Characterization of the triazine, T4, a representative from a novel series of CaV2 inhibitors with strong state-dependence, poor use-dependence, and distinctively fast kinetics.

There is strong pharmacological, biological, and genetic evidence supporting the role of N-type calcium channels (CaV2.2) in nociception. There is also human validation data from ziconotide, the CaV2.

A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats.

Activation of T-type Ca²⁺ channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²⁺ channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model.

Mechanistic insights into the analgesic efficacy of A-1264087, a novel neuronal Ca(2+) channel blocker that reduces nociception in rat preclinical pain models.

Unlabelled: Voltage-gated Ca(2+) channels play an important role in nociceptive transmission. There is significant evidence supporting a role for N-, T- and P/Q-type Ca(2+) channels in chronic pain. Here, we report that A-1264087, a structurally novel state-dependent blocker, inhibits each of these human Ca(2+) channels with similar potency (IC50 = 1-2 μM).

A mixed Ca2+ channel blocker, A-1264087, utilizes peripheral and spinal mechanisms to inhibit spinal nociceptive transmission in a rat model of neuropathic pain.

N-, T- and P/Q-type voltage-gated Ca(2+) channels are critical for regulating neurotransmitter release and cellular excitability and have been implicated in mediating pathological nociception. A-1264087 is a novel state-dependent blocker of N-, T- and P/Q-type channels. In the present studies, A-1264087 blocked (IC50 = 1.

Synthesis and SAR of 4-aminocyclopentapyrrolidines as N-type Ca²⁺ channel blockers with analgesic activity.

A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels.