Chemistry:Z3517967757

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-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

↑ ^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."
↑ "AlphaFold2 structures template ligand discovery". bioRxiv. December 2023. doi:10.1101/2023.12.20.572662. PMID 38187536.
↑ "AlphaFold found thousands of possible psychedelics. Will its predictions help drug discovery?". Nature News. 18 January 2024. doi:10.1038/d41586-024-00130-8. PMID 38238624.
↑ "AlphaFold2 structures guide prospective ligand discovery". Science (New York, N.Y.). May 2024. doi:10.1126/science.adn6354. PMID 38753765.

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[GumpperNichols2024-1] 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."

[pmid38187536-2] "AlphaFold2 structures template ligand discovery". bioRxiv. December 2023. doi:10.1101/2023.12.20.572662. PMID 38187536.

[3] "AlphaFold found thousands of possible psychedelics. Will its predictions help drug discovery?". Nature News. 18 January 2024. doi:10.1038/d41586-024-00130-8. PMID 38238624.

[pmid38753765-4] "AlphaFold2 structures guide prospective ligand discovery". Science (New York, N.Y.). May 2024. doi:10.1126/science.adn6354. PMID 38753765.

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v t e Phenethylamines
Phenethylamines	Psychedelics: 25B-NBOMe 25C-NBOMe 25D-NBOMe 25I-NBOMe 25N-NBOMe 2C-B 2C-B-AN 2C-Bn 2C-Bu 2C-C 2C-CN 2C-CP 2C-D 2C-E 2C-EF 2C-F 2C-G 2C-G-1 2C-G-2 2C-G-3 2C-G-4 2C-G-5 2C-G-6 2C-G-N 2C-H 2C-I 2C-iP 2C-N 2C-NH2 2C-O 2C-O-4 2C-P 2C-Ph 2C-SE 2C-T 2C-T-2 2C-T-3 2C-T-4 2C-T-5 2C-T-6 2C-T-7 2C-T-8 2C-T-9 2C-T-10 2C-T-11 2C-T-12 2C-T-13 2C-T-14 2C-T-15 2C-T-16 2C-T-17 2C-T-18 2C-T-19 2C-T-20 2C-T-21 2C-T-22 2C-T-22.5 2C-T-23 2C-T-24 2C-T-25 2C-T-27 2C-T-28 2C-T-30 2C-T-31 2C-T-32 2C-T-33 2C-TFE 2C-TFM 2C-YN 2C-V Allylescaline DESOXY Escaline Isoproscaline Jimscaline Macromerine MEPEA Mescaline Metaescaline Methallylescaline Proscaline Psi-2C-T-4 TCB-2 Stimulants: Phenylethanolamine Hordenine Phenethylamine α-Methylphenethylamine (amphetamine) β-Methylphenethylamine m-Methylphenethylamine N-Methylphenethylamine o-Methylphenethylamine p-Methylphenethylamine Methylphenidate Entactogens: Lophophine MDPEA MDMPEA Others: BOH DMPEA
Amphetamines	Psychedelics: 3C-BZ 3C-E 3C-P Aleph Beatrice Bromo-DragonFLY D-Deprenyl DMA DMCPA DMMDA DOB DOC DOEF DOET DOI DOM DON DOPR DOTFM Ganesha MMDA MMDA-2 Psi-DOM TMA TeMA Stimulants: 2-FA 2-FMA 3-FA 3-FMA Acridorex Alfetamine Amfecloral Amfepentorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Benfluorex Benzphetamine Cathine Clobenzorex Dimethylamphetamine Ephedrine Etilamfetamine Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Flucetorex Fludorex Formetorex Furfenorex Gepefrine 4-Hydroxyamphetamine Iofetamine Isopropylamphetamine Lefetamine Lisdexamfetamine Mefenorex Metaraminol Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxyphenamine MMA Morforex Norfenfluramine L -Norpseudoephedrine N,alpha-Diethylphenylethylamine Oxifentorex Oxilofrine Ortetamine PBA PCA Phenpromethamine PFA PFMA PIA PMA PMEA PMMA Phenylpropanolamine Pholedrine Prenylamine Propylamphetamine Pseudoephedrine Sibutramine Tiflorex Tranylcypromine Xylopropamine Zylofuramine Entactogens: 4-FA 4-FMA 4-MA 4-MMA 4-MTA 5-APB 5-APDB 5-EAPB 5-IT 5-MAPB 5-MAPDB 6-APB 6-APDB 6-Chloro-MDMA 6-EAPB 6-IT 6-MAPB 6-MAPDB EDA IAP 2,3-MDA 3,4-MDA (tenamfetamine) MDEA MDHMA MDMA (midomafetamine) MDOH Methamnetamine MMDMA Naphthylaminopropane TAP Others: 3,4-DCA Amiflamine DiFMDA Selegiline (also D -Deprenyl)
Phentermines	Stimulants: Chlorphentermine Cloforex Clortermine Etolorex Mephentermine Pentorex Phentermine Entactogens: MDPH MDMPH Others: Cericlamine
Cathinones	Stimulants: 3-FMC 4-MC 4-BMC 4-CMC 4-EMC 4-FMC 4-MEC 4-MeMABP 4-MPD Amfepramone Benzedrone Brephedrone Buphedrone Bupropion Cathinone Dimethylcathinone Ethcathinone Eutylone Hydroxybupropion Methcathinone Methedrone NEB N-Ethylhexedrone N-Ethylpentedrone Pentedrone Pentylone Radafaxine Entactogens: 3,4-DMMC 3-MMC Butylone Ethylone Methylone Methylenedioxycathinone Mephedrone
Phenylisobutylamines	Entactogens: 4-CAB 4-MAB Ariadne BDB Butylone EBDB Eutylone MBDB Stimulants: Phenylisobutylamine
Phenylalkylpyrrolidines	Stimulants: α-PBP α-PHP α-PPP α-PVP MDPBP MDPPP MDPV 4-MePBP 4-MePHP 4-MePPP MOPPP MOPVP MPBP MPHP MPPP Naphyrone PEP Prolintane Pyrovalerone
Catecholamines (and close relatives)	6-FNE 6-OHDA a-Me-DA a-Me-TRA Adrenochrome Ciladopa D -DOPA (Dextrodopa) Dimetofrine Dopamine Epinephrine Epinine Etilefrine Ethylnorepinephrine Fenclonine Ibopamine Isoprenaline Isoetarine L -DOPA (Levodopa) L -DOPS (Droxidopa) L -Phenylalanine L -Tyrosine m-Tyramine Metanephrine Metaraminol Metaterol Metirosine Methyldopa N,N-Dimethyldopamine Nordefrin (Levonordefrin) Norepinephrine Norfenefrine (m-Octopamine) Normetanephrine Orciprenaline p-Octopamine p-Tyramine Phenylephrine Synephrine
Miscellaneous	AL-LAD Amidephrine Arbutamine Cafedrine Denopamine Desvenlafaxine Diphenidine Dizocilpine Dobutamine Dopexamine Ephenidine Etafedrine ETH-LAD Famprofazone Fluorolintane Hexapradol IP-LAD Lysergic acid amide Lysergic acid 2-butyl amide Lysergic acid 2,4-dimethylazetidide Lysergic acid diethylamide Methoxamine Methoxphenidine MT-45 PARGY-LAD Phenibut PRO-LAD Pronethalol Salbutamol (Levosalbutamol) Solriamfetol Theodrenaline Thiamphenicol UWA-101

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