更新于：2024-11-01

PDE1B

更新于：2024-11-01

基本信息

别名

63 kDa Cam-PDE、Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B、Cam-PDE 1B

+ [6]

简介

Cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes (PubMed:8855339, PubMed:9419816, PubMed:15260978). Has a preference for cGMP as a substrate (PubMed:9419816).

关联

项与 PDE1B 相关的药物

Compound 2(UCSI)

靶点

PDE10A x PDE1B

作用机制

PDE10A调节剂 [+1]

在研机构

Consejo Superior de Investigaciones Científicas

原研机构

UCSI University

在研适应症

真菌病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PDE1B 相关的临床结果

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100 项与 PDE1B 相关的转化医学

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0 项与 PDE1B 相关的专利（医药）

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项与 PDE1B 相关的文献（医药）

2024-10-01·Heliyon

Structural insight into the lead identification of a dual inhibitor of PDE1B and PDE10A: Integrating pharmacophore-based virtual screening, molecular docking, and structure-activity-relationship approaches

Article

作者: Soon, Ching Wen ; Al-Nema, Mayasah ; Gaurav, Anand ; Gautam, Vertika

Schizophrenia is a chronic neuropsychiatric disorder affecting more than 1% of the world's population. Current antipsychotic treatments show inadequacy in mitigating the negative and cognitive symptoms of schizophrenia. In addition, these medications cause undesirable extrapyramidal side effects. According to the studies, inhibition of phosphodiesterase (PDE) 1B and PDE10A simultaneously can alleviate positive, negative, and cognitive symptoms of schizophrenia. Thus, this study aims to identify new dual inhibitors of PDE1B and PDE10A using ligand-based pharmacophore modelling, virtual screening, and molecular docking studies. Accordingly, the generated pharmacophore models of PDE1B and PDE10A comprised hydrogen bond acceptor, aromatic ring, and hydrophobic features. These features were essential for retrieving the active hits from the Universal Natural Product Database in the virtual screening. Additional filters were subsequently employed to identify potential hits that could be developed into central nervous system-active compounds. Hits meeting all the screening criteria were subjected to docking studies with PDE1B and PDE10A. Among these hits, UNPD167314 exhibited significant binding affinities for the target receptors. It occupied the P-clamp and displayed hydrophobic, aromatic, and hydrogen bond interactions with the active site residues of both receptors, thus selected as a lead compound for the design of potent and selective dual inhibitors. The structural modifications of UNPD167314 resulted in the design of 35 novel inhibitors. Out of 35, four compounds exhibited high and comparable binding affinities for both PDE1B and PDE10A, making them promising candidates for further evaluation and optimisation.

2024-06-05·The Journal of Neuroscience

Circuit-Wide Gene Network Analysis Reveals Sex-Specific Roles for Phosphodiesterase 1b in Cocaine Addiction

Article

作者: Futamura, Rita ; Dong, Yan ; Zinsmaier, Alexander ; Minier-Toribio, Angelica ; Shen, Li ; Schmidt, Kyra H ; Ramakrishnan, Aarthi ; van der Zee, Yentl Y ; Markovic, Tamara ; Browne, Caleb J ; Azizian, Corrine H ; Yim, Yun Young ; Martinez-Rivera, Freddyson J ; Walker, Deena M ; Lucerne, Kelsey E ; Nestler, Eric J ; Zhou, Xianxiao ; Pulido, Nathalia V ; Zhang, Bin ; Holt, Leanne M ; Teague, Collin D ; Godino, Arthur

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b ( Pde1b ), a Ca 2+ /calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, Pde1b overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine.

2024-06-01·Journal of Applied Physiology

Fetal sex and the relative reactivity of human umbilical vein and arteries are key determinants in potential beneficial effects of phosphodiesterase inhibitors

Article

作者: Tolsa, Jean-François ; Beaumann, Manon ; Peyter, Anne-Christine ; Baud, David ; Delhaes, Flavien ; Menétrey, Steeve ; Joye, Sébastien

The effects of phosphodiesterase inhibition on the umbilical circulation depend on the presence of intrauterine growth restriction, the fetal sex, vessel type, and vasoconstrictors implicated. The human umbilical vascular tone regulation is complex and depends on the amount and activity of specific proteins but also probably on the subcellular organization mediating protein interactions. Therefore, therapeutic interventions using phosphodiesterase inhibitors to improve the placental-fetal circulation should consider fetal sex and both umbilical vein and artery reactivity.