Chemistry:List of miscellaneous 5HT2A agonists

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This is a list of agonists of the serotonin receptor subtype 5-HT2A (and other 5-HT2 subtypes to a varying extent) which fall outside the common structural classes. Most agonists at this receptor are either substituted phenethylamine derivatives from the 2C, DOx and 25-NB groups, or substituted tryptamines and related compounds along with more complex derivatives of these such as lysergamides and iboga-type alkaloids[1] There are however numerous 5-HT2A receptor agonists which do not fall within any of these groups, some representative examples of which are listed below. Ki and EC50 values vary depending on the assay conditions used and so may not be directly comparable between sources. Many of these compounds have been designed to be non-psychoactive derivatives for medical applications, and it should not be assumed that a compound which acts as a 5-HT2A agonist will necessarily be psychedelic in nature.

Structure Name Chemical name h5-HT2A Ki (EC50) (nM) PubChem CAS number Reference
11a from Bioorg Med Chem Lett 2003, 13, 2369 structure.png Compound 11a 11-chloro-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole 6.5 20726100 599173-28-1 [2]
23 from Bioorg Med Chem Lett 2003, 13, 2369 structure.png Compound 23 9-Chloro-7-(2-ethoxy-phenyl)-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole 32 44315398 599173-25-8 [2]
10d from Bioorg Med Chem Lett 2005, 15, 1467 structure.png Compound 10d 7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 22 10472780 616201-60-6 [3]
22.67 from WO 2009-079765 structure.png Example 22.67 4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)thiomorpholine 21 44124494 [4]
3d from J Med Chem 2013, 56, 1211 structure.png Compound 3d (N-Bn-THAZ) 2-benzyl-5,6,7,8-tetrahydro-4H-[1,2]oxazolo[4,5-d]azepin-3-one (549) 14515725 125115-66-4 [5]
WO2021-0137908-1 structure.png Example 1 (ZC-B) 3-(4-bromo-2,5-dimethoxyphenyl)azetidine (1.6) 156337249 2641630-65-9 [6]
11 from WO 2021-076572 structure.png Compound 11 (3R)-N,N-diethyl-5-(1H-indol-4-yl)-1-methyl-3,6-dihydro-2H-pyridine-3-carboxamide (<10) 156278040 [7]
106 from ACS Med Chem Lett 2022, 13, 4, 648 structure.png Compound 106 6-chloro-1-(2,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 4376990 528525-37-3 [8]
6c from J Med Chem 2023, 66, 11536 structure.png Compound 6c (6S)-2,3-dichloro-7,8,9,10-tetrahydro-6H-6,9-epiminocyclohepta[b]quinoxaline (400) [9]
2CB-AR structure.png 2C-B-aminorex 5-(4-bromo-2,5-dimethoxyphenyl)-4,5-dihydro-1,3-oxazol-2-amine 165360199 [10]
2C-B-PP Structure.svg 2C-B-PP 1-(2,5-dimethoxy-4-bromophenyl)piperazine 4738744 100939-87-5 [11]
