ZINC000443438219
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| Other names | Z0443438219; '8219 |
| Drug class | Atypical selective serotonin reuptake inhibitor (SSRI) |
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| Chemical and physical data | |
| Formula | C15H18FN3S |
| Molar mass | 291.39g·mol−1 |
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ZINC000443438219 (also known as Z0443438219 or '8219) is a piperazine derivative which acts as a potent and selective serotonin reuptake inhibitor (SSRI).[1] It was developed as an elaborated hit from an ultra-large-scale docking screen, looking for molecules which would bind to the orthosteric site of the serotonin transporter (SERT) in the extracellular-closed, inward-open state favored by compounds such as ibogaine, noribogaine, and MDMA, as opposed to the outward-open conformation favored by compounds such as cocaine and conventional SSRI antidepressants like fluoxetine or citalopram.[1] [2] (R)-'8219 binds to SERT with a binding affinity (Ki) of 3nM and produced antidepressant- and anxiolytic-like effects in animal studies, while the (S) enantiomer '8221 was also active but with a much weaker Ki of 170nM.[1] The drug is not a substrate-type serotonin releasing agent.[1] '8219 was first described in the scientific literature by Bryan L. Roth and colleagues in 2023.[1]
See also
[edit ]References
[edit ]- 1 2 3 4 5 Singh I, Seth A, Billesbølle CB, Braz J, Rodriguiz RM, Roy K, et al. (May 2023). "Structure-based discovery of conformationally selective inhibitors of the serotonin transporter". Cell. 186 (10): 2160–2175.e17. doi:10.1016/j.cell.2023年04月01日0. PMC 10306110 . PMID 37137306.
- ↑ Nielsen JC, Loland CJ (2025). "Substrate Binding and Conformational Dynamics of the Monoamine Transporters". Monoamine Transporters. Vol. 46. Cham: Springer Nature Switzerland. pp. 35–62. doi:10.1007/978-3-031-96364-3_2. ISBN 978-3-031-96363-6. PMID 41051705 . Retrieved 30 June 2026.
A comparison of the fluorescence "footprints" of 5-HT and MDMA to those of different inhibitors known to stabilize outward-facing (cocaine, s-citalopram, and imipramine) and inward-facing (noribogaine [33]) conformations of SERT hints at the conformations induced by the substrates. At the extracellular position, 5-HT and MDMA left footprints that were alike that of noribogaine, while being different from the inhibitors stabilizing the outward-facing conformation. This points towards that substrate binding stabilize an inward-facing conformation. However, at the intracellular position, 5-HT and MDMA left unique footprints that were also different from that of noribogaine, suggesting that they do not stabilize an inward-open conformation similar to that stabilized by noribogaine [30].