C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models

Antagonists - such as Ziconotide and Gabapentin - of the CaV2.2 (N-type) calcium channels are used clinically as analgesics for chronic pain. However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse, and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of CaV2.2. Here, we report the identification of C2230, an aryloxy-hydroxypropylamine, as a CaV2.2 blocker. C2230 trapped and stabilized inactivated CaV2.2 in a slow-recovering state and accelerated the open-state inactivation of the channel, conferring an advantageous use-dependent inhibition profile. C2230 inhibited CaV2.2 during high-frequency stimulation, while sparing other voltage-gated ion channels. C2230 inhibited CaV2.2 in dorsal root and trigeminal ganglia neurons from rats, marmosets, and humans in a G-protein-coupled-receptor-independent manner. Further, C2230 reduced evoked excitatory postsynaptic currents and excitatory neurotransmitter release in the spinal cord, leading to relief of neuropathic, orofacial, and osteoarthritic pain-like behaviors via 3 different routes of administration. C2230 also decreased fiber photometry-based calcium responses in the parabrachial nucleus, mitigated aversive behavioral responses to mechanical stimuli after neuropathic injury, and preserved protective pain responses, all without affecting motor or cardiovascular function. Finally, site-directed mutation analysis demonstrated that C2230 binds differently than other known CaV2.2 blockers, making it a promising lead compound for analgesic development.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Investigation
Published
2024-12-10
DOI
https://doi.org/10.1172/jci177429
Citations
13
Primary Topic
Pain Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
4.25

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models

Paramjit S. Arora, Cheng Tang, Olga A. Korczeniewska, Rajesh Khanna et al.
13 citations
Journal of Clinical Investigation
Pain Mechanisms and Treatments
4.25
article

C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models

Paramjit S. Arora, Cheng Tang, Olga A. Korczeniewska, Rajesh Khanna, Amol Patwardhan, Sara Hestehave, Aida Calderón‐Rivera, Bijal Shah, Santiago Loya‐López, Kimberly Gómez, Samantha Perez‐Miller, Nihar R. Panigrahi, Erick J. Rodríguez‐Palma, Theodore J. Price, Shivani Ruparel, Heather N. Allen, Raju S. Kanumuri, Tyler S. Nelson, Abhisheak Sharma, Paz Duran, Jie Yu, Yan Chen, Ravindra K. Sharma, Morgan K. Schackmuth
article en
13 citations

Abstract

Antagonists - such as Ziconotide and Gabapentin - of the CaV2.2 (N-type) calcium channels are used clinically as analgesics for chronic pain. However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse, and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of CaV2.2. Here, we report the identification of C2230, an aryloxy-hydroxypropylamine, as a CaV2.2 blocker. C2230 trapped and stabilized inactivated CaV2.2 in a slow-recovering state and accelerated the open-state inactivation of the channel, conferring an advantageous use-dependent inhibition profile. C2230 inhibited CaV2.2 during high-frequency stimulation, while sparing other voltage-gated ion channels. C2230 inhibited CaV2.2 in dorsal root and trigeminal ganglia neurons from rats, marmosets, and humans in a G-protein-coupled-receptor-independent manner. Further, C2230 reduced evoked excitatory postsynaptic currents and excitatory neurotransmitter release in the spinal cord, leading to relief of neuropathic, orofacial, and osteoarthritic pain-like behaviors via 3 different routes of administration. C2230 also decreased fiber photometry-based calcium responses in the parabrachial nucleus, mitigated aversive behavioral responses to mechanical stimuli after neuropathic injury, and preserved protective pain responses, all without affecting motor or cardiovascular function. Finally, site-directed mutation analysis demonstrated that C2230 binds differently than other known CaV2.2 blockers, making it a promising lead compound for analgesic development.

Journal of Clinical InvestigationVol. 135(4)
Rutgers, The State University of New Jersey (US), Zhejiang Chinese Medical University (CN), The University of Texas at Dallas (US), The University of Texas at San Antonio Health Science Center (US), Hunan Normal University (CN), University of Florida (US), Pain Management Institute (US), Therapeutics Clinical Research (US), Institute of Molecular Medicine (IN), New York University (US), The University of Texas Southwestern Medical Center (US)
University of Florida, Education Department of Hunan Province, Texas Biomedical Research Institute, York University, National Institutes of Health, University of Texas Health Science Center at San Antonio, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 5%
Pain Mechanisms and Treatments
4.25
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.