Optimization of bifunctional piperidinamide derivatives as σ1R Antagonists/MOR agonists for treating neuropathic pain

Xiong, Jiaying; Zhuang, Tao; Ma, Yurong; Xu, Jianguo; Ye, Jiaqi; Ma, Ru; Zhang, Shuang; Liu, Xin; Liu, Bi‐Feng; Hao, Chao; Zhang, Guisen; Chen, Yin

doi:10.1016/j.ejmech.2021.113879

Cited by 13 publications

(13 citation statements)

References 54 publications

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“…The MTDL strategy involving σ1 has also recently associated histamine H3, 38 or µ opioid receptor. 39 Further work will be needed to probe the full therapeutic potential of a D4 and σ1 dual ligand, but it might be very promising, as judged by the prominent role of both receptors in CNS functions.…”

Section: Discussionmentioning

confidence: 99%

Discovery of potent dual ligands for dopamine D4 and σ1 receptors

Levoin

Murthy

Narendar³

et al. 2022

Bioorganic & Medicinal Chemistry

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Section: Discussionmentioning

confidence: 99%

Discovery of potent dual ligands for dopamine D4 and σ1 receptors

Levoin

Murthy

Narendar³

et al. 2022

Bioorganic & Medicinal Chemistry

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“…Over a period of 15 min, unrestrained mice were monitored. The inspiration time, expiration time, peak inspiratory flow, peak expiratory flow, VOLBAL, frequency, tidal volume, minute volume, accumulated volume, expiratory flow 50 (expiratory flow at 50% volume), end expiratory pause, end inspiratory pause, relaxation time, enhanced pause, and ratio of TE (peak expiratory flow relative to total expiratory time) were determined by ResMass version 1.4.2.8 (TOW‐INT TECH) as previously described (Sun et al, 2021; Xiong et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

“…Cell proliferation was analyzed by CCK-8 assay (#C0038; Beyotime Institute of Biotechnology) as previously described (Jin et al, 2017). Xiong et al, 2021).…”

Section: Cell Proliferationmentioning

confidence: 99%

Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription

et al. 2022

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Determining the mechanism of senescence‐associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence‐associated pulmonary fibrosis by activating TGF‐β1/IL‐11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF‐β1/IL‐11/MEK/ERK signaling‐mediated senescence‐associated pulmonary fibrosis in vitamin D‐deficient (Cyp27b1−/−) mice, and whether Sirt1 downregulated IL‐11 expression transcribed by TGF‐β1/Smad2 signaling through deacetylating histone at the IL‐11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild‐type (WT) mice were examined for cell senescence, fibrosis markers, and TGF‐β1/IL‐11/MEK/ERK signaling proteins, and 1,25(OH)2D3 and IL‐11 levels were detected in serum. Nine‐week‐old WT, Sirt1 mesenchymal transgene (Sirt1Tg), Cyp27b1−/−, and Sirt1TgCyp27b1−/− mice were observed the pulmonary function, aging, and senescence‐associated secretory phenotype and TGF‐β1/IL‐11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF‐β1/IL‐11/MEK/ERK signaling, and promoting senescence‐associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence‐associated secretory phenotype, and fibrosis through downregulating TGF‐β1/IL‐11/MEK/ERK signaling in Cyp27b1−/− mice. Sirt1 negatively regulated IL‐11 expression through deacetylating H3K9/14ac mainly at the region from −871 to −724 of IL‐11 promoter, also the major binding region of Smad2 which regulated IL‐11 expression at the transcriptional level, and subsequently inhibiting TGF‐β1/IL‐11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence‐associated pulmonary fibrosis induced by vitamin D deficiency.

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“…These authors combined ( Figure 11 ) N -phenylpropionamide fragment (of fentanyl structure) with the 4-benzylpiperidine (of RC-106 8.85 , a pan-sigma ligand) [ 119 ]. In the works of theirs [ 119 , 120 ], over 60 dual ligands ( 8.86 – 8.147 , Figure 11 and Table S6 ) were reported to have been synthesized and tested ( Table S6 ). Around a half of the published examples had K i < 100 nM for either of the receptors of focus.…”

Section: Fentanyl-related Mtas Targeting Mor and σ 1 ...mentioning

confidence: 99%

“…As a result of SAR work around compound 8.104 [ 120 ], racemic compounds 8.110 ( Figure 11 B) and 8.131 ( Table S6 ) were identified as very promising. Enantiomers of 8.110 were synthesized and assayed ( 8.146 and 8.147 , Figure 11 B).…”

Section: Fentanyl-related Mtas Targeting Mor and σ 1 ...mentioning

confidence: 99%

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

Lipiński

Matalińska

2022

IJMS

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One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached. The non-opioid ‘second’ targets included proteins as diverse as imidazoline I2 binding sites, CB1 cannabinoid receptor, NK1 tachykinin receptor, D2 dopamine receptor, cyclooxygenases, fatty acid amide hydrolase and monoacylglycerol lipase and σ1 receptor. Reviewing the individual attempts, we outline the chemistry, the obtained pharmacological properties and structure-activity relationships. Finally, we discuss the possible directions for future work.

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Optimization of bifunctional piperidinamide derivatives as σ1R Antagonists/MOR agonists for treating neuropathic pain

Cited by 13 publications

References 54 publications

Discovery of potent dual ligands for dopamine D4 and σ1 receptors

Discovery of potent dual ligands for dopamine D4 and σ1 receptors

Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics

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