Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity

Ibogaine (12-methoxyibogamine) exhibited moderate affinity for sigma 2 sites (Ki = 201 nM) and low affinity for sigma 1 sites (Ki = 8554 nM), thus showing 43-fold selectivity for sigma 2 receptors. Tabernanthine (13-methoxyibogamine) and (+/-)-ibogamine had sigma 2 Ki = 194 nM and 137 nM, respectively. However, they showed 3- to 5-fold higher sigma 1 affinity compared to ibogaine, resulting in about 14-fold selectivity for sigma 2 sites over sigma 1. A potential ibogaine metabolite, O-des-methyl-ibogaine, had markedly reduced sigma 2 affinity relative to ibogaine (Ki = 5,226 nM) and also lacked significant affinity for sigma 1 sites. (+/-)-Coronaridine ((+/-)-18-carbomethoxyibogamine) and harmaline (1-methyl-7-methoxy-3,4-dihydro-beta-carboline) lacked significant affinity for either sigma subtype. Thus, sigma 2 receptors could play a role in the actions of ibogaine.