Determinants of interactions of a novel next-generation gabapentinoid NVA1309 and mirogabalin with the Cavα2δ-1 subunit DOI Creative Commons
Ivana A. Souza, María A. Gandini, Md Yousof Ali

et al.

Molecular Brain, Journal Year: 2024, Volume and Issue: 17(1)

Published: Aug. 7, 2024

Abstract NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared effects of with Mirogabalin, drug higher affinity voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which approved post-herpetic neuralgia in Japan, Korea Taiwan. Both mirogabalin inhibit Cav2.2 currents vitro decrease plasma membrane expression efficacy Mutagenesis classical residue arginine newly identified lysine K615 reverse effect on current, but not that NVA1309.

Language: Английский

EMC chaperone–CaV structure reveals an ion channel assembly intermediate DOI
Zhou Chen, Abhisek Mondal, Fayal Abderemane-Ali

et al.

Nature, Journal Year: 2023, Volume and Issue: 619(7969), P. 410 - 419

Published: May 17, 2023

Language: Английский

Citations

48
Structural biology of voltage-gated calcium channels DOI Creative Commons
Xia Yao, Shuai Gao, Nieng Yan

et al.

Channels, Journal Year: 2023, Volume and Issue: 18(1)

Published: Dec. 7, 2023

Voltage-gated calcium (Cav) channels mediate Ca2+ influx in response to membrane depolarization, playing critical roles diverse physiological processes. Dysfunction or aberrant regulation of Cav can lead life-threatening consequences. Cav-targeting drugs have been clinically used treat cardiovascular and neuronal disorders for several decades. This review aims provide an account recent developments the structural dissection channels. High-resolution structures significantly advanced our understanding working disease mechanisms channels, shed light on molecular basis their modulation, elucidated modes actions (MOAs) representative toxins. The progress studies lays foundation future drug discovery efforts targeting channelopathies.

Language: Английский

Citations

23
Electrosome assembly: Structural insights from high voltage-activated calcium channel (CaV)–chaperone interactions DOI Creative Commons
Zhou Chen, Daniel L. Minor

Biochemical Society Transactions, Journal Year: 2025, Volume and Issue: 53(01)

Published: Feb. 6, 2025

Ion channels are multicomponent complexes (termed here as“electrosomes”) that conduct the bioelectrical signals required for life. It has been appreciated decades assembly is critical proper channel function, but knowledge of factors undergird this important process lacking. Although there now exemplar structures representatives most major ion classes, no direct structural information to inform how these complicated, multipart put together or whether they interact with chaperone proteins aid in their assembly. Recent characterization a complex endoplasmic membrane protein (EMC) and voltage-gated calcium (CaV) intermediate comprising pore-forming CaVα1 cytoplasmic CaVβ subunits offers first view into member largest class, voltagegated (VGIC) superfamily. The structure shows EMC remodels CaVα1/CaVβ through set rigid body movements handoff extracellular CaVα2δ subunit complete involves intersubunit coordination divalent cation ordering elements. These findings new framework deciphering underpinnings biogenesis implications understanding drugs disease mutations act, investigating other may engage ubiquitous chaperone.

Language: Английский

Citations

0
Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Cavα2δ‐1 Subunit of Voltage‐Gated Calcium Channel and the μ‐Opioid Receptor DOI
Anita Wegert,

Menno C. F. Monnee,

Wouter de Graaf

et al.

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(10)

Published: Jan. 17, 2024

Abstract The synthesis and pharmacological activity of a new series dual ligands combining activities towards the α2δ‐1 subunit voltage‐gated calcium channels (Ca v α2δ‐1) μ‐opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration pharmacophores related to both targets, which in principle had few common characteristics, led design compounds exhibiting activities. construction started from published Ca ligands, onto MOR ligand pharmacophoric elements were added. This exercise amino‐acidic substances with good affinities on targets well metabolic physicochemical profiles low potential for drug‐drug interactions. representative compound, (2 S ,4 )‐4‐(4‐chloro‐3‐((( cis )‐4‐(dimethylamino)‐4‐phenylcyclohexyl)methyl)‐5‐fluorophenoxy)pyrrolidine‐2‐carboxylic acid, displayed promising analgesic several vivo models reduced side‐effect profile relation morphine.

Language: Английский

Citations

2
Mechanism of Analgesia by Gabapentinoid Drugs: Involvement of Modulation of Synaptogenesis and Trafficking of Glutamate-Gated Ion Channels DOI Creative Commons
Gyula Váradi

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2023, Volume and Issue: 388(1), P. 121 - 133

Published: Nov. 2, 2023

Gabapentinoids have clinically been used for treating epilepsy, neuropathic pain, and several other neurological disorders >30 years, however, the definitive molecular mechanism responsible their therapeutic actions remained uncertain. The conventional pharmacological observation regarding efficacy in chronic pain modulation is weakening of glutamate release at presynaptic terminals spinal cord. While α2/δ-1 subunit voltage-gated calcium channels (VGCCs) has identified as primary drug receptor gabapentinoids, lack consistent effect this class on VGCC function indicative a minor role regulating ion channel9s activity. This current review targets gabapentinoids pain. discovery interaction with thrombospondins established protein major synaptogenic neuronal thrombospondins. Other findings powerful regulator NMDA AMPA receptors by potentiating synaptic expression, putative pathophysiological Further, interdependent interactions between thrombospondin contribute to states, while gabapentinoid ligands efficaciously reverse such conditions. Gabapentin normalizes even blocks NMDAR AMPAR targeting activity elicited nerve injury. Significance Statement Gabapentinoid drugs are treat various conditions including In states gene expression cacnα2/δ-1 upregulated promote aberrant excitatory synaptogenesis. complex trait associations that involve thrombospondins, further, an association C-tail constitutes macromolecular signaling forms crucial elements mode action gabapentinoids.

Language: Английский

Citations

3
Naturally Inspired Molecules for Neuropathic Pain Inhibition—Effect of Mirogabalin and Cebranopadol on Mechanical and Thermal Nociceptive Threshold in Mice DOI Creative Commons
Kinga Sałat, Paula Zaręba, Michał Awtoniuk

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(23), P. 7862 - 7862

Published: Nov. 30, 2023

Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin cebranopadol have become a subject of interest because their potential utility as chronic treatment. However, they not been investigated thoroughly in some types neuropathic pain, both humans experimental animals. Methods: This study used the von Frey test, hot plate test two-plate thermal place preference supported by image analysis machine learning assess effect intraperitoneal subcutaneous on mechanical nociceptive threshold mouse models induced streptozotocin, paclitaxel oxaliplatin. Results: Mirogabalin effectively attenuated tactile allodynia streptozotocin paclitaxel. Cebranopadol was more effective than respect. Both drugs also elevated heat mice. In oxaliplatin model, reduced cold-exacerbated pain. Conclusions: Since animal seem be promising therapies various patients, particular those who resistant analgesics.

Language: Английский

Citations

1
Determinants of interactions of a novel next-generation gabapentinoid NVA1309 and mirogabalin with the Cavα2δ-1 subunit DOI Creative Commons
Ivana A. Souza, María A. Gandini, Md Yousof Ali

et al.

Molecular Brain, Journal Year: 2024, Volume and Issue: 17(1)

Published: Aug. 7, 2024

Abstract NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared effects of with Mirogabalin, drug higher affinity voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which approved post-herpetic neuralgia in Japan, Korea Taiwan. Both mirogabalin inhibit Cav2.2 currents vitro decrease plasma membrane expression efficacy Mutagenesis classical residue arginine newly identified lysine K615 reverse effect on current, but not that NVA1309.

Language: Английский

Citations

0