Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula.
Hugo R Arias, Xiaotao Jin, Dominik Feuerbach, Ryan M Drenan
The international journal of biochemistry & cell biology October 16, 2017 DOI: 10.1016/j.biocel.2017.10.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro receptor pharmacology and electrophysiology study Peer reviewed |
|---|---|
| Population | Human α4β2, α7, and α3β4 nicotinic acetylcholine receptors expressed in cell systems, and neurons from the ventral inferior medial habenula of mice |
| Interventions | (+)-catharanthine (±)-18-methylaminocoronaridine bupropion (-)-ibogaine |
| Topics | Ibogaine |
| Keywords | Neurons Animals Mice, inbred c57bl Receptors, nicotinic Nicotinic antagonists Protein conformation Male Nicotinic acetylcholine receptor Brain slices Medial habenula 18-methoxycoronaridine Coronaridine congeners +-catharanthine |
| Key points | Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors with higher selectivity than α4β2 or α7 subtypes, and also inhibit α3β4* receptors in mouse medial habenula neurons, with (+)-catharanthine and (±)-18-methoxycoronaridine showing lower potency on neurons (27±4 µM and 28±6 µM) than on human α3β4 receptors. Bupropion binds ibogaine sites on desensitized human α3β4 receptors with twofold higher affinity than on resting receptors, suggesting a shared binding site. The authors propose these receptors are important targets for the compounds' anti-addictive effects. |
Abstract
The inhibitory activity of coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca2+ influx results clearly establish that coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxycoronaridine [(±)-18-MC]>(+)-catharanthine>(±)-18-methylaminocoronaridine [(±)-18-MAC] ∼ (±)-18-hydroxycoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine>(±)-18-MC>(±)-18-HC>(±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27±4μM) and (±)-18-MC (28±6μM) on MHb (VI) neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupropion with (-)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.
Comparable studies
Other preclinical and animal studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine TE671/RD cells (human muscle-type nAChR) and SH-SY5Y neuroblastoma cells (human... | 1999 | In vitro study | |
| Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Ibogaine- or harmaline-treated rats | 1993 | Experimental animal study | |
| Effects and aftereffects of ibogaine on morphine self-administration in rats. Rats | 1991 | Preclinical experimental study | |
| Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Rats | 1994 | Experimental study | |
| Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Rats | 2005 | Experimental study |
Citations in the library
Cited by 4
- What We Have Gained from Ibogaine: α3β4 Nicotinic Acetylcholine Receptor Inhibitors as Treatments for Substance Use Disorders. Journal of Medicinal Chemistry January 12, 2023
- Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters. ACS Chemical Neuroscience May 1, 2024
- The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs. Natural Product Reports March 4, 2021
- (+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission. European Journal of Pharmacology December 19, 2022
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and 5 more in the library