Cannabidiol inhibits Nav channels through two distinct binding sites

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 17, 2023

Abstract Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with huge variety proteins, but which targets are most relevant clinical actions still unclear. Here we show that Na v 1.7 channels at sub-micromolar concentrations state-dependent manner. Electrophysiological experiments binds to the inactivated state dissociation constant about 50 nM. The cryo-EM structure bound reveals two distinct binding sites. One IV-I fenestration near upper pore. other site directly next “wedged” position Ile/Phe/Met (IFM) motif on short linker between repeats III IV, mediates fast inactivation. Consistent producing direct stabilization state, mutating residues this greatly reduced CBD. identification may enable design compounds improved properties compared itself.

Language: Английский

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Voltage-gated sodium channels in excitable cells as drug targets

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Language: Английский

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Drugs exhibit diverse binding modes and access routes in the Nav1.5 cardiac sodium channel pore

The Journal of General Physiology, Journal Year: 2025, Volume and Issue: 157(2)

Published: Jan. 7, 2025

Small molecule inhibitors of the sodium channel are common pharmacological agents used to treat a variety cardiac and nervous system pathologies. They act on via binding within pore directly block conduction pathway and/or modulate favor non-conductive state. Despite their abundant clinical use, we lack specific knowledge protein–drug interactions subtle variations between different compound structures. This study investigates accessibility nine compounds in cavity Nav1.5 using enhanced sampling simulations. We find that most share location binding—near mouth DII–III fenestration—associated with high number aromatic residues this region. In contrast, some other prefer lateral fenestrations where they compete lipids, rather than central cavity. Overall, our simulation results suggest drug is highly promiscuous, drugs having multiple low-affinity sites. Access interior two out four hydrophobic favorable for majority compounds. Our indicate polyspecific diffuse contributes varied nature inhibitory effects can be exploited future discovery optimization.

Language: Английский

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Nav1.8, an analgesic target for nonpsychotomimetic phytocannabinoids

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(4)

Published: Jan. 21, 2025

Pain impacts billions of people worldwide, but treatment options are limited and have a spectrum adverse effects. The search for safe nonaddictive pain treatments has led to focus on key mediators nociceptor excitability. Voltage-gated sodium (Nav) channels in the peripheral nervous system—Nav1.7, Nav1.8, Nav1.9—play crucial roles signaling. Among these, Nav1.8 shown promise due its rapid recovery from inactivation role repetitive firing, with recent clinical studies providing proof-of-principal that block can reduce humans. We report here three nonpsychotomimetic cannabinoids—cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN)—effectively inhibit suggesting their potential as analgesic compounds. In particular, CBG shows significant ability effectively excitability sensory neurons. These findings highlight therapeutic cannabinoids, particularly CBG, agents may attenuate via warranting further vivo studies.

Language: Английский

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Molecular Pharmacology of Selective Na_V1.6 and Dual Na_V1.6/Na_V1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(6), P. 1169 - 1184

Published: Feb. 15, 2024

Voltage-gated sodium channel (NaV) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal action potential firing reduce excitability in the brain. However, all currently available NaV-targeting antiseizure medications nonselectively inhibit brain channels NaV1.1, NaV1.2, and NaV1.6, which potentially limits efficacy therapeutic safety margins these drugs. Here, we report on XPC-7724 XPC-5462, represent a new class small molecule compounds. compounds specifically target inhibition NaV1.6 NaV1.2 channels, abundantly expressed excitatory pyramidal neurons. They have > 100-fold molecular selectivity against NaV1.1 predominantly inhibitory Sparing preserves activity bind stabilize inactivated state thereby reducing higher potency, with longer residency times slower off-rates, than clinically carbamazepine phenytoin. The is demonstrated slices cortical neurons, without impacting fast spiking interneurons. XPC-5462 also suppresses epileptiform an ex vivo slice seizure model, whereas XPC-7224 does not, suggesting possible requirement Nav1.2 0-Mg2+- or 4-AP-induced models. profiles will facilitate pharmacological dissection physiological roles neurons help define role specific disease states. This unique profile provides approach selectively downregulating circuits.

