NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors.
N. Daniel Berger,Vinicius M. Gadotti,Ravil R. Petrov,Kevin Chapman,Philippe Diaz,Gerald W. Zamponi +5 more
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TLDR
This work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation, and provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/T-type channels.Abstract:
Background: T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund’s Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. Results: NMP-7 delivered by either i.p. or i.g. routes produced dose-dependent inhibition of mechanical hyperalgesia in mouse models of inflammatory and neuropathic pain, without altering spontaneous locomotor activity in the open-field test at the highest active dose. Neither i.p. nor i.g. treatment reduced peripheral inflammation per se ,a s evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in CaV3.2-null mice, confirming CaV 3.2 as ak ey target. The analgesic action of intraperitoneally delivered NMP-7 was not affected by pretreatment of mice with the CB1 antagonist AM281, but was significantly attenuated by pretreatment with the CB2 antagonist AM630, suggesting that CB2 receptors, but not CB1 receptors are involved in the action of NMP-7 in vivo. Conclusions: Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/ T-type channel blockers.read more
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Diarylation of N- and O-nucleophiles through a metal-free cascade reaction
TL;DR: Yang et al. as mentioned in this paper presented an atom-efficient and metal-free difunctionalization of N- and O-nucleophiles with two different aryl groups in one step.
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The terpenes camphene and alpha-bisabolol inhibit inflammatory and neuropathic pain via Cav3.2 T-type calcium channels.
TL;DR: Camphene and alpha-bisabolol have been shown to have a wide spectrum of analgesic action by virtue of inhibiting Cav3.2 T-type calcium channels.
Dissertation
Étude des effets modulateurs des plantes médicinales méditerranéennes sur les canaux calciques de type T et l’évaluation de leurs effets anticonvulsivants et antiépileptiques
TL;DR: C’interet de ce travail est d'explorer le potentiel therapeutique des plantes medicinales connues pour leurs vertus neuromodulatrices et potentiellement d’intseret pour le traitement of maladies neurologiques, en etudiant leur capacite a cibler l’activite des canaux calciques de type T.
Journal ArticleDOI
Theoretical Study of the Structural Stability, Chemical Reactivity, and Protein Interaction for NMP Compounds as Modulators of the Endocannabinoid System
Maricruz Rangel-Galván,M. Castro,Jose Manuel Perez-Aguilar,Norma A. Caballero,A. Rangel-Huerta,Francisco J. Melendez +5 more
TL;DR: In this article , DFT calculations were performed to characterize theoretically their structural and chemical reactivity properties using the BP86/cc-pVTZ level of theory, which revealed that a major participation of the carbazole group is in the donor-acceptor interactions of the NMP compounds.
Journal ArticleDOI
Differential regulation of Cav3.2 and Cav2.2 calcium channels by CB1 receptors and cannabidiol
Erika K. Harding,Ivana A. Souza,Maria A. Gandini,Vinicius M. Gadotti,Md. Yousof Ali,Sun Huang,Flavia T T Antunes,Tuan Trang,Gerald W. Zamponi +8 more
TL;DR: In this article , the authors hypothesized that cannabinoids and receptor agonists target different types of voltage gate calcium (Cav) channels through distinct mechanisms, and they found that Cav channels are one mechanism through which cannabinoids may produce analgesia, but clinical trials often fail to report analgesic efficacy of cannabinoids.
References
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