Stereospecific Effects of Benzimidazolonepiperidine Compounds on T-Type Ca2+Channels and Pain

Kimberly Gomez, Cheng Tang, Bin Tan, Samantha Perez-Miller, Dongzhi Ran, Santiago Loya, Aida Calderon-Rivera, Harrison J. Stratton, Paz Duran, Kyleigh A. Masterson, Anna T. Gabrielsen, Omar Alsbiei, Angie Dorame, Maria Serafini, Aubin Moutal, Jun Wang, Rajesh Khanna

Research output: Contribution to journalArticlepeer-review


T-type calcium channels activate in response to subthreshold membrane depolarizations and represent an important source of Ca2+influx near the resting membrane potential. These channels regulate neuronal excitability and have been linked to pain. For this reason, T-type calcium channels are suitable molecular targets for the development of new non-opioid analgesics. Our previous work identified an analogue of benzimidazolonepiperidine, 5bk, that preferentially inhibited CaV3.2 channels and reversed mechanical allodynia. In this study, we synthesized and screened a small library of 47 compounds derived from 5bk. We found several compounds that inhibited the Ca2+influx in DRG neurons of all sizes. After separating the enantiomers of each active compound, we found two compounds, 3-25-R and 3-14-3-S, that potently inhibited the Ca2+influx. Whole-cell patch clamp recordings from small- to medium-sized DRG neurons revealed that both compounds decreased total Ca2+. Application of 3-14-3-S (but not 3-25-R) blocked transiently expressed CaV3.1-3.3 channels with a similar IC50value. 3-14-3-S decreased T-type, but not N-type, Ca2+currents in DRG neurons. Furthermore, intrathecal delivery of 3-14-3-S relieved tonic, neuropathic, and inflammatory pain in preclinical models. 3-14-3-S did not exhibit any activity against G protein-coupled opioid receptors. Preliminary docking studies also suggest that 3-14-3-S can bind to the central pore domain of T-type channels. Together, our chemical characterization and functional and behavioral data identify a novel T-type calcium channel blocker with in vivo efficacy in experimental models of tonic, neuropathic, and inflammatory pain.

Original languageEnglish (US)
Pages (from-to)2035-2047
Number of pages13
JournalACS Chemical Neuroscience
Issue number13
StatePublished - Jul 6 2022


  • Ca3
  • inflammatory pain
  • low-voltage-activated calcium channels
  • neuropathic pain
  • non-opioid
  • tonic pain

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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