Chemistry:Z3517967757

From HandWiki

Z3517967757, or simply Z7757, is a 3-phenylpiperidine derivative which acts as an agonist at the 5-HT2 family of serotonin receptors, first reported in 2024. It can also be viewed as a ring-restrained phenethylamine.[1] It has strongest activity at the 5-HT2A receptor and lower affinity at the 5-HT2B and 5-HT2C receptors. However, it has been reported to have excellent selectivity for the 5-HT2A receptor, with no agonistic activity at the 5-HT2B and 5-HT2C receptors.[1] The drug was developed using in silico modelling to dock a large library of compounds against a 5-HT2A receptor model generated by the artificial intelligence program AlphaFold, and then synthesised and tested in the laboratory to confirm activity. It has two stereogenic centers and four possible isomers,[2][3][4] and was docked to the 5-HT2A receptor as the (1R,3R) enantiomer YEQ.[5]

Active enantiomer

See also

References

  1. ↑ 1.0 1.1 Chemistry/structural biology of psychedelic drugs and their receptor(s), Authorea, Inc., 23 August 2024, doi:10.22541/au.172441788.88647620/v1, "Another compound to come out of a large-scale docking screen is the recently reported Z7757 (Figure 5B) (Lyu et al., 2024). This compound was discovered from a 1.6 billion molecule docking screen against the AlphaFold model of the 5-HT2A receptor. Similar to the recent report of LPH-5, Z7757 is a ring-restrained phenethylamine. However, it has a pyrimidine ring substituent coming off the tertiary nitrogen. Remarkably, Z7757 shows excellent selectivity for 5-HT2A with no activity being detected for 5-HT2B or 5-HT2C in calcium mobilization assays, but further optimization to increase potency and in vivo testing is needed." 
  2. ↑ Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, Barros-Álvarez X, Sakamoto K, Kim Y, DiBerto J, Kim K, Tummino TA, Huang S, Irwin JJ, Tarkhanova OO, Moroz Y, Skiniotis G, Kruse AC, Shoichet BK, Roth BL (December 2023). "AlphaFold2 structures template ligand discovery". bioRxiv 10.1101/2023.12.20.572662.
  3. ↑ "AlphaFold found thousands of possible psychedelics. Will its predictions help drug discovery?". Nature News 626 (7997): 14–15. 18 January 2024. doi:10.1038/d41586-024-00130-8. PMID 38238624. Bibcode: 2024Natur.626...14C. 
  4. ↑ "AlphaFold2 structures guide prospective ligand discovery". Science (New York, N.Y.) 384 (6702). May 2024. doi:10.1126/science.adn6354. PMID 38753765. Bibcode: 2024Sci...384n6354L. 
  5. ↑ 5HT2AR-miniGq heterotrimer in complex with a novel agonist obtained from large scale docking. Protein Data Bank 29 May 2024



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Z3517967757&oldid=4433765"