Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability

Kinney, William A.; McDonnell, Mark E.; Zhong, Hua; Liu, Chaomin; Yang, Lanyi; Ling, Wei; Tao, Qian; Chen, Yu; Cai, Zixing; Petkanas, Dean; Brenneman, Douglas E.

doi:10.1021/acsmedchemlett.6b00009

Cited by 43 publications

(47 citation statements)

References 21 publications

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“…Other studies have used dissociated hippocampal cultures derived from embryonic day 18 rats to measure toxicity and neuroprotective responses to CBD. These studies indicate that the EC 50 of CBD is within the 1–4 μ m range while causing neurotoxicity at 33 μ m ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of cannabidiol on voltage-dependent sodium currents

Ghovanloo

Shuart

Mezeyova

et al. 2018

Journal of Biological Chemistry

154

243

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Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1–1.7 currents, with an IC50 of 1.9–3.8 μm, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures. We conclude that CBD's mode of action likely involves 1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and 2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.

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Section: Introductionmentioning

confidence: 99%

Inhibitory effects of cannabidiol on voltage-dependent sodium currents

Ghovanloo

Shuart

Mezeyova

et al. 2018

Journal of Biological Chemistry

154

243

View full text Add to dashboard Cite

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“…The neuroprotective properties of CBD against oligomycin, an inhibitor of ATP synthetase, 10 and ammonium acetate and ethanol in the hippocampal neuron culture also have been reported. 13 Oxidative stress is thought to cause pathological conditions in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotropic lateral sclerosis. 14,15 The cytoprotective effect of CBD against hydrogen peroxide (H 2 O 2 ), a crucial metabolic molecule in the oxidative stress, 16 was reported for cerebellar granule cells 17 and oligodendrocyte progenitor cells, 18 but there have been no reports on its effect against H 2 O 2 in the neurons that are more relevant to the brain function, such as hippocampal neurons.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Cannabidiol Against Hydrogen Peroxide in Hippocampal Neuron Culture

Jungnam

Choi

Seo

et al. 2021

Cannabis and Cannabinoid Research

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Introduction: Reports on the neurotoxic and neuroprotective effects of cannabidiol (CBD) have not been in complete accord, showing different and somewhat contradictory results depending upon the brain cell types and experimental conditions employed. This work systematically examines the neuroprotective capability of CBD against oxidative stress (i.e., hydrogen peroxide [H 2 O 2 ]) as well as its toxicity profile in the in vitro culture platform of primary hippocampal neurons. Materials and Methods: The low cell-density (100 neurons per mm 2) culture was used for analyzing the viability and morphology of neurons at a single-cell level with a confocal laser-scanning microscope (CLSM). Primary neurons were obtained from the hippocampal tissues of embryonic day-18 (E18) Sprague-Dawley rat pups and treated with CBD (0.1-100 lM) and/or H 2 O 2 (0.1-50 lM) at 1 DIV (days in vitro). Results: The lethal concentration 50 (LC 50) value (the concentration causing 50% cell death) of CBD was calculated to be 9.85 lM after 24 h of incubation, and that of H 2 O 2 was 2.46 lM under the same conditions. The neuroprotection ratio of CBD against H 2 O 2 ([H 2 O 2 ] = 10 lM) was 2.40 with 5 lM of CBD, increasing the cell viability to 57% from 24%. The CLSM analysis suggested that the cell-death mechanisms were different for CBD and H 2 O 2 , and CBD did not completely rescue the morphological alterations of primary hippocampal neurons caused by H 2 O 2 , such as neurite degeneration, at least in the in vitro neuron culture. Conclusion: Although CBD showed both neurotoxic and neuroprotective effects on hippocampal neurons in the in vitro setting, the use of low-concentrated (i.e., 5 lM) CBD, not causing toxic effects on the neurons, significantly rescued the neurons from the oxidative stress (H 2 O 2), confirming its neuroprotection capability.

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“…Synthetic C4′ analogs of (−)‐CBD have been designed and executed for achieving better potency, safety, and permeability, as a neuroprotective drug, than (−)‐CBD . For example, the compound 43 , having the N ‐acetyl azetidine moiety, showed better pharmacological performance: the EC 50 value of 2,000 n m (EC 50 of (−)‐CBD: 40 m m ) and 400‐fold‐enhanced in vitro safety for hippocampal neurons. The synthesis of the compound 43 was started with the compound 50 (Scheme ).…”

Section: C4′ Analogsmentioning

confidence: 99%

Synthetic Strategies for (−)‐Cannabidiol and Its Structural Analogs

Jung

Lee

Jungnam

et al. 2019

Chemistry An Asian Journal

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À)-Cannabidiol ((À)-CBD), an on-psychoactive phytocannabinoid from Cannabis,a nd its structural analogs have received growinga ttention in recent years because of their potentialt herapeutic benefits, including neuroprotective, anti-epileptic,a nti-inflammatory,a nxiolytic, and anticancer properties. (À)-CBD and its analogs have been obtained mainly based on extraction from the natural source; however,t he conventional extraction-based methods have some drawbacks, such as poor quality controla long with purification difficulty.C hemical-synthetic strategies for (À)-CBD could tackle these issues, and, additionally,g enerate novel (À)-CBD analogs that exhibit advanced biological activities. This review concisely summarizes the historic and recent milestones in the synthetic strategies for (À)-CBD and its analogs.

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Discovery of KLS-13019, a Cannabidiol-Derived Neuroprotective Agent, with Improved Potency, Safety, and Permeability

Cited by 43 publications

References 21 publications

Inhibitory effects of cannabidiol on voltage-dependent sodium currents

Inhibitory effects of cannabidiol on voltage-dependent sodium currents

Neuroprotective Effect of Cannabidiol Against Hydrogen Peroxide in Hippocampal Neuron Culture

Synthetic Strategies for (−)‐Cannabidiol and Its Structural Analogs

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