Chemistry and Pharmacology of Iboga Alkaloids - SUMMARY
Chemistry and Pharmacology of Iboga Alkaloids
Ibogaine is the major psychoactive alkaloid of Tabernanthe iboga, a shrub native to West Central Africa.
Since the 1960’s, ibogaine has been known for its ability to interrupt drug addiction. In light of the growing drug
use and drug overdose epidemics in the U.S., there is an urgent need for new therapeutics to treat opioid use
disorder (OUD) and other substance use disorders (SUDs) - and ibogaine represents an important prototype in
this direction. Two recent observational clinical studies confirmed the earlier reports of ibogaine’s effects that
include a rapid and long-lasting relief of opioid withdrawal symptoms and cravings, and an increased rate and
duration of abstinence in opioid-dependent subjects. The observed response size was comparable to that of
methadone replacement therapy. These clinical observations have been replicated in preclinical rodent models
of SUDs, including attenuation of self-administration of opioids, cocaine, alcohol and nicotine, mitigation of
naloxone-precipitated withdrawal symptoms, and reversal of analgesic tolerance in opioid-dependent animals. The
current mechanistic model for ibogaine invokes a role for several key molecular targets, including the a3b4
nicotinic receptor, kappa opioid receptor (KOR), and monoamine transporters. An active metabolite, noribogaine,
also makes a significant contribution to the pharmacological effects of ibogaine. We have developed new synthetic
methods for de novo synthesis of the iboga alkaloid scaffold, which unlocks unlimited exploration of its
pharmacology. We have found that substitution of the indole amine group with other heteroatoms enables
accentuation of specific mechanisms of the noribogaine pharmacological profile. The proposed research will
focus on benzofuran analogs of noribogaine (oxa-noribogaine) that represent a new class of KOR modulators.
Our preliminary results have shown that oxa-noribogaine induces a potent analgesia with no
sedative/dissociative side effects in mice, and complete and long-lasting suppression of morphine self-
administration in rats, providing a strong rationale for the proposed research. In this application, we will
explore the oxa-iboga system in terms of synthetic methods, KOR and opioid receptor pharmacology and
signaling, off-target pharmacology, in vivo target validation, and efficacy examination in rat models of
OUD. We will also explore the central hypothesis that the benzofuran iboga analogs exhibit an atypical KOR
modulator profile that underlies the favorable separation of analgesia and side effects, as well as the efficacy
in OUD models. We have assembled an interdisciplinary team with significant experience in synthetic
chemistry, computational design, opioid receptor signaling, mouse behavior, and SUD preclinical
pharmacology.
