IQM-PC332, a Novel DREAM Ligand with Antinociceptive Effect on Peripheral Nerve Injury-Induced Pain

Abstract

Neuropathic pain is a form of chronic pain arising from damage of the neural cells that sense, transmit or process sensory information. Given its growing prevalence and common refractoriness to conventional analgesics, the development of new drugs with pain relief effects constitutes a prominent clinical need. In this respect, drugs that reduce activity of sensory neurons by modulating ion channels hold the promise to become effective analgesics. Here, we evaluated the mechanical antinociceptive effect of IQM-PC332, a novel ligand of the multifunctional protein downstream regulatory element antagonist modulator (DREAM) in rats subjected to chronic constriction injury of the sciatic nerve as a model of neuropathic pain. IQM-PC332 administered by intraplantar (0.01–10 µg) or intraperitoneal (0.02–1 µg/kg) injection reduced mechanical sensitivity by ≈100% of the maximum possible effect, with ED50 of 0.27 ± 0.05 µg and 0.09 ± 0.01 µg/kg, respectively. Perforated-patch whole-cell recordings in isolated dorsal root ganglion (DRG) neurons showed that IQM-PC332 (1 and 10 µM) reduced ionic currents through voltage-gated K+ channels responsible for A-type potassium currents, low, T-type, and high voltage-activated Ca2+ channels, and transient receptor potential vanilloid-1 (TRPV1) channels. Furthermore, IQM-PC332 (1 µM) reduced electrically evoked action potentials in DRG neurons from neuropathic animals. It is suggested that by modulating multiple DREAM–ion channel signaling complexes, IQM-PC332 may serve a lead compound of novel multimodal analgesics.

Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice

“…Whether an increase in the dosage or a change in administration pattern of RP could render a significant effect on motor coordination, body weight loss, or lifespan in ALS mice remains to be investigated. Moreover, the potential benefits of the new DREAM binding molecules of the PC-series, like PC330 or PC260 [14,[88][89][90][91], in SOD1G93A mice remain to be investigated. Noteworthy, the SOD1G93A mouse model is a quite aggressive model of familial ALS, showing a very early onset and very fast disease progression [92].…”

KV Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review

“…Recently, a novel KChIP3 ligand, IQM-PC332, was reported to reduce mechanical hypersensitivity in rats subjected to chronic constriction injury of the sciatic nerve. Mechanistically, IQM-PC332 binds to KChIP3 and reduces ionic currents mediated by TRPV1 channels, K V 4.3 channels, low-voltage-activated T-type Ca 2+ channels, and high-voltage-activated Ca 2+ channels in DRG neurons [136]. This is a potential chemical tool and the elucidation of the structural basis of the analgesic effect of IQM-PC332 will be one of the possible steps towards a better understanding of how KChIP3 controls pain.…”

“…In addition, K V 4.2 channels play an important role in both synaptic plasticity and cognition, which in part contributes to the regulatory effect of KChIP3 on learning and memory [144]. channels, low-voltage-activated T-type Ca 2+ channels, and high-voltage-activated Ca 2+ channels in DRG neurons [136]. This is a potential chemical tool and the elucidation of the structural basis of the analgesic effect of IQM-PC332 will be one of the possible steps towards a better understanding of how KChIP3 controls pain.…”

KV Channel-Interacting Proteins in Neurological and Cardiovascular System: An Updated Review

“…It has been reported that IQM-PC332, a ligand of KChIP3, can reduce mechanical hypersensitivity in mice with chronic constriction injury of the sciatic nerve. Mechanistically, IQM-PC332 binds to KChIP3 and reduces ionic currents mediated by TRPV1 channels, KV4.3 channels, low voltage-activated T-type Ca 2+ channels and high voltage-activated Ca 2+ channels in DRG neurons [121].…”