CPD-1 Structure.svg CPD-1 (3S)-3-Methyl-1-[4-(trifluoromethyl)-1-benzofuran-7-yl]piperazine 9925822 325145-37-7 [12]
Efavirenz.svg Efavirenz (4S)-6-Chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one 64139 154598-52-4 [13]
IHCH-7113.svg IHCH-7113 (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline 21302499 313368-85-3 [14]
NDTDI structure.png NDTDI N,N-diethyl-3-[methyl(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)amino]propanamide 163192742 [15]
Mefloquine structure without stereochemistry.svg Mefloquine 2,8-bis(trifluoromethyl)quinolin-4-yl-(2-piperidyl)methanol 40692 53230-10-7 [16]
Org12962 structure.png ORG-12962 1-(5-trifluoromethyl-6-chloropyridin-2-yl)piperazine 9796408 210821-63-9 [17]
ORG-37684.svg ORG-37684 (3S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]pyrrolidine 9794656 213007-95-5 [18]
OSU-6162.svg OSU-6162 (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine 9795741 156907-84-5 [19]
PHA-57378.svg PHA-57378 2,7,8,9,10,11-hexahydro-1H-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole 4.1 10198481 303798-94-9 [2]
P-54 structure.png P-54 2-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)-N,N-dimethylethanamine 168946740 [20]
R69 structure.png (R)-69 3-[(5R)-5-methyl-1,2,5,6-tetrahydropyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine 164513426 [21]
RH-34 structure.png RH-34 3-[2-(2-methoxybenzylamino)ethyl]-1H-quinazoline-2,4-dione 10041987 1028307-48-3 [22]
SCHEMBL5334361.svg SCHEMBL5334361 7-[(3-methoxyphenoxy)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (0.4) 59027940 959867-47-1 [23]
Tabernanthalog.svg Tabernanthalog 8-methoxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole 146026994 2483829-59-8 [24]
WXVL BT0793LQ2118 structure.png WXVL_BT0793LQ2118 6-fluoro-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole [25]
Z2825713589 structure.png Z2825713589 (4-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-(6-methoxypyrazin-2-yl)methanone 167788805 [25]
Z2876442907 structure.png Z2876442907 ethyl 2-[[2-(4-methyl-1H-indol-3-yl)ethylamino]methyl]-1,3-thiazole-5-carboxylate 167850865 [25]
Z3517967757 structure.png Z3517967757 4-[1-(1-pyrimidin-2-ylethyl)piperidin-3-yl]phenol 167949972 [25]
Z3881312504 structure.png Z3881312504 2-bromo-4-[2-[methyl-[2-(1,3-thiazol-2-yl)ethyl]amino]ethyl]phenol 167904469 [25]
Z4154032166 structure.png Z4154032166 2,2,2-trifluoro-1-[6-(1,2,3,6-tetrahydropyridin-5-yl)pyridin-2-yl]ethanol 167878716 [25]
Z5247692566 structure.png Z5247692566 4-[(3,3-dimethyloxolan-2-yl)methyl]-3-[(1H-indol-3-yl)methyl]morpholine [25]
Z5247692629 structure.png Z5247692629 1-(1-bicyclo[1.1.1]pentanyl)-4-[[5-(4-chlorophenyl)-1H-pyrazol-4-yl]methyl]piperazine 166358273 [25]

See also

References

  1. ↑ "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences 36: 1–43. 2018. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524. 
  2. ↑ 2.0 2.1 2.2 "2,3,4,5-tetrahydro- and 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indoles: new templates for 5-HT(2C) agonists". Bioorganic & Medicinal Chemistry Letters 13 (14): 2369–2372. July 2003. doi:10.1016/s0960-894x(03)00403-7. PMID 12824036. 
  3. ↑ "Discovery and SAR of new benzazepines as potent and selective 5-HT(2C) receptor agonists for the treatment of obesity". Bioorganic & Medicinal Chemistry Letters 15 (5): 1467–1470. March 2005. doi:10.1016/j.bmcl.2004.12.080. PMID 15713408. 
  4. ↑ Slassi A, et al. Compounds with activity at the 5-ht2c receptor. WO 2009/079765
  5. ↑ "Design, synthesis, and pharmacological characterization of N- and O-substituted 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-d]azepin-3-ol analogues: novel 5-HT(2A)/5-HT(2C) receptor agonists with pro-cognitive properties". Journal of Medicinal Chemistry 56 (3): 1211–1227. February 2013. doi:10.1021/jm301656h. PMID 23301527. 
  6. ↑ Kristensen JL, Jensen AA, Märcher-Rørsted E, "5-HT2A Agonists for Use in Treatment of Depression.", US patent 2021/0137908, published 13 May 2021, assigned to Lophora ApS.
  7. ↑ Olson DE, et al., "Ergoline-like compounds for promoting neural plasticity", WO patent 2021/076572
  8. ↑ "Discovery of Highly Potent Serotonin 5-HT2 Receptor Agonists Inspired by Heteroyohimbine Natural Products". ACS Medicinal Chemistry Letters 13 (4): 648–657. April 2022. doi:10.1021/acsmedchemlett.1c00694. PMID 35450369. 
  9. ↑ "Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library". Journal of Medicinal Chemistry 66 (16): 11536–11554. August 2023. doi:10.1021/acs.jmedchem.3c01059. PMID 37566000. 
  10. ↑ New Psychoactive Substances: Global Markets, Glocal Threats and the COVID-19 Pandemic. An update from the EU Early Warning System. Luxembourg: Publications Office of the European Union. December 2020. doi:10.2810/921262. ISBN 978-92-9497-557-7. https://www.emcdda.europa.eu/system/files/publications/13464/20205648_TD0320796ENN_PDF_rev.pdf. 
  11. ↑ "Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergic agents". Journal of Medicinal Chemistry 29 (5): 630–634. May 1986. doi:10.1021/jm00155a008. PMID 3701781. 
  12. ↑ "Identification of novel serotonin 2C receptor ligands by sequential virtual screening". Bioorganic & Medicinal Chemistry 17 (13): 4559–4568. July 2009. doi:10.1016/j.bmc.2009.05.003. PMID 19464901. 
  13. ↑ "The HIV antiretroviral drug efavirenz has LSD-like properties". Neuropsychopharmacology 38 (12): 2373–2384. November 2013. doi:10.1038/npp.2013.135. PMID 23702798. 
  14. ↑ "Structure-based discovery of nonhallucinogenic psychedelic analogs". Science 375 (6579): 403–411. January 2022. doi:10.1126/science.abl8615. PMID 35084960. Bibcode: 2022Sci...375..403C. 
  15. ↑ Analytical Report: NDTDI. Nacionalni Forenzični Laboratorij, Slovenia, June 2017
  16. ↑ "Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro". Psychopharmacology 231 (14): 2771–2783. July 2014. doi:10.1007/s00213-014-3446-0. PMID 24488404. 
  17. ↑ "Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells". British Journal of Pharmacology 128 (1): 13–20. September 1999. doi:10.1038/sj.bjp.0702751. PMID 10498829. 
  18. ↑ "Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors". Naunyn-Schmiedeberg's Archives of Pharmacology 370 (2): 114–123. August 2004. doi:10.1007/s00210-004-0951-4. PMID 15322733. 
  19. ↑ "I. In vivo evidence for partial agonist effects of (-)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors". Journal of Neural Transmission 118 (11): 1511–1522. November 2011. doi:10.1007/s00702-011-0704-8. PMID 21874578. 
  20. ↑ Banister S, Jorgensen W, Jinlong T, "Compounds", WO patent 2023115165, published 29 June 2023
  21. ↑ "Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity". Nature 610 (7932): 582–591. October 2022. doi:10.1038/s41586-022-05258-z. PMID 36171289. Bibcode: 2022Natur.610..582K. 
  22. ↑ "Theoretical studies on the interaction of partial agonists with the 5-HT2A receptor". Journal of Computer-Aided Molecular Design 25 (1): 51–66. January 2011. doi:10.1007/s10822-010-9400-2. PMID 21088982. Bibcode: 2011JCAMD..25...51S. 
  23. ↑ Mohapatra S, Hellberg MR, Feng Z, "Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma", WO patent 2007149728, assigned to Alcon Manufacturing, Ltd.
  24. ↑ "A non-hallucinogenic psychedelic analogue with therapeutic potential". Nature 589 (7842): 474–479. January 2021. doi:10.1038/s41586-020-3008-z. PMID 33299186. Bibcode: 2021Natur.589..474C. 
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 25.7 "AlphaFold2 structures template ligand discovery". bioRxiv. December 2023. doi:10.1101/2023.12.20.572662. PMID 38187536. 



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