dihydropyridines and Neuralgia

P2X7 receptors (P2X7Rs) belong to a family of ATP-gated non-selective cation channels. Microglia represent a major cell type expressing P2X7Rs. The activation of microglial P2X7Rs causes the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This response has been implicated in neuroinflammatory states in the central nervous system and in various diseases, including neuropathic pain. Thus, P2X7R may represent a potential therapeutic target. In the present study, we screened a chemical library of clinically approved drugs (1979 compounds) by high-throughput screening and showed that the Ca

Topics: Calcium Channel Blockers; Dihydropyridines; High-Throughput Screening Assays; Humans; Interleukin-1beta; Microglia; Neuralgia; Receptors, Purinergic P2X7

Cilnidipine is a dihydropyridine derivative that inhibits N-type and L-type voltage-gated Ca

Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Conotoxins; Dihydropyridines; Evoked Potentials; Long-Term Potentiation; Male; Mice; Nerve Fibers, Unmyelinated; Neuralgia; Nicardipine; Rats; Spinal Cord Dorsal Horn

We have recently identified a class of dihydropyridine (DHP) analogues with 30-fold selectivity for T-type over L-type calcium channels that could be attributed to a modification of a key ester moiety. Based on these results, we examined a second series of compounds with similar attributes to determine if they had enhanced affinity for T-type channels. Whole-cell patch clamp experiments in transfected tsA-201 cells were used to screen these DHP derivatives for high affinity and selectivity for Cav3.2 over Cav1.2 L-type channels. The effects of the two lead compounds, termed N10 and N12, on Cav3.2 channel activity and gating were characterized in detail. When delivered intrathecally or intraperitoneally, these compounds mediated analgesia in a mouse model of acute inflammatory pain. The best compound from the initial screening, N12, was also able to reverse mechanical hyperalgesia produced by nerve injury. The compounds were ineffective in Cav3.2 null mice. Altogether, our data reveal a novel class of T-type channel blocking DHPs for potential pain therapies.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, T-Type; Cell Line; Dihydropyridines; Humans; Inflammation; Ion Channel Gating; Mice; Mice, Inbred C57BL; Neuralgia; Small Molecule Libraries

Voltage-activated calcium channels are important facilitators of nociceptive transmission in the primary afferent pathway. Consequently, molecules that block these channels are of potential use as pain therapeutics. Our group has recently reported on the identification of a novel class of dihydropyridines (DHPs) that included compounds with preferential selectivity for T-type over L-type channels. Among those compounds, M4 was found to be an equipotent inhibitor of both Cav1.2 L- and Cav3.2 T-type calcium channels. Here, we have further characterized the effects of this compound on other types of calcium channels and examined its analgesic effect when delivered either spinally (i.t.) or systemically (i.p.) to mice. Both delivery routes resulted in antinociception in a model of acute pain. Furthermore, M4 was able to reverse mechanical hyperalgesia produced by nerve injury when delivered intrathecally. M4 retained partial activity when delivered to Cav3.2 null mice, indicating that this compound acts on multiple targets. Additional whole-cell patch clamp experiments in transfected tsA-201 cells revealed that M4 also effectively blocks Cav3.3 (T-type) and Cav2.2 (N-type) currents. Altogether, our data indicate that broad-spectrum inhibition of multiple calcium channel subtypes can lead to potent analgesia in rodents.

Topics: Analgesics; Animals; Calcium Channel Blockers; Calcium Channels; Cell Line; Dihydropyridines; Humans; Neuralgia; Rats