Discovery of WLB-89462, a New Drug-like and Highly Selective σ2 Receptor Ligand with Neuroprotective Properties DOI

Ute Christmann,

José Luis Dı́az, Rosalía Pascual

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(17), С. 12499 - 12519

Опубликована: Авг. 22, 2023

The synthesis and pharmacological activity of a new series isoxazolylpyrimidines as sigma-2 receptor (σ2R) ligands are reported. Modification hit retrieved in an HTS campaign allowed the identification compound WLB-89462 (20c) with good σ2R affinity (Ki = 13 nM) high selectivity vs both σ1R 1777 general panel 180 targets. It represents one first drug-like properties, linked to physicochemical ADMET profile (good solubility, no CYP inhibition, metabolic stability, permeability, brain penetration, oral exposure rodents). Compound 20c shows neuroprotective vitro improves short-term memory impairment induced by hippocampal injection amyloid β peptide rats. Together promising effects chronic models where is currently being evaluated, these results pave way toward its clinical development agent.

Язык: Английский

Structures of the σ2 receptor enable docking for bioactive ligand discovery DOI
Assaf Alon, Jiankun Lyu, João M. Bráz

и другие.

Nature, Год журнала: 2021, Номер 600(7890), С. 759 - 764

Опубликована: Дек. 8, 2021

Язык: Английский

Процитировано

148
Reducing acetylated tau is neuroprotective in brain injury DOI Creative Commons

Min-Kyoo Shin,

Edwin Vázquez‐Rosa, Yeojung Koh

и другие.

Cell, Год журнала: 2021, Номер 184(10), С. 2715 - 2732.e23

Опубликована: Апрель 14, 2021

Язык: Английский

Процитировано

143
Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury DOI Creative Commons
Sarah Barker, Bindu D. Paul, Andrew A. Pieper

и другие.

Biomedicines, Год журнала: 2023, Номер 11(4), С. 1154 - 1154

Опубликована: Апрель 11, 2023

Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number TBI survivors, impact and awareness this problem are growing. The mechanisms by which increases disease, however, not completely understood. a result, there no protective treatments for patients. Here, we review current literature surrounding epidemiology potential mechanistic relationships between In addition to increasing all forms dementia, most prominent conditions that accelerated amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), Alzheimer's (AD), with ALS FTD being least well-established. Mechanistic links reviewed include oxidative stress, dysregulated proteostasis, neuroinflammation. Disease-specific TAR DNA binding protein 43 motor cortex lesions FTD; alpha-synuclein, dopaminergic cell death, synergistic toxin exposure PD; insulin resistance, amyloid beta pathology, tau pathology AD. While compelling have been identified, expanded investigation field is needed develop therapies protect

Язык: Английский

Процитировано

27
P7C3-A20 treatment one year after TBI in mice repairs the blood–brain barrier, arrests chronic neurodegeneration, and restores cognition DOI Creative Commons
Edwin Vázquez‐Rosa, Min‐Kyoo Shin, Matasha Dhar

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2020, Номер 117(44), С. 27667 - 27675

Опубликована: Окт. 21, 2020

Significance Chronic neurodegeneration, a major cause of the long-term disabilities that afflict survivors traumatic brain injury (TBI), is linked to an increased risk for late-life neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s vascular dementia, and chronic encephalopathy. Here, we report on restoration blood–brain barrier (BBB) structure function by P7C3-A20 when administered 12 mo after TBI. This pharmacotherapy was associated with cessation neurodegeneration recovery normal cognitive function, benefits persisted long treatment cessation. Pharmacologic renewal BBB integrity may thus provide new option patients who have suffered remote TBI, or other neurological conditions deterioration.

Язык: Английский

Процитировано

60
Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation DOI Creative Commons
Catherine Larochelle,

Beatrice Wasser,

Hélène Jamann

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(34)

Опубликована: Авг. 20, 2021

Significance Multiple sclerosis (MS) is a neuroinflammatory, demyelinating disease that represents one of the most frequent causes irreversible disability in young adults. Treatment options to halt are limited. We discovered T helper (Th)17 cells contact with oligodendrocytes produce higher levels glutamate and induce significantly greater oligodendrocyte damage than their Th2 counterpart. Blockade CD29, which linked release pathways expressed high on Th17 cells, preserved human processes from Th17-mediated injury. Our data thus provide evidence for direct deleterious attack myelin compartment show potential therapeutic opportunities protect oligodendrocytes’ myelinating MS.

