose of this study was to determine how the catalytic subunit, Cα, might affect R1α's function and determine its effects on anxiety-related behaviors. The marble bury (MB) and elevated plus maze (EPM) tests were used to assess anxiety-like behavior and the hotplate test to assess nociception in wild type (WT) mouse, a Prkar1a heterozygote (Prkar1a+/-) mouse with haploinsufficiency for the regulatory subunit (R1α), a Prkaca heterozygote (Prkaca+/-) mouse with haploinsufficiency for the catalytic subunit (Cα), and a double heterozygote mouse (Prkar1a+/-/Prkaca+/-) with haploinsufficiency for both R1α and Cα. We then examined specific brain nuclei involved in anxiety. Results of MB test showed a genotype effect, with increased anxiety-like behavior in Prkar1a+/- and Prkar1a+/-/Prkaca+/- compared to WT mice. In the EPM, Prkar1a+/- spent significantly less time in the open arms, while Prkaca+/- and Prkar1a+/-/Prkaca+/- mice displayed less exploratory behavior compared to WT mice. The loss of one Prkar1a allele was associated with a significant increase in PKA activity in the basolateral (BLA) and central (CeA) amygdala and ventromedial hypothalamus (VMH) in both Prkar1a+/- and Prkar1a+/- /Prkaca+/- mice. Alterations of PKA activity induced by haploinsufficiency of its main regulatory or most important catalytic subunits result in anxiety-like behaviors. The BLA, CeA, and VMH are implicated in mediating these PKA effects in brain.

show abstract

Section: Introductionmentioning

confidence: 99%

Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA’s catalytic subunits in anxiety

Briassoulis

Keil²,

Naved³

et al. 2016

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…These observations show that these compounds are bound to the PDE4B active site in a similar manner to other selective inhibitors . Additionally, this docking experiment shows that compounds as 6 or 12 are existing as two 4‐methoxyphenylpyridazinone units that individually contribute to the enzyme binding.…”

Section: Resultsmentioning

confidence: 52%

Design and Synthesis of Substituted Pyridazinone‐1‐Acetylhydrazones as Novel Phosphodiesterase 4 Inhibitors

Abdel‐Rahman

Abdel‐Aziz

Tinsley

et al. 2015

Archiv der Pharmazie

View full text Add to dashboard Cite

A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit phosphodiesterase 4 (PDE4B). The prepared compounds were evaluated for their in vitro ability to inhibit the PDE4B enzyme; several of these compounds showed moderate activity compared to the reference drug, rolipram. Compounds 6, 12, and 14 emerged as the most potent inhibitors in this series. The [3-(4-methoxyphenyl)-6-oxo-5,6-dihydro-4H-pyridazin-1-yl]acetic acid [1-(3,4,5-trimethoxyphenyl)ethylidene]hydrazide (12) showed an IC50 value of 13 μM against PDE4B. Docking of 6, 12, and 14 into the active site of PDE4B illustrates their possible binding mode and provides insights for further optimization of this drug scaffold.

show abstract

“…Since PDE-4-inhibitors increase intracellular cAMP concentrations and activate PKA, the tonic and phasic contractions are suppressed easily, suggesting the inhibition of other target proteins through PKA-mediated phosphorylation, such as Rho-kinase (ROCK), because ROCK phosphorylates the myosin phosphatase-targeting subunit (MLCP-MYPT1), diphosphorylates the myosin regulatory light chain, and phosphorylates MLCP to cause contraction, as reported in vascular smooth muscle and human myometrium [323334]. Further evidence indicates that some PDE-4 inhibitors could block the calcium influx, such as rolipram and the thalidomide analogs herein tested, because of their similar structure to nifedipine, verapamil and nicardipine, what leads to uterine relaxation [62935]; in fact, the present results again suggest that both analogs blocked the calcium influx. In sum, the results are in agreement with other reports where forskolin and rolipram [3637], as well as these thalidomide analogs cause uterine relaxation by increasing cAMP and perhaps by the novel mechanism of action of rolipram and thalidomide analogs as potential Ca 2+ -channel blockers [6].…”

Section: Discussionmentioning

confidence: 91%

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

Muñoz-Pérez

Fernández-Martínez

Ponce‐Monter

et al. 2017

Korean J Physiol Pharmacol

View full text Add to dashboard Cite

The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K+-induced tonic, and Ca2+-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-1β, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced TNFα and IL-1β uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.

show abstract

Selective Phosphodiesterase 4B Inhibitors: A Review

Cited by 44 publications

References 76 publications

Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA’s catalytic subunits in anxiety

Studies of mice with cyclic AMP-dependent protein kinase (PKA) defects reveal the critical role of PKA’s catalytic subunits in anxiety

Design and Synthesis of Substituted Pyridazinone‐1‐Acetylhydrazones as Novel Phosphodiesterase 4 Inhibitors

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus

Contact Info

Product

Resources

About