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

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

  • J Clin Invest. 2024 Dec 10;135(4):e177429. doi: 10.1172/JCI177429.
Cheng Tang 1 2 3,  Kimberly Gomez 4,  Yan Chen 3,  Heather N Allen 4,  Sara Hestehave 1 2,  Erick J Rodríguez-Palma 4,  Santiago Loya-Lopez 4,  Aida Calderon-Rivera 4,  Paz Duran 1 2,  Tyler S Nelson 4,  Siva Rama Raju Kanumuri 5,  Bijal Shah 6,  Nihar R Panigrahi 7,  Samantha Perez-Miller 4,  Morgan K Schackmuth 8,  Shivani Ruparel 9,  Amol Patwardhan 10,  Theodore J Price 8,  Paramjit S Arora 7,  Ravindra K Sharma 11,  Abhisheak Sharma 5,  Jie Yu 12,  Olga A Korczeniewska 6,  Rajesh Khanna 4 13
Affiliations

Affiliations

  • 1 Department of Molecular Pathobiology, College of Dentistry, and.
  • 2 Pain Research Center, New York University, New York, New York, USA.
  • 3 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China.
  • 4 Department of Pharmacology and Therapeutics, College of Medicine and.
  • 5 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
  • 6 Center for Orofacial Pain and Temporomandibular Disorders, Department of Diagnostic Sciences, Rutgers School of Dental Medicine, Newark, New Jersey, USA.
  • 7 Department of Chemistry, New York University, New York, New York, USA.
  • 8 University of Texas at Dallas, School of Behavioral and Brain Sciences, Department of Neuroscience, Center for Advanced Pain Studies, Richardson, Texas, USA.
  • 9 Department of Endodontics, School of Dentistry, University of Texas Health Science Center at San Antonio, and Center for Pain Therapeutics and Addiction Research, San Antonio, Texas, USA.
  • 10 Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • 11 Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, Florida, USA.
  • 12 Institute of Chinese Medicine Clinical Basics, Institute of Chinese Medicine on Rheumatology, College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, China.
  • 13 McKnight Brain Institute, University of Florida, Gainsville, Florida, USA.
PMID: 39656529 DOI: 10.1172/JCI177429
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.

Keywords

Calcium channels; Neuroscience; Pain; Pharmacology.

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