Targeting the CaVα–CaVβ interaction yields an antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy

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, γ and α2δ subunits. The β subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. We targeted the high-affinity protein–protein interface of CaVβ's 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 (IPPQ). 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 sensory neurons, decreased presynaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory postsynaptic potentials and miniature excitatory postsynaptic potentials, and inhibited release of the nociceptive neurotransmitter calcitonin gene–related peptide from spinal cord. IPPQ did not target opioid receptors nor did it engage inhibitory G protein–coupled receptor signaling. IPPQ was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (postsurgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. IPPQ did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. IPPQ, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaVα–CaVβ function and ultimately be developed as a nonopioid therapeutic for chronic pain.

Antinociceptive Activity of Chemical Components of Essential Oils That Involves Docking Studies: A Review

“…Another study by Khanna et al (2019) also used virtual screening to identify small molecules that disrupt the CaVa-CaVb interaction. A commercially available library at ChemBridge was used to couple 50,000 small commercially available drug-like molecules.…”

Partners in Crime: Towards New Ways of Targeting Calcium Channels

“…As a conclusion, many approaches using permeant peptides but also nonpeptidic synthetic molecules [42,43] have managed to alter the interaction between voltage-dependent calcium channel partners in order to successfully reverse various symptoms associated with different pathologies. These interactions are summarized in Figure 1.…”

“…The members of the TRP channel super-family are regarded as cellular sensors [47] integrating external and endogenous stimuli, and thus contribute to cell-to-cell communication and maintain many forms of homeostasis. TRP channels are associated with several pathophysiological processes, which include (but are not limited to) diseases linked to pain, cardiovascular function, pulmonary function, inflammation, skin, neurological disorders, kidney, bone, obesity, as well as proliferative diseases via dysregulation of the cell cycle, carcinogenesis, and tumor angiogenesis [40][41][42]. TRP channels therefore serve as communication hubs for the cells that express them, and their regulation is crucial for their function.…”

Activity of T-type calcium channels is independent of CRMP2 in sensory neurons

“…In chronic pain, proteins regulating the N-type (CaV2.2) VGCCs can modulate nociception [1]. One such protein is the collapsin response mediator protein 2 (CRMP2) [3][4][5][6][7][8][9][10][11][12][13][14][15]. Our continuing studies have established CRMP2 as a bona fide binding partner and regulator of the presynaptic trafficking of CaV2.2 [4,8,13,[15][16][17][18].…”