Structural insights into tryptamine psychedelics: The role of hydroxyl indole ring site in 5-HT2A receptor activation and psychedelic-like activity.
European journal of medicinal chemistry January 5, 2025 Miyuan Zhang, Yuefeng Yang, Zhishuai Yang et al. 10 citations
The position of the hydroxyl group on the indole ring of psilocin analogs determines their ability to activate the 5-HT2A receptor and produce psychedelic-like effects. Analogs with the hydroxyl group at the 4th or 5th position (psilocin and bufotenine) show significantly higher agonistic activity and head-twitch responses than those with the group at the 6th or 7th position. Computer simulations reveal that the 4- and 5-position analogs form a crucial hydrogen bond with residue L229 and a stable salt bridge and hydrogen bond with residue D155, guiding them into the binding site. Analogs lacking these interactions fail to reach the orthosteric site and have poor receptor activity.