Multiple subtypes of voltage-gated calcium channels (VGCCs) including N-, P/Q- and T-types have been implicated in mediating the nociceptive behaviors observed in preclinical models of inflammatory and neuropathic pain using both selective peptide blockers and genetic knockout animals.  The implication of VGCCs in nociception is consistent with N- and P/Q-type calcium channels being localized in the spinal cord and having a critical role in regulating neurotransmitter release, whereas T-type calcium channels are expressed peripherally and have been demonstrated to modulate neuronal excitability.  N-type calcium channels have also been clinically validated with the FDA approval of the selective peptide blocker Prialt� for the treatment of severe chronic pain.  Recent efforts have focused on identifying orally bioavailable small molecule blockers that circumvent the need for intrathecal delivery that is required for peptide blockers.  We now report the discovery of orally active and structurally novel mixed N-, P/Q- and T-type calcium channel blocker.  Electrophysiology studies demonstrated that these molecules inhibits recombinant N- and T-type calcium channels in a state-dependent manner with a potency similar to that observed at native calcium currents in DRG neurons.  These VGCC blockers also inhibited potassium-evoked release of the pro-nociceptive peptide CGRP from rat DRG neurons in a dose-dependent manner.  Following oral administration, compound completely reversed grip force impairment in a rat model of osteoarthritic and neuropathic pain.  This observation was associated with a concomitant reduction in osteoarthritic-induced MAPK activation in DRG neurons and the spinal cord of animals treated with VGCC blockers.  Taken together, these studies demonstrate that VGCC blockers can effectively modulate the neurochemical signaling pathways associated with central sensitization in this preclinical model of osteoarthritis pain.

Targeting calcium channel blockers for the treatment of pain

247th National Meeting (2014)

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