A new class of iboga alkaloids, called oxa-iboga, was created by modifying the iboga molecular structure to replace a key component with a benzofuran ring. These compounds lack the heart rhythm risks (proarrhythmic effects) of ibogaine and noribogaine when tested on human heart cells. In male rats, oxa-iboga compounds were more effective than ibogaine at reducing opioid use. They act as potent kappa opioid receptor agonists but produce different behavioral effects than typical kappa agonists. A single dose or short treatment with oxa-noribogaine led to long-lasting reductions in morphine, heroin, and fentanyl intake, reversed persistent opioid-induced pain sensitivity, and suppressed drug-seeking behavior in relapse models. These compounds offer a mechanistically distinct approach to treating opioid use disorder.
A sensitive UPLC-MS/MS method was developed and validated to quantify ibogaine, noribogaine, ibogamine, and oxa-noribogaine in rat brain microdialysate, measuring pharmacologically active, unbound drug in brain extracellular fluid rather than total tissue content. The method achieved lower limits of quantification of 0.78-1.56 ng/mL with a 6-minute run time, and calibration curves were linear over 0.78-75 ng/mL for ibogamine and 1.56-75 ng/mL for the other analytes. Accuracy and precision met acceptance criteria. Applied to rats (n=4), noribogaine in nucleus accumbens after 10 mg/kg intraperitoneal administration reached a peak unbound concentration of 292 ± 68 ng/mL at 50 minutes, demonstrating suitability for real-time neuropharmacokinetic profiling of iboga alkaloids.