SERT Efflux Data - Prism File

<b>Anecdotal reports and preliminary clinical trials suggest that the psychoactive alkaloid ibogaine and its active metabolite noribogaine</b> <b>have powerful anti-addictive properties, producing long-lasting therapeutic effects across a range of substance use disorders and co-occurring neuropsychiatric diseases such as depression and post-traumatic stress disorder.</b><b>[i]</b>^{<strong>,</strong>}^{<strong>[ii]</strong>}^{<strong>,</strong>}^{<strong>[iii]</strong>}<b> The mechanisms by which ibogaine and noribogaine exert their therapeutic effects are poorly understood, though several hypotheses have emerged related to neuroplasticity in addiction-related circuitry</b><b>[iv]</b>^{<strong>,</strong>}^{<strong>[v]</strong>}^{<strong>,</strong>}^{<strong>[vi]</strong>}<b> and modulation of serotonin transporter (SERT) function.</b><b>[vii]</b><b> Currently, ibogaine and related alkaloids are obtained via extraction from natural plant sources, which drastically limits the quantities available for mechanistic biological studies or clinical trials and raises major concerns about ecological sustainability. Here, we report a gram-scale, 7-step synthesis of ibogaine from pyridine.</b><b> </b><b>Key features of this strategy enabled the first enantioselective total synthesis of (+)-ibogaine, the first syntheses of tabernanthine and ibogaline, and the construction of four novel analogues. Biological testing revealed that the unnatural enantiomer of ibogaine does not produce ibogaine-like effects on cortical neuron growth, while (–)-10-fluoroibogamine exhibits exceptional psychoplastogenic properties and facilitates SERT-mediated serotonin efflux. This work provides a platform for accessing iboga alkaloids and congeners for further biological study.</b><br>[i]. Kock, P., Froelich, K., Walter, M., Lang, U., Dursteler, K. M. A systematic literature review of clinical trials and therapeutic applications of ibogaine<i>. J. Subst. Abuse. Treat.</i> <b>138.</b> 108717 (2022).[ii]. Wasko, M. J., Witt-Enderby, P. A., Surratt, C. K. DARK classics in chemical neuroscience: ibogaine. <i>ACS Chem. Neurosci.</i> 9, 2475—2483 (2018).[iii]. Iyer, R. N., Favela, D., Zhang, G. &amp; Olson, D. E. The iboga enigma: the chemistry and neuropharmacology of iboga alkaloids and related analogs. Nat. Prod. Rep. https://doi.org/ 10.1039/D0NP00033G (2020).[iv]. He, D. Y. et al. Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption. <i>J. Neurosci.</i> <b>25</b>, 619—628 (2005).[v]. Marton, S. et al. Ibogaine administration modifies GDNF and BDNF expression in brain regions involved in mesocorticolimbic and nigral dopaminergic circuits. Front. Pharmacol. 10, 193 (2019).[vi]. Ly, C., Greb, A. C., Cameron, L. P., Ori-McKenney, K. M., Gray, J. A., Olson, D. E. Psychedelics promote structural and functional neural plasticity. Cell Rep. <b>23</b>, 3170—3182 (2018).[vii]. Singh, I. et. al. Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. <i>Cell</i>. <b>186</b>, 2160—2175 (2023)