更新于：2024-11-01

PDE4 x GABAA receptor

更新于：2024-11-01

基本信息

关联

项与 PDE4 x GABAA receptor 相关的药物

AP-778

靶点

GABAA receptor x PDE4

作用机制

GABAA receptor调节剂 [+1]

在研机构-

原研机构

Algiax Pharmaceuticals GmbH

在研适应症-

非在研适应症

认知障碍 [+1]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

Etazolate

靶点

GABAA receptor x PDE4

作用机制

GABAA receptor调节剂 [+2]

在研机构-

原研机构

Bristol Myers Squibb Co.

在研适应症-

非在研适应症

阿尔茨海默症 [+4]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 PDE4 x GABAA receptor 相关的临床试验

NCT00880412 / Completed临床2期

A Pilot, Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicentre, Phase IIA Study to Determine the Clinical Safety/Tolerability and Exploratory Efficacy of EHT 0202 (40 and 80 mg Bid) as Adjunctive Therapy to Acetylcholinesterase Inhibitor Over a 3-month Period in Ambulatory Patients Suffering From Mild to Moderate Alzheimer's Disease (EHT 0202/002 Protocol)

The objective of this 3-month study is to assess the safety and efficacy of EHT 0202 in addition to acetylcholinesterase inhibitor in patients suffering from Alzheimer's Disease.

开始日期2008-04-01

申办/合作机构

Exonhit

EUCTR2007-005549-39-FR / Unknown statusN/A

A pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, phase IIa study to determine the clinical safety/tolerability and exploratory efficacy of EHT 0202 (40 and 80 mg bid) as adjunctive therapy to acetylcholinesterase inhibitor over a 3-month period in ambulatory patients suffering from mild to moderate Alzheimer’s Disease (EHT 0202/002 protocol).

开始日期2007-12-19

申办/合作机构

Exonhit

100 项与 PDE4 x GABAA receptor 相关的临床结果

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100 项与 PDE4 x GABAA receptor 相关的转化医学

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0 项与 PDE4 x GABAA receptor 相关的专利（医药）

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项与 PDE4 x GABAA receptor 相关的文献（医药）

2023-06-15·Neuropharmacology

Selective PDE4B and PDE4D inhibitors produce distinct behavioral responses to ethanol and GABAergic drugs in mice.

Article

作者: Blednov, Yuri A ; Mayfield, Jody ; Da Costa, Adriana ; Mason, Sonia ; Messing, Robert O

Apremilast is a phosphodiesterase (PDE) type 4 inhibitor that is nonselective at subtypes PDE4A-D. It modulates ethanol and GABAergic responses via protein kinase A (PKA) phosphorylation of specific GABA_A receptor subunits and has opposite effects on ethanol-induced ataxia in wild-type and GABA_A β3-S408/409A knock-in mice. We hypothesized that these different effects are due to preferential actions at different PDE4 subtypes. To test this hypothesis, we compared effects of selective PDE4 inhibitors on responses to ethanol and GABAergic drugs in male and female C57BL/6J mice. The PDE4B inhibitor A33 accelerated recovery from ataxia induced by ethanol and diazepam but did not alter ataxia induced by propofol. The PDE4D inhibitor D159687 accelerated recovery from diazepam-induced ataxia but prolonged recovery from ethanol- and propofol-induced ataxia. A33 shortened, while D159687 prolonged, the sedative-hypnotic effects of ethanol. Both drugs shortened diazepam's sedative-hypnotic effects. The modulatory effects of A33 and D159687 were completely prevented by the PKA inhibitor H89. Only D159687 prevented development of acute functional tolerance to ethanol-induced ataxia. D159687 transiently reduced two-bottle choice drinking in male and female mice that had consumed ethanol for 3 weeks and transiently reduced two-bottle choice, every-other-day drinking in male mice. A33 did not alter ethanol drinking in either procedure. Neither drug altered binge-like ethanol consumption or blood ethanol clearance. Thus, D159687 produced behavioral effects similar to apremilast, although it produced a more transient and smaller reduction in drinking. These results indicate that PDE4D inhibition contributes to apremilast's ability to reduce ethanol drinking, whereas PDE4B inhibition is not involved.

2018-05-01·Journal of Cellular and Molecular Medicine2区 · 医学

DW2008S and its major constituents from Justicia procumbens exert anti‐asthmatic effect via multitargeting activity

2区 · 医学

ArticleOA

作者: Lee, Hyunyong ; Yoon, Joobyoung ; Youm, Jihyun ; Choi, Youngwoo

AbstractOur previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin‐induced airway inflammation and airway hyper‐responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti‐asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A‐activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A3 (A3AR), which mediates mast cell‐dependent inflammation and bronchoconstriction. DW2008S and JB inhibited human phosphodiesterase 4 (PDE4), which is known to cause bronchoconstriction; however, the required concentrations were higher than those needed to affect TIGIT . These findings suggest that DW2008S can potentially ameliorate Th2‐driven airway inflammation and bronchoconstriction through negative regulation of TIGIT and blockade of A3AR and PDE4 activities.

2015-08-01·Neuroscience3区 · 医学

Methylxanthine-evoked perturbation of spontaneous and evoked activities in isolated newborn rat hippocampal networks

3区 · 医学

Article

作者: Kantor, C ; Kilb, W ; Sharopov, S ; Kuribayashi, J ; Luhmann, H J ; Ruangkittisakul, A ; Mildenberger, E ; Ballanyi, K

Treatment of apnea of prematurity with methylxanthines like caffeine, aminophylline or theophylline can evoke hippocampal seizures. However, it is unknown at which interstitial brain concentrations methylxanthines promote such neonatal seizures or interfere with physiological 'early network oscillations' (ENOs) that are considered as pivotal for maturation of hippocampal neural networks. We studied theophylline and caffeine effects on ENOs in CA3 neurons (CA3-ENOs) and CA3 electrical stimulation-evoked monosynaptic CA1 field potentials (CA1-FPs) in sliced and intact hippocampi, respectively, from 8 to 10-days-old rats. Submillimolar doses of theophylline and caffeine, blocking adenosine receptors and phosphodiesterase-4 (PDE4), did not affect CA3-ENOs, ENO-associated cytosolic Ca(2+) transients or CA1-FPs nor did they provoke seizure-like discharges. Low millimolar doses of theophylline (⩾1mM) or caffeine (⩾5mM), blocking GABAA and glycine receptors plus sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase (SERCA)-type Ca(2+) ATPases, evoked seizure-like discharges with no indication of cytosolic Ca(2+) dysregulation. Inhibiting PDE4 with rolipram or glycine receptors with strychnine had no effect on CA3-ENOs and did not occlude seizure-like events as tested with theophylline. GABAA receptor blockade induced seizure-like discharges and occluded theophylline-evoked seizure-like discharges in the slices, but not in the intact hippocampi. In summary, submillimolar methylxanthine concentrations do not acutely affect spontaneous CA3-ENOs or electrically evoked synaptic activities and low millimolar doses are needed to evoke seizure-like discharges in isolated developing hippocampal neural networks. We conclude that mechanisms of methylxanthine-related seizure-like discharges do not involve SERCA inhibition-related neuronal Ca(2+) dysregulation, PDE4 blockade or adenosine and glycine receptor inhibition, whereas GABA(A) receptor blockade may contribute partially.