Z3517967757

Z3517967757
Clinical data
Other names	Z7757
Identifiers
	IUPAC name 4-[1-(1-pyrimidin-2-ylethyl)piperidin-3-yl]phenol;
CAS Number	None;
PubChem CID	167949972;
Chemical and physical data
Formula	C17H21N3O
Molar mass	283.375 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC(C1=NC=CC=N1)N2CCCC(C2)C3=CC=C(C=C3)O;
	InChI 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 piperidine 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-HT_2A receptor and lower affinity at the 5-HT_2B and 5-HT_2C receptors. However, it has been reported to have excellent selectivity for the 5-HT_2A receptor, with no agonistic activity at the 5-HT_2B and 5-HT_2C receptors.^[1] The drug was developed using in silico modelling to dock a large library of compounds against a 5-HT_2A 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, but has only been tested as a racemic mixture.^[2]^[3]^[4]

References

^ ^a ^b 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.
^ Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, et al. (December 2023). "AlphaFold2 structures template ligand discovery". bioRxiv. doi:10.1101/2023.12.20.572662. PMC 10769324. PMID 38187536.
^ Callaway E (18 January 2024). "AlphaFold found thousands of possible psychedelics. Will its predictions help drug discovery?". Nature News. doi:10.1038/d41586-024-00130-8. PMID 38238624.
^ Lyu J, Kapolka N, Gumpper R, Alon A, Wang L, Jain MK, et al. (May 2024). "AlphaFold2 structures guide prospective ligand discovery". Science. New York, N.Y.: eadn6354. doi:10.1126/science.adn6354. PMID 38753765.

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