Iboga derivatives, particularly iboga-alcohol, reduce pain and inflammation in rodent models of acute and chronic pain without causing psychedelic effects. In formalin-induced acute pain, the compounds decreased paw swelling, reversed reduced tail flick latency, and improved locomotor activity. They also reduced inflammatory markers such as Substance P, CGRP, COX-2, and p65 nuclear translocation, and lowered serum IL-6 and TNF-α levels. Iboga-alcohol inhibited mechanical allodynia and heat hyperalgesia in chronic pain and restored impaired motor activity. The derivatives reversed BDNF depletion and modulated GDNF elevation. These findings suggest the compounds are promising candidates for non-psychedelic pain treatments.
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.