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.
Rational structure-based design strategy identifies a quinazoline antagonist of the N-type voltage-gated calcium channel with a broad antinociceptive efficacy
aDepartment of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States
bThe BIO5 Institute, University of Arizona, Tucson, AZ, United States
cDepartment of Anesthesiology, College of Medicine, University of Arizona, Tucson, AZ, United States
dThe Center for Innovation in Brain Sciences, The University of Arizona Health Sciences, Tucson, AZ, United States
eCollege of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
fConvergence Research Center for Dementia, Korea Institute of Science and Technology, Seoul, Korea
gDivision of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology, Seoul, Korea
hKHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Korea
iDepartment of Physiology and Cellular Biophysics and
jPharmacology, Columbia University College of Physicians and Surgeons, New York, NY, United States
Corresponding author. Address: Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Dr, P.O. Box 245050, Tucson, AZ 85724, United States. Tel.: (520) 626-4281; fax: (520) 626-2204. E-mail address: email@example.com (R. Khanna).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
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Received November 30, 2018
Received in revised form January 18, 2019
Accepted February 05, 2019