Development of Bioisosteric Iboga-alkaloids as Antinociceptive and Anxiolytic Agents with Neuroprotective Effects

Abstract

The clinical importance of iboga alkaloids lies in their efficacy in reversing drug addiction and modulating drug tolerance. However, due to safety concerns, their use is restricted to appropriate medical supervision. These alkaloids often cause severe hallucinogenic effects due to differential binding to various brain receptors and cardiotoxicity by blocking the human ether-a-go-go-related gene (hERG) potassium channel. To create safer analogs, our group previously synthesized various benzofuran-containing iboga analogs with good opioid binding selectivity and excellent antinociceptive property. However, the present manuscript disclosed a step-economical and cost-effective synthesis of modified ibogaine/ibogamine analogs (C1, C2, C3 & C4) with bio-isosteric replacement of the indole scaffold with a benzofuran moiety, and comparing their antinociceptive/anxiolytic activity with their natural counterparts. Among the synthesized iboga analogs, the Endo-iboga analogs (C2 & C4, epimers of C1 and C3, respectively) not only exhibited superior anti-inflammatory and oxidative stress-relieving activity, but also effectively improved restricted locomotor activity in a formalin-induced acute pain model in mice. These Endo-iboga analogs significantly elevated the levels of inhibitory neurotransmitters (GABA and dopamine) and brain-derived neurotrophic factor (BDNF) compared to their Exo-counterparts or previously published benzofuran-containing iboga analogs lacking the tetrahydroazepine ring. Amongst, C2 and C4, the latter exhibited superior cardiac safety profile in C2C12 cells (IC50 = 235 {micro}M) and showed no adverse effects on rat hearts during in vivo ECG tests, indicated by no significant QTc prolongation. Overall, the development of bioisosteric iboga analogs, particularly C4, demonstrated significant potential for acute pain management without notable cardiotoxicity, representing a breakthrough in pain therapy innovation.