DM506

The antiseizure properties of ibogalogs, including ibogaminalog (DM506), ibogainalog (IBG), and nor-IBG, were assessed in rodents using the pentylenetetrazol (PTZ)-induced seizure test. The behavioral findings indicated that ibogalogs exhibited mild acute antiseizure effects in mice, with endpoint- and time window-dependent differences between the compounds. The antiseizure effect was suppressed by volinanserin and SB242084, consistent with the involvement of 5-HT_2A and 5-HT_2C receptors. The antiseizure activity after repeated administration (7 and 14 days) of subthreshold doses of nor-IBG (3 mg/kg) or DM506 (5 mg/kg) was higher than that after acute treatment, indicating augmented efficacy. Subthreshold doses of DM506 and nor-IBG restored the impact of PTZ on monoamine levels in hippocampal tissue following repeated administration, but not after a single dose. Additionally, the influence of ibogalogs was evaluated on epileptiform discharges induced by kainic acid (KA) in the CA3 region of the hippocampus. The results showed that nor-IBG and DM506 decreased epileptiform discharges in a concentration-dependent manner. Nor-IBG activity was inhibited by volinanserin, supporting a role for the 5-HT_2AR. Functional studies have shown that ibogalogs are more potent agonists at 5-HT_2A/2CRs than at 5-HT_1A/1BRs, supporting the role of 5-HT_2AR. In conclusion, repetitive treatment with ibogalogs induced antiseizure activity in mice through 5-HT_2A/2CR activation, accompanied by normalization of PTZ-induced alterations in hippocampal monoamines. In the hippocampal CA3 subfield, ibogalogs reduced KA-induced epileptiform discharges, where nor-IBG activity was mediated by 5-HT_2AR activation.

Indole-tetrahydroazepine derivatives of iboga alkaloids (ibogalogs) exhibit antidepressant, anxiolytic, promnesic, and antineuropathic effects, mainly via serotonergic targets. However, their physicochemical properties relevant to redox biology, including antioxidant activity and membrane stability, have remained poorly characterized. We investigated the antioxidant properties of three ibogalogs: ibogaminalog (DM506), ibogainalog (IBG), and tabernanthalog (TBG), using model lipid membranes (liposomes), human erythrocytes, and rat hippocampal and cortical synaptosomes exposed to AAPH-induced oxidative stress. Physicochemical descriptors, bond dissociation enthalpies, and ionization potentials were also calculated to assess membrane interactions and the antioxidant potential. All ibogalogs protected erythrocytes by reducing hemolysis, potassium efflux, and malondialdehyde levels, with the strongest effects observed for TBG; none induced hemolysis or K⁺ efflux at 0.01-10 μM. Ibogalogs also decreased lipid peroxidation in rat hippocampal and cortical synaptosomes. In liposomal systems, TBG showed the highest efficacy against lipid-peroxyl-radical-induced peroxidation, whereas DM506 and IBG mainly slowed autoxidation. Theoretical analysis indicated that the methoxy group substitution critically influences bond dissociation enthalpies, radical delocalization, and antioxidant potency. This first physicochemical characterization of antioxidant properties of ibogalogs enhances the understanding of their membrane-protective actions, complementing their neuromodulatory profiles.