Language: Английский

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Cannabidiol and Sodium Channel Pharmacology: General Overview, Mechanism, and Clinical Implications

The Neuroscientist, Journal Year: 2021, Volume and Issue: 28(4), P. 318 - 334

Published: May 24, 2021

Voltage-gated sodium (Nav) channels initiate action potentials in excitable tissues. Altering these channels’ function can lead to many pathophysiological conditions. Nav are composed of several functional and structural domains that could be targeted pharmacologically as potential therapeutic means against various neurological Mutations have been suggested underlie clinical syndromes different tissues association with conditions ranging from epileptic muscular problems. Treating those mutations increase the excitability requires inhibitors effectively reduce channel firing. The main non-psychotropic constituent cannabis plant, cannabidiol (CBD), has recently gained interest a viable compound treat some associated malfunctions. In this review, we discuss an overview followed by in-depth description interactions CBD channels. We conclude implications use hyperexcitability based on series preclinical studies published date, focus Nav/CBD interactions.

Language: Английский

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Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability

British Journal of Pharmacology, Journal Year: 2022, Volume and Issue: 179(15), P. 4010 - 4030

Published: March 17, 2022

Cannabigerol (CBG), a non-psychotropic phytocannabinoid and precursor of ∆

Language: Английский

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Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels

Journal of Chemical Theory and Computation, Journal Year: 2023, Volume and Issue: 19(10), P. 2953 - 2972

Published: April 28, 2023

The recent determination of cryo-EM structures voltage-gated sodium (Nav) channels has revealed many details these proteins. However, knowledge ionic permeation through the Nav pore remains limited. In this work, we performed atomistic molecular dynamics (MD) simulations to study structural features various neuronal based on homology modeling structure human Nav1.4 channel and, in addition, recently resolved configuration for Nav1.2. particular, single Na+ events during standard MD runs suggest that ion resides inner part selectivity filter (SF). On-the-fly free energy parametrization (OTFP) temperature-accelerated (TAMD) was also used calculate two-dimensional surfaces (FESs) related single/double translocation SF homology-based Nav1.2 model and structure, with different realizations DEKA domain. These additional distinct mechanisms double wild-type SF, which a charged lysine ring. Moreover, configurations ions corresponding metastable states FESs are specific each motif. Overall, description gives us new insights into conduction cryo-EM-based could advance understanding systems how they differ from potassium bacterial channels.

Language: Английский

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Long-term use of cannabidiol-enriched medical cannabis in a prospective cohort of children with drug-resistant developmental and epileptic encephalopathy

Seizure, Journal Year: 2022, Volume and Issue: 95, P. 56 - 63

Published: Jan. 4, 2022

Language: Английский

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Cannabidiol Inhibits Multiple Ion Channels in Rabbit Ventricular Cardiomyocytes

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: Feb. 3, 2022

Cannabidiol (CBD), a major non-psychotropic cannabinoid found in the Cannabis plant, has been shown to exert anti-nociceptive, anti-psychotic, and anti-convulsant effects also influence cardiovascular system. In this study, of CBD on ion currents were investigated using patch-clamp technique rabbit ventricular myocytes. inhibited voltage-gated Na+ Ca2+ channels with IC50 values 5.4 4.8 µM, respectively. addition, CBD, at lower concentrations, suppressed mediated by rapidly slowly activated delayed rectifier K+ 2.4 2.1 up 10 μM, did not have any significant effect inward IK1 transient outward Ito currents. The these developed gradually, reaching steady-state levels within 5-8 min, recoveries usually slow partial. Hill coefficients higher than unity concentration-inhibition curves suggested multiple binding sites channels. These findings indicate that affects cardiac electrophysiology acting diverse range suggest caution should be exercised when is administered carriers channelopathies or individuals drugs known affect rhythm contractility heart.

Language: Английский

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