Quaternary Lidocaine Derivatives: Past, Present, and Future

Wang, Qi; Zhang, Yujun; Liu, Jin; Zhang, Wensheng

doi:10.2147/dddt.s291229

Cited by 11 publications

(7 citation statements)

References 83 publications

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“…We next decided to explore molecules targeting membrane proteins. The quaternary ammonium-based sodium channel blockers QX222 and QX314 are commonly used in neuroscience and lack cellular permeability. − When applied internally (e.g., through a patch pipet), channel blocking can be observed, while external application to cells does not show any effect (Figure S6). We decided to synthesize a series of analogs without lipid tail ( C0-QX ), with a MCL tail ( C10-QX ), and with a LCL tail ( C16-QX ).…”

Section: Resultsmentioning

confidence: 99%

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

et al. 2022

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The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule–membrane interactions, and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the “natural product lipidome”. According to this analysis, lipidated natural products predominantly contain saturated medium-chain lipids (MCLs), which are significantly shorter than the long-chain lipids (LCLs) found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that MCL conjugation can render molecules cell-permeable and modulate their bioactivity. With all explored chemotypes, MCL-conjugates consistently exhibited superior uptake or bioactivity compared to LCL-conjugates and either comparable or superior uptake or bioactivity to short-chain lipid (SCL)-conjugates. Together, our findings suggest that conjugation of small molecules with MCLs could be a powerful strategy for the design of probes and drugs.

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Section: Resultsmentioning

confidence: 99%

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

et al. 2022

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“…The short duration of action remains the major shortcoming of lidocaine, limiting its use in certain clinical scenarios. Although the discovery of bupivacaine seemed to solve this problem, the pronounced cardiotoxicity with difficult resuscitation remains a concern in the clinical setting [59 ▪▪ ].…”

Section: Quaternary Lidocaine Derivatives: Novel Developments In Regi...mentioning

confidence: 99%

“…A novel class of local anesthetics known as quaternary lidocaine derivatives (QLD) has recently gained significant research interest with high hopes that they might solve some of the issues described with current local anesthetics [59 ▪▪ ]. Although the mechanism of action of QLD is identical to other local anesthetics [60], the hydrophilic nature and permanent positive charge requires substantial time and concentration gradient to penetrate the neuronal and axonal membrane, which accounts for both the slow onset and prolonged duration of action of QLD.…”

Section: Quaternary Lidocaine Derivatives: Novel Developments In Regi...mentioning

confidence: 99%

Novel anesthetics in pediatric practice: is it time?

Useinovic¹,

Jevtović-Todorović²

2022

Current Opinion in Anaesthesiology

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Purpose of reviewSteadily mounting evidence of anesthesia-induced developmental neurotoxicity has been a challenge in pediatric anesthesiology. Considering that presently used anesthetics have, in different animal models, been shown to cause lasting behavioral impairments when administered at the peak of brain development, the nagging question, 'Is it time for the development of a new anesthetic' must be pondered. Recent findingsThe emerging 'soft analogs' of intravenous anesthetics aim to overcome the shortcomings of currently available clinical drugs. Remimazolam, a novel ester-analog of midazolam, is a well tolerated intravenous drug with beneficial pharmacological properties. Two novel etomidate analogs currently in development are causing less adrenocortical suppression while maintaining equally favorable hemodynamic stability and rapid metabolism. Quaternary lidocaine derivatives are explored as more potent and longer lasting alternatives to currently available local anesthetics. Xenon, a noble gas with anesthetic properties, is being considered as an anesthetic-sparing adjuvant in pediatric population. Finally, alphaxalone is being reevaluated in a new drug formulation because of its favorable pharmacological properties.

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“…The quaternary ammonium-based sodium channel blockers QX222 and QX314 are commonly used in neuroscience and lack cellular permeability. [53][54][55] When applied internally (e.g. through a patch pipette), channel blocking can be observed, while external application to cells does not show any effect.…”

Section: Cellular Uptake Of Fluorophore-lipid Conjugatesmentioning

confidence: 99%

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

Capecchi

Hinnah²,

Petit-Jacques

et al. 2021

Preprint

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The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule-membrane interactions and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the ‘natural product lipidome’. According to this analysis, lipidated natural products predominantly contain saturated linear medium-length lipids, which are significantly shorter than those found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that medium-length lipid tails can render impermeable molecules cell-permeable and switch on their bioactivity. Saturated medium-length lipids (e.g. C10) are found to be ideal for the bioactivity of small molecules in mammalian cells, while saturated long-chain lipids (e.g. C18) often significantly reduce bioavailability and activity. Together, our findings suggest that conjugation of small molecules with medium-length lipids could be a powerful strategy for the design of probes and drugs.

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Quaternary Lidocaine Derivatives: Past, Present, and Future

Cited by 11 publications

References 83 publications

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity

Novel anesthetics in pediatric practice: is it time?

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

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