Язык: Английский

Процитировано

44
Accurate identification of circRNA landscape and complexity reveals their pivotal roles in human oligodendroglia differentiation DOI Creative Commons
Yangping Li, Feng Wang, Peng Teng

и другие.

Genome biology, Год журнала: 2022, Номер 23(1)

Опубликована: Фев. 7, 2022

Circular RNAs (circRNAs), a novel class of poorly conserved non-coding that regulate gene expression, are highly enriched in the human brain. Despite increasing discoveries circRNA function neurons, landscape and developing oligodendroglia, myelinating cells govern neuronal conductance, remains unexplored. Meanwhile, improved experimental computational tools for accurate identification circRNAs needed.We adopt published approach enrichment develop CARP (CircRNA using A-tailing RNase R Pseudo-reference alignment), comprehensive 21-module framework quantification. Using CARP, we identify developmentally programmed oligodendroglia landscapes HOG oligodendroglioma cell line, distinct from landscapes. Numerous display oligodendroglia-specific regulation upon differentiation, among which subclass is regulated independently their parental mRNAs. We find flanking introns often contain cis-regulatory elements RNA editing predicted to bind differentiation-regulated splicing factors. In addition, discover sponge microRNAs, co-operatively promote development. Furthermore, clusters derived alternative circularization events within same gene, each containing common circular exon, achieving additive sponging effects differentiation.Our results reveal dynamic during early differentiation suggest critical roles circRNA-miRNA-mRNA axis advancing

Язык: Английский

Процитировано

23
Highly specific σ 2 R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response DOI Creative Commons
Muhammad Saad Yousuf,

James J. Sahn,

Hongfen Yang

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(52)

Опубликована: Дек. 20, 2023

The sigma 2 receptor (σ

Язык: Английский

Процитировано

13
Sigma-2 Receptor—A Potential Target for Cancer/Alzheimer’s Disease Treatment via Its Regulation of Cholesterol Homeostasis DOI Creative Commons
Kai Yang, Cheng Zeng,

Changcai Wang

и другие.

Molecules, Год журнала: 2020, Номер 25(22), С. 5439 - 5439

Опубликована: Ноя. 20, 2020

The sigma receptors were classified into sigma-1 and sigma-2 receptor based on their different pharmacological profiles. In the past two decades, our understanding of biological properties is increasing; however, little known about receptor. Recently, molecular identity has been identified as TMEM97. Although more evidence showed that ligands have ability to treat cancer Alzheimer’s disease (AD), mechanisms connecting these diseases are unknown. Data obtained over few years from human animal models indicate cholesterol homeostasis altered in AD cancer, underscoring importance cancer. this review, accumulated evidence, we proposed beneficial roles might be mediated by regulation homeostasis.

Язык: Английский

Процитировано

35
Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of Pancreatic Cancer DOI
Joyeeta Roy, Armita Kyani,

Maha Hanafi

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(3), С. 1990 - 2019

Опубликована: Янв. 24, 2023

Sigma 2 receptor (σ2R) is overexpressed in select cancers and regarded as a biomarker for tumor proliferation. σ2R ligands are emerging promising theranostics cancer neurodegenerative diseases. Herein, we describe the design synthesis of series novel quinolyl pyrazinamides selective potent that show sub-micromolar potency pancreatic cell lines. Compounds 14 (JR1-157) 17 (JR2-298) bind with Ki 47 10 nM, respectively. Importantly, compound has an oral bioavailability 60% shows significant vivo efficacy without obvious toxicity syngeneic model cancer. The cytotoxicity significantly enhanced presence copper diminished copper-chelator tetrathiomolybdate. In conclusion, water-soluble, metabolically stable, orally active, increases expression autophagy marker LC3B warrants further development treatment

Язык: Английский

Процитировано

12
Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury DOI Creative Commons
Preethy Sridharan, Yeojung Koh, Emiko Miller

и другие.

Cell Reports Medicine, Год журнала: 2024, Номер 5(9), С. 101715 - 101715

Опубликована: Сен. 1, 2024

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers persisting 17 months later, equivalent to many human decades. We show increased mouse related levels 1 protein (Fis1) and Fis1 also TBI. Pharmacologically preventing from binding its partner, dynamin-related (Drp1), for 2 weeks normalizes the balance fission/fusion prevents chronically impaired bioenergetics, oxidative damage, microglial activation lipid droplet formation, blood-brain barrier deterioration, neurodegeneration, cognitive impairment. Delaying treatment until 8 offers protection. Thus, time-sensitive inhibition may represent strategy protect patients neurodegeneration.

Язык: Английский

Процитировано

4