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Z3517967757

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Z3517967757
Image
Clinical data
Other namesZ7757, YEQ
Drug classSerotonin receptor modulator; Serotonin 5-HT2A receptor agonist
ATC code
  • None
Identifiers
  • 4-[1-(1-pyrimidin-2-ylethyl)piperidin-3-yl]phenol
CAS Number
PubChem CID
ChemSpider
PDB ligand
Chemical and physical data
FormulaC17H21N3O
Molar mass283.375 g·mol−1
3D model (JSmol)
  • CC(C1=NC=CC=N1)N2CCCC(C2)C3=CC=C(C=C3)O
  • InChI=1S/C17H21N3O/c1-13(17-18-9-3-10-19-17)20-11-2-4-15(12-20)14-5-7-16(21)8-6-14/h3,5-10,13,15,21H,2,4,11-12H2,1H3
  • Key:JDCMEPNJYDYSCB-UHFFFAOYSA-N

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]

Image
Active enantiomer (YEQ)[6]

See also

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References

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  1. 1 2 Gumpper RH, Nichols DE (23 August 2024), Chemistry/structural biology of psychedelic drugs and their receptor(s), Authorea, Inc., 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, et al. (December 2023). "AlphaFold2 structures template ligand discovery". bioRxiv 10.1101/2023.12.20.572662.
  3. ↑ Callaway E (18 January 2024). "AlphaFold found thousands of possible psychedelics. Will its predictions help drug discovery?". Nature News. 626 (7997): 14–15. Bibcode:2024Natur.626...14C. doi:10.1038/d41586-024-00130-8. PMID 38238624.
  4. ↑ Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, et al. (May 2024). "AlphaFold2 structures guide prospective ligand discovery". Science. 384 (6702) eadn6354. New York, N.Y. Bibcode:2024Sci...384n6354L. doi:10.1126/science.adn6354. PMC 11253030. PMID 38753765.
  5. ↑ 5HT2AR-miniGq heterotrimer in complex with a novel agonist obtained from large scale docking. Protein Data Bank 29 May 2024
  6. ↑ "4-{(3R)-1-[(1R)-1-(pyrimidin-2-yl)ethyl]piperidin-3-yl}phenol". PubChem. Retrieved 4 July 2026.
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