DOI: 10.1101/492181Dec 10, 2018Paper

Targeting the CaV&#945-&#946 interaction yields a selective antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy

BioRxiv : the Preprint Server for Biology
Aude ChefdevilleRajesh Khanna

Abstract

Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, β and α2δ subunits. The β-subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming &#945 subunit of CaV. We targeted the high-affinity protein-protein interface of CaVβ pocket within the CaVα-subunit. Structure-based virtual screening of 50,000 small molecule library docked to the β-subunit led to the identification of 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide (compound 45). This small molecule bound to CaVβ and inhibited its coupling with N-type voltage-gated calcium (CaV2.2) channels, leading to a reduction in CaV2.2 currents in rat dorsal root ganglion (DRG) sensory neurons, decreased pre-synaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory post-synaptic potentials (sEPSC), and inhibited release of the nociceptive neurotransmitter calcitonin gene related peptide (CGRP) from spinal cord. 45 was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (post-surgical) and neuropathic (spin...Continue Reading

Related Concepts

Analogs & derivatives
Brain
Calcitonin Gene-Related Peptide
Ganglia, Spinal
Genes
Ion Channel
Ligation
Afferent Neuron
Neurotransmitters
Nociceptors

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