The international journal of biochemistry & cell biology
September 1, 2010
Hugo R Arias, Avraham Rosenberg, Katarzyna M Targowska-Duda et al.
29 citations
Ibogaine blocks human alpha3beta4-nicotinic acetylcholine receptors (AChRs) by binding to a site in the receptor's ion channel, with about nine times higher potency than phencyclidine (PCP). Ibogaine binds with relatively high affinity (Kd = 0.46 ± 0.06 μM) to a single site in the channel and dissociates more slowly from the desensitized receptor than from the resting one, which may prolong the desensitized state. PCP inhibits ibogaine binding, indicating overlapping binding sites between the serine and valine/phenylalanine rings. The interaction is mainly via van der Waals contacts, with local conformational changes suggested by entropic contributions. These findings suggest ibogaine's mechanism involves stabilizing the receptor in a shut-down state.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
June 17, 2024
Hugo R Arias, L. Micheli, Deborah Rudin et al.
14 citations
New non-hallucinogenic iboga alkaloid derivatives, called ibogalogs (TBG, IBG, and DM506), reduce pain hypersensitivity in mouse models of neuropathic and visceral pain. IBG provided the longest pain relief at a lower dose, while DM506 acted fastest. The pain-relieving effect was blocked by the 5-HT2A receptor antagonist ketanserin, indicating that activation of the 5-HT2A receptor, not its inhibition, mediates this activity. Ibogalogs activate 5-HT2A and 5-HT6 receptors and act as inverse agonists (except TBG) at the 5-HT7 receptor. Based on prior work, 5-HT6 inhibition and 5-HT7 activation relieve pain, so these receptors are not involved. The anti-hypersensitivity activity of ibogalogs in mice is mediated by 5-HT2A receptor activation.
European Journal of Pharmacology
March 5, 2024
Hugo R Arias, Deborah Rudin, Dustin J Hines et al.
12 citations
A non-hallucinogenic compound derived from ibogamine, DM506, produces anxiolytic- and sedative-like effects in mice without causing hallucinogenic head-twitch responses. At 15 mg/kg, DM506 induces both acute and long-lasting anxiety-reducing behavior in naive and stressed mice. Repeated 5 mg/kg doses show no cumulative effects or side effects. Higher doses (40 mg/kg) cause sedation that is blocked by the 5-HT2A receptor antagonist volinanserin. DM506 binds to human 5-HT2A (Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors, activating them with EC50 values of 9 nM and 3 nM, respectively, acting as a partial agonist compared to the full agonist DOI. Electroencephalography shows increased transition from alert to deep-sleep brain wave activity.
The international journal of biochemistry & cell biology
September 1, 2011
Hugo R Arias, Dominik Feuerbach, Katarzyna M Targowska-Duda et al.
10 citations
Ibogaine analogs inhibit epibatidine-induced calcium influx in human muscle acetylcholine receptors with a potency order: 18-methylaminocoronaridine and 18-methoxycoronaridine are most potent, followed by ibogaine and catharanthine, then albifloranine. The analogs bind more strongly to the TCP binding site when the receptor is in the desensitized state versus the resting state, and they enhance cytisine binding to resting receptors. The affinity of the analogs correlates with their molecular volume, with an optimal volume around 345 cubic angstroms for the ibogaine site, suggesting the size of the binding site between the serine and nonpolar rings is crucial for binding and desensitization.
Neurochemistry International
September 1, 2010
Hugo R Arias, Dominik Feuerbach, Katarzyna M Targowska-Duda et al.
9 citations
Catharanthine alkaloids such as ibogaine, vincristine, and vinblastine inhibit muscle nicotinic acetylcholine receptors (AChRs) in a noncompetitive manner, blocking ion flow and promoting receptor desensitization. These compounds inhibit epibatidine-induced calcium influx in TE671 cells with similar potencies (IC50 = 17–25 μM). They bind more tightly to desensitized than resting AChRs and enhance binding of cytisine to resting receptors, indicating desensitizing properties. Phencyclidine (PCP) inhibits ibogaine binding to the AChR through steric hindrance. Docking experiments suggest neutral ibogaine forms hydrogen bonds with the serine ring at position 6', a site shared with PCP, while protonated ibogaine may form a salt bridge with acidic residues at the outer ring. The catharanthine moiety is the minimal structure required for AChR inhibition.
ACS Chemical Neuroscience
May 1, 2024
Benjamin M Williams, Nathan D Steed, Joel T Woolley et al.
7 citations
Catharanthine and 18-methoxycoronaridine (18-MC), iboga alkaloids, reduce nicotine's effects on dopamine transmission and behavior. In male mice, both compounds inhibited evoked dopamine release in the nucleus accumbens core, with catharanthine's effect depending on α4 and α6 nicotinic receptors. Catharanthine slowed dopamine reuptake ex vivo but increased extracellular dopamine in vivo. Both compounds suppressed firing of striatal cholinergic interneurons and acetylcholine currents in oocytes. In male rats, catharanthine and 18-MC blocked nicotine-enhanced locomotor activity, and catharanthine dose-dependently reduced nicotine self-administration without affecting food reinforcement. Combining catharanthine with nicotine increased head twitch responses, suggesting a potential synergistic hallucinogenic effect.
Biomedicine & Pharmacotherapy
November 13, 2025
Abdeslam Chagraoui, Luis A Haro Santillan, Renata Bocian et al.
5 citations
Ibogalogs, particularly DM506 and IBG, improve short- and long-term spatial memory in mice, while DM506 alone enhances long-term recognition memory. Tabernanthalog (TBG) showed less efficacy. These memory enhancements involve serotonin 5-HT2A and 2C receptors, as antagonists partially blocked the effects. Electrophysiological experiments linked ibogalogs to hippocampal function: TBG and DM506 increased theta rhythm power and amplitude in CA1, while volinanserin and high DM506 concentrations decreased them. DM506 enhanced NMDAR-mediated currents in CA1 neurons (EC50 = 20 ± 15 nM), blocked by Mg2+. TBG had a lower effect at high concentrations. The findings indicate ibogalogs enhance memory via 5-HT2A/2CR activation, modulating NMDAR activity and theta rhythm in hippocampal CA1.
The FASEB Journal
April 1, 2012
Ilana Emert, Katarzyna M Targowska-Duda, Dominik Feuerbach et al.
Ibogaine inhibits calcium influx through human α3β4 nicotinic acetylcholine receptors with roughly nine times higher potency than phencyclidine (PCP). Radioligand binding shows ibogaine binds to a single site on the receptor with a dissociation constant of 0.46 μM, and it has slightly higher affinity for desensitized receptors than for resting ones. Docking studies indicate both compounds interact with a binding domain between the serine (position 6′) and valine/phenylalanine (position 13′) rings, primarily through van der Waals contacts, consistent with the measured enthalpic contribution. Entropic contributions suggest local conformational changes upon binding.