Development of Bioisosteres of Iboga Alkaloids: A Step-Economical Synthesis to Enhance the Antinociceptive and Anxiolytic Activity with Neuroprotective Effects
ACS Pharmacology & Translational Science April 14, 2026 Abhishek Gupta, Tuhin Bhattacharya, Subhamoy Pratihar et al.
Iboga alkaloids can reverse drug addiction and modulate drug tolerance, but their use is limited by severe psychedelic effects and cardiotoxicity from hERG potassium channel blockade. Researchers synthesized four modified ibogaine/ibogamine analogs (C1–C4) with a benzofuran moiety replacing the indole scaffold. Among these, the Endo-iboga analogs C2 and C4 showed notable anti-inflammatory and oxidative stress-relieving activity and improved restricted locomotor activity in a formalin-induced acute pain model in mice. C4 exhibited superior cytocompatibility (IC50 = 235 μM in C2C12 cells), no significant QTc prolongation in rat ECG tests, and the lowest hERG blockade risk (IC50 = 21.25 ± 4.89 μM). C4 acted as a potent KOR agonist and MOR antagonist, with weak 5HT2A agonist and σ1 antagonist activity, suggesting potential for acute pain management without notable cardiotoxicity.