更新于：2024-11-01

PDE1B x PDE10A

更新于：2024-11-01

基本信息

关联

项与 PDE1B x PDE10A 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 x PDE10A 相关的临床结果

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100 项与 PDE1B x PDE10A 相关的转化医学

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0 项与 PDE1B x PDE10A 相关的专利（医药）

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项与 PDE1B x PDE10A 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.

2019-10-01·Neurochemistry International3区 · 医学

Effect of phosphodiesterase (1B, 2A, 9A and 10A) inhibitors on central nervous system cyclic nucleotide levels in rats and mice

3区 · 医学

Article

作者: Zook, Douglas ; Crickard, Lindsay ; Tabatabaei, Ali ; Chen, Jie

Phosphodiesterase (PDE) inhibition has been broadly investigated as a target for a wide variety of indications including central nervous system (CNS) disorders. Cyclic nucleotide (cNT) changes within associated tissues may serve as a biomarker of PDE inhibition. We recently developed robust sample harvesting and bioanalytical methods to quantify cNT levels in rodent brain and cerebrospinal fluid (CSF). Herein, we report on the application of those methods to study rodent species-specific and rodent brain region-specific cNT changes following individual or concomitant PDE inhibitor administration. Male Sprague Dawley (Crl:CD^® [SD]) rats were dosed subcutaneously (sc) with a PDE1B inhibitor (DNS-0056), a PDE2A inhibitor (PF-05180999), a PDE9A inhibitor (PF-4447943), and a PDE10A inhibitor (MP10), each at a single dose of 10 or 30 mg/kg, or concomitantly with all 4 inhibitors at 10 mg/kg each. Male Carworth Farms (Crl:CF1 ^®[CF-1]) mice were dosed intraperitoneally (ip) with the four individual inhibitors at a single dose of 10 mg/kg or concomitantly with all 4 inhibitors at 10 mg/kg each. The doses studied are generally adequate for affecting measurable cNT levels in the tissues of interest and were thereby chosen for this investigation. Measured 3',5'-cyclic adenosine monophosphate (cAMP) changes were generally statistically insignificant in the brain, striatum and CSF after administration of the aforementioned PDE inhibitors. However, the levels of 3',5'-cyclic guanosine monophosphate (cGMP) increased in both rat and mouse striatum (2.2-, 2.1- and 1.7-fold and 6.4-, 2.8- and 1.7-fold, respectively) after PDE2A, 9A, and 10A inhibitor dosing. In all cases, the cNT changes followed the same trend in the brain, striatum and CSF after PDE inhibitor dosing and dose response was observed in rats. Concomitant treatment with PDE1B, PDE2A, PDE9A and PDE10A inhibitors resulted in a 4.4- and 36.7-fold increase of cGMP in rat and mouse striatum. The drug exposures after concomitant treatment were also higher than in the individual inhibitor-treated animals. cGMP enhancement observed could be due to synergistic effects, though an additive effect of the combined inhibitor concentrations may also contribute.

2019-02-01·Neurochemistry International3区 · 医学

Huntington's disease pattern of transcriptional dysregulation in the absence of mutant huntingtin is produced by knockout of neuronal GLT-1

3区 · 医学

Article

作者: Yan Sun ; Geraldine T. Petr ; Eileen M. Denovan-Wright ; Robert B. Laprairie ; Paul A. Rosenberg ; Kathryn D. Fischer

GLT-1 is the major glutamate transporter in the brain, and is expressed in astrocytes and in axon terminals in the hippocampus, cortex, and striatum. Neuronal GLT-1 accounts for only 5-10% of total brain GLT-1 protein, and its function is uncertain. In HD, synaptic dysfunction of the corticostriate synapse is well-established. Transcriptional dysregulation is a key feature of HD. We hypothesized that deletion of neuronal GLT-1, because it is expressed in axon terminals in the striatum, might produce a synaptopathy similar to that present in HD. If true, then some of the gene expression changes observed in HD might also be observed in the neuronal GLT-1 knockout. In situ hybridization using ³³P labeled oligonucleotide probes was carried out to assess localization and expression of a panel of genes known to be altered in expression in HD. We found changes in the expression of cannabinoid receptors 1 and 2, preproenkaphalin, and PDE10A in the striatum of mice in which the GLT-1 gene was inactivated in neurons by expression of synapsin-Cre, compared to wild-type littermates. These changes in expression were observed at 12 weeks of age but not at 6 weeks of age. No changes in DARPP-32, PDE1B, NGFIA, or β-actin expression were observed. In addition, we found widespread alteration in expression of the dynamin 1 gene. The changes in expression in the neuronal GLT-1 knockout of genes thought to exemplify HD transcriptional dysregulation suggest an overlap in the synaptopathy caused by neuronal GLT-1 deletion and HD. These data further suggest that specific changes in expression of cannabinoid receptors, preproenkephalin, and PDE10A, considered to be the hallmark of HD transcriptional dysregulation, may be produced by an abnormality of glutamate homeostasis under the regulation of neuronal GLT-1, or a synaptic disturbance caused by that abnormality, independently of mutation in huntingtin.