Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration

Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

“…The Ca 2+ influx results indicate that the studied coronaridine congeners inhibit h␣3␤4 AChRs with relatively high potency (Table 1) (Glick et al, 2002b;Pace et al, 2004). In addition to our previous results in Torpedo AChRs (Arias et al, 2011), this is the first time that the inhibitory potency for (+)-catharanthine, the scaffold structure for the coronaridine congener series, is obtained in the h␣3␤4 AChR.…”

“…1 and those from Pace et al (2004). Common overlapping features of these molecules, including acidity, basicity, hydrophobic centroids, aromatic rings, and hydrogen bond acceptors and donors were assigned as described elsewhere (Richmond et al, 2006).…”

“…Coronaridine congeners, including (−)-ibogaine [12-Q2 methoxyibogamine or 7-ethyl-6,2,7,8,9,10,12,13-octahydro-2-methoxy-6,9-methano 5H-pyrido(1 ,2 :1,2-azepine(4,5-)indole)] and (±)-18-methoxycoronaridine [(±)-18-MC], decrease drug selfadministration in animals (reviewed in Maisonneuve and Glick, 2003), interrupt drug dependence in humans (reviewed in Alper et al, 2008), and behave pharmacologically as noncompetitive antagonists (NCAs) of several nicotinic acetylcholine receptors (AChRs) (Badio et al, 1997;Fryer and Lukas, 1999;Glick et al, 2002a;Pace et al, 2004;Arias et al, 2010aArias et al, ,b,c, 2011. Previous studies support the hypothesis that the inhibition of ␣3␤4 AChRs expressed at the habenulo-interpeduncular cholinergic pathway is the main mechanism underlying the anti-addictive properties of coronaridine congeners (McCallum et al, 2012;Glick et al, 2002b;reviewed in Maisonneuve and Glick, 2003;Ortells and Arias, 2010).…”

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

“…[167] Interestingly, contrary to what happens regarding their interaction with opioid receptors, [168] the enantiomers of 74, the most potent antagonist, display the same potency on recombinant a3b4 nAChR expressed in HEK 293 cells. [169] Dextromethorphan (75 a: R 1 = Me, R 2 = OMe) is another noncompetitive nicotinic antagonist, potentially useful as anti-addictive agent. [170] Some analogues (general formula 75) were tested on recombinant a3b4 receptor in Xenopus oocytes by means of voltage-clamp, showing a potency similar to that of the parent compound, with an IC 50 value in the micromolar range.…”

A role for neuronal nicotinic acetylcholine receptors in ethanol-induced stimulation, but not cocaine- or methamphetamine-induced stimulation

“…18-Methoxycoronaridine does not appear to alter the acute locomotor response to MA or COC (Szumlinski et al 2000a, b). However, 18-methoxycoronaridine has been shown to attenuate operant responding for COC and MA (Glick et al , 2000Maisonneuve and Glick 2003;Pace et al 2004) and to decrease EtOH consumption and preference in a two-bottle choice paradigm (Rezvani et al 1997). To our knowledge, 18-methoxycoronaridine has not been used to study EtOH stimulation.…”