Development of Bioisosteres of Iboga Alkaloids: A Step-Economical Synthesis to Enhance the Antinociceptive and Anxiolytic Activity with Neuroprotective Effects

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 psychedelic 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 the bioisosteric replacement of the indole scaffold with a benzofuran moiety and compared their antinociceptive/anxiolytic activity with their natural counterparts. Among the synthesized iboga analogs, the Endo-iboga analogs (C2 & C4) not only exhibited notable anti-inflammatory and oxidative stress-relieving activity but also effectively improved restricted locomotor activity in a formalin-induced acute pain model in mice. C2 & C4 significantly elevated the levels of inhibitory neurotransmitters (GABA and dopamine) and brain-derived neurotrophic factor (BDNF) compared to their respective Exo-counterparts or previously published benzofuran-containing iboga analogs lacking the tetrahydroazepine ring. Among C2 and C4, the latter exhibited superior cytocompatibility in C2C12 cells (IC50 = 235 μM) and showed no adverse effects on rat hearts during in vivo ECG tests, indicated by no significant QTc prolongation. The hERG Fluorescence Polarization assay identified C4 (IC50 = 21.25 ± 4.89 μM) as the compound with the lowest risk for hERG channel blockade as compared to C2 (19.31 ± 4.02 μM). C4 also showed no alteration of the serum potassium level in rats and, moreover, significantly acted as a potent KOR agonist in C6 cells and a MOR antagonist in MCF7 cells. Apart from MOR and KOR, C4 acted as a weak agonist for 5HT2A and a weak antagonist for the σ1 receptor. In silico binding further confirmed its relatively higher binding energies with reduced stability within the receptor active sites. Overall, the development of bioisosteric iboga analogs, particularly C4, demonstrated significant potential for acute pain management without notable cardiotoxicity, representing a potential pharmacophore in pain therapy innovation.