Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects

Chris Bladen, Steven W. McDaniel, Vinicius M. Gadotti, Ravil R. Petrov, N. Daniel Berger, Philippe Diaz, Gerald W. Zamponi

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure–activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels.
Original languageEnglish
Pages (from-to)277-287
Number of pages11
JournalACS Chemical Neuroscience
Volume6
Issue number2
Early online date5 Nov 2014
DOIs
Publication statusPublished - 18 Feb 2015
Externally publishedYes

Keywords

  • hCav 3.2
  • T-type calcium channel
  • inflammatory pain
  • neuropathic pain
  • carbazole scaffold
  • electrophysiology

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