1,4-Dihydropyridine derivatives with T-type calcium channel blocking activity attenuate inflammatory and neuropathic pain

Abstract

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.

Recent advances in the development of T‐type calcium channel blockers for pain intervention

“…One of the non‐selective compounds (termed M4) also inhibited Ca v 2.2 N‐type calcium channels and was found to have analgesic properties in mouse models of inflammatory and neuropathic pain (Gadotti et al, ). A series of additional derivatives was then created and showed improved affinity and selectivity for T‐type over L‐type channels (Bladen et al, ). Two such compounds, termed N10 and N12, were found to be efficacious in animal models of inflammatory pain after both intrathecal and systemic delivery (Figure ).…”

Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain

“…On the other hand, Cav3.2 knockout mice have reduced pain responses [7] and knockdown of Cav3.2 channels with antisense oligonucleotides by intrathecal injection mediated potent analgesia in different models of chronic pain [3]. Therefore, various blockers of Cav3.2 channels have been shown to mediate analgesia in models of inflammatory and neuropathic pain [1,2,11]. Some of the known T-type calcium channel inhibitors with analgesic actions have been shown to also block other types of ion channels, such as N-type calcium channels [13] and voltage-gated sodium channels [18] that are also important for the transmission of pain-related information.…”

3-Benzamides and 3,4,5-trimethoxyphenyl amines as calcium channel blockers

“…induced mechanical hyperalgesia 16 Further study for the mechanism underlying how compound 10 inhibits neuropathic pain after SCI is needed.…”