Ganomycin C, a <i>Ganoderma</i> Meroterpenoid, Alleviates Pain and Absence Seizures in Mice by Targeting Ca_v3.1 and Ca_v3.2 Low‐Voltage‐Gated Calcium Channels

Low-voltage-gated calcium channels (LVGCCs; Ca_v3.1-3.3) are promising targets for treating pain and absence seizures (ASs). Traditional Chinese medicines are potential sources of LVGCC inhibitors. In this study, we aimed to identify analgesic and anti-ASs agents targeting LVGCCs from the well-known neuropharmacological Traditional Chinese medicine Ganoderma cochlear and determine their mechanisms of action. We conducted in vitro and ex vivo electrophysiological studies to assess LVGCCs inhibition by Ganoderma meroterpenoids and the mechanism of action of the selected candidate. Molecular docking analysis was used to explore the structure-activity relationships and modes of action of these meroterpenoids. Furthermore, the antinociceptive and anti-ASs efficacies of the chosen compound were evaluated using four distinct mouse pain models and γ-butyrolactone-induced mice with ASs. Ganomycin C (GMC) was the most potent inhibitor among the eight meroterpenoids, exhibiting five-fold higher selectivity for Ca_v3.1 and Ca_v3.2 over Ca_v3.3. GMC modulated LVGCCs in a distinct manner compared to Z944, an LVGCC inhibitor currently under clinical investigation. Additionally, the side chain features of GMC and its derivatives are crucial for their activity. By preferentially inhibiting LVGCCs, GMC suppressed the evoked excitability of isolated mouse nociceptive primary afferent neurons and burst spikes highly associated with ASs in neurons from the cortico-thalamo-cortical circuits without affecting tonic firing. In three of the pain models, GMC demonstrated robust antinociception comparable to that of Z944 and outperformed ethosuximide, a standard-of-care drug for ASs, in mitigating ASs. Our findings provide insights into GMC as an analgesic and anti-AS agent targeting LVGCCs, specifically Ca_v3.1 and Ca_v3.2.