Ibogainalog

Ibogainalog (IBG; 9-methoxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole; CAS 802581-10-8) is a synthetic tricyclic azepinoindole and a structurally simplified analog of the iboga alkaloid ibogaine, first described in the chemical literature by Hester and colleagues in the late 1960s and subsequently characterized in pharmacological detail by the Olson laboratory at the University of California, Davis, beginning in 2020. The compound belongs to the ibogalog structural class, a family of substituted hexahydroazepino[4,5-b]indoles that retain the fused indole-azepine core of the iboga alkaloids while eliminating the isoquinuclidine ring system, yielding a dramatically simplified molecular architecture that is amenable to practical gram-scale synthesis. Ibogainalog is a non-selective serotonin receptor modulator with potent agonist activity at the 5-HT2A receptor (Ki approximately 670 nM; functional EC50 18 to 85 nM, 55 to 93 percent efficacy), the 5-HT6 receptor (EC50 7.1 to 8.8 nM, 83 to 99 percent efficacy), the 5-HT1F receptor (EC50 35 nM, 85 percent efficacy), and the 5-HT1B receptor (EC50 170 nM, 76 percent efficacy), with additional inverse agonist activity at the 5-HT7 receptor (EC50 335 nM) and mixed agonist-antagonist activity at the 5-HT2B and 5-HT2C receptors. The compound is a moderate serotonin reuptake inhibitor (SERT IC50 approximately 400 nM) with selectivity over the norepinephrine and dopamine transporters, and a noncompetitive inhibitor of the alpha-7 nicotinic acetylcholine receptor (IC50 approximately 11.4 micromolar) and a competitive inhibitor of the alpha-9-alpha-10 nicotinic acetylcholine receptor (IC50 approximately 2.9 micromolar). Critically, ibogainalog exhibits dramatically reduced potency at the hERG potassium channel relative to ibogaine (approximately 10-fold reduction), conferring a substantially improved cardiac safety profile; this is a principal design objective of the ibogalog class, given that ibogaine-associated QT prolongation and fatal cardiac arrhythmias have been a central safety concern limiting the clinical translation of ibogaine itself. The compound shows no agonist activity at opioid receptors, distinguishing it from the active ibogaine metabolite noribogaine. In preclinical behavioral models, ibogainalog at 10 mg/kg produces sustained antidepressant-like activity (persisting 72 hours in naive mice and 48 hours in chronically stressed mice) through a volinanserin-sensitive, 5-HT2A receptor-dependent serotonergic mechanism. The compound also produces dose-dependent antinociceptive activity in chronic constriction injury models of neuropathic pain and in dextran sulfate sodium-induced colitis models of visceral pain, with the longest anti-hyperalgesic duration among tested ibogalogs at comparatively lower doses. Analgesic activity is abolished by the 5-HT2A receptor antagonist ketanserin and involves synergistic crosstalk between 5-HT2A and metabotropic glutamate type 2 (mGlu2) receptors. As a psychoplastogen, ibogainalog promotes dendritic arborization and spinogenesis in cortical neurons at levels comparable to ibogaine, an activity mediated through 5-HT2A receptor signaling. Unlike the closely related ibogalog tabernanthalog, ibogainalog produces a measurable head-twitch response in rodent models, suggesting that it may retain psychedelic activity in humans, though the response magnitude is substantially reduced relative to classical psychedelics such as 5-methoxy-N,N-dimethyltryptamine. The compound is not in clinical development as of the date of this monograph; all evidence is preclinical. This monograph reviews the chemistry, synthesis, and structural class of ibogainalog; its multi-receptor serotonergic and nicotinic pharmacology; the available pharmacokinetic inference from the ibogalog class; the preclinical evidence base across antidepressant, analgesic, anti-addictive, and psychoplastogenic endpoints; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal from preclinical safety pharmacology; and a comparative assessment of five structurally or mechanistically related compounds against ibogainalog on five competency standards.