List of miscellaneous 5HT2A agonists explained

This is a list of agonists of the serotonin receptor subtype 5-HT_2A (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-HT_2A receptor agonists which do not fall within any of these groups, some representative examples of which are listed below. K_i 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-HT_2A agonist will necessarily be psychedelic in nature.^[2]

Structure	Name	Chemical name	h5-HT2A Ki (EC50) (nM)	PubChem	CAS number	Reference
	Compound 11a	11-chloro-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole	6.5	20726100	599173-28-1	^[3]
	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
	Compound 10d	7-Benzyloxy-8-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine	22	10472780	616201-60-6	^[4]
	Example 22.67	4-(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)thiomorpholine	21	44124494		^[5]
	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	^[6]
	Compound 11	(3R)-N,N-diethyl-5-(1H-indol-4-yl)-1-methyl-3,6-dihydro-2H-pyridine-3-carboxamide	(<10)	156278040		^[7]
	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]
	Compound 6c	(6S)-2,3-dichloro-7,8,9,10-tetrahydro-6H-6,9-epiminocyclohepta[b]quinoxaline	(400)			^[9]
	Compound 70	3-(4-bromo-2-methylpyrazol-3-yl)-N-(4-chlorophenyl)-4-methoxyaniline	1.77	9952456		^[10]
	Compound 22	7-(trifluoromethoxy)-2,3,4,10b-tetrahydro-1H-pyrazino[1,2-b]isoindol-6-one	67 (87)	11448649
	Example 1 (ZC-B)	3-(4-bromo-2,5-dimethoxyphenyl)azetidine	(1.6)	156337249	2641630-65-9	^[11]
	2C-B-aminorex	5-(4-bromo-2,5-dimethoxyphenyl)-4,5-dihydro-1,3-oxazol-2-amine		165360199		^[12]
	2-(2,5-dimethoxy-4-bromophenyl)morpholine	2-(2,5-dimethoxy-4-bromophenyl)morpholine	20.6	11429275		^[13]
	DM-506	3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole		24183	7546-66-9	^[14]
	LPH-5	(3S)-3-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]piperidine	(3.2)	156337168	2641630-97-7	^[15]
	2C-B-PP	1-(2,5-dimethoxy-4-bromophenyl)piperazine		4738744	100939-87-5	^[16]
	cis-urocanic acid (cis-UCA)	(Z)-3-(1H-imidazol-5-yl)prop-2-enoic acid	4.6	1549103	7699-35-6	^[17] ^[18] ^[19]
	CPD-1	(3S)-3-Methyl-1-[4-(trifluoromethyl)-1-benzofuran-7-yl]piperazine		9925822	325145-37-7	^[20]
	Efavirenz	(4S)-6-Chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one		64139	154598-52-4	^[21]
	IHCH-7079	(6bR,10aS)-8-(2-Methoxyphenethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline		169488014	2957888-63-8	^[22]
	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	^[23]
	NDTDI	N,N-diethyl-3-[methyl(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)amino]propanamide		163192742		^[24]
	Mefloquine	2,8-bis(trifluoromethyl)quinolin-4-yl-(2-piperidyl)methanol		40692	53230-10-7	^[25]
	ORG-12962	1-(5-trifluoromethyl-6-chloropyridin-2-yl)piperazine		9796408	210821-63-9	^[26]
	ORG-37684	(3S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]pyrrolidine		9794656	213007-95-5	^[27]
	OSU-6162	(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine		9795741	156907-84-5	^[28]
	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
	P-54	2-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)-N,N-dimethylethanamine		168946740		^[29]
	I-28	N-[2-(8-methoxynaphthalen-1-yl)ethyl]-N-methylpropan-2-amine		170604481		^[30]
	(R)-69	3-[(5R)-5-methyl-1,2,5,6-tetrahydropyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine		164513426		^[31]
	RS134-49	4-methyl-3-(1,2,3,6-tetrahydropyridin-5-yl)-1H-indole		168941768		^[32] ^[33]
	RH-34	3-[2-(2-methoxybenzylamino)ethyl]-1H-quinazoline-2,4-dione		10041987	1028307-48-3	^[34]
	SCHEMBL5334361	7-[(3-methoxyphenoxy)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepine	(0.4)	59027940	959867-47-1	^[35]
	Tabernanthalog	8-methoxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole		146026994	2483829-59-8	^[36]
	TKU-II-100	[(1S,2S)-2-(2-fluorophenyl)cyclopropyl]methanamine	0.62	44572747		^[37]
	WAY-470	1,16-diazatetracyclo[8.8.1.0<sup>2,9</sup>.0<sup>14,19</sup>]nonadeca-2(9),10,12,14(19)-tetraene	36	10037962		^[38]
	WXVL_BT0793LQ2118	6-fluoro-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole				^[39]
	Z2825713589	(4-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-(6-methoxypyrazin-2-yl)methanone		167788805
	Z2876442907	ethyl 2-2-(4-methyl-1H-indol-3-yl)ethylaminomethyl]-1,3-thiazole-5-carboxylate		167850865
	Z3517967757	4-[1-(1-pyrimidin-2-ylethyl)piperidin-3-yl]phenol		167949972
	Z3881312504	2-bromo-4-[2-[methyl-[2-(1,3-thiazol-2-yl)ethyl]amino]ethyl]phenol		167904469
	Z4154032166	2,2,2-trifluoro-1-[6-(1,2,3,6-tetrahydropyridin-5-yl)pyridin-2-yl]ethanol		167878716
	Z5247692566	4-[(3,3-dimethyloxolan-2-yl)methyl]-3-[(1H-indol-3-yl)methyl]morpholine
	Z5247692629	1-(1-bicyclo[1.1.1]pentanyl)-4-5-(4-chlorophenyl)-1H-pyrazol-4-ylmethyl]piperazine		166358273

See also

• DPCPX
• LY-341,495
• Robalzotan
• WAY-100635
• UH-301
• Substituted benzofuran
• Substituted phenylmorpholine
• List of fentanyl analogues

Notes and References

1. Nichols DE . Chemistry and Structure-Activity Relationships of Psychedelics . Current Topics in Behavioral Neurosciences . 36 . 1–43 . 2018 . 28401524 . 10.1007/7854_2017_475 . 978-3-662-55878-2 .
2. Duan W, Cao D, Wang S, Cheng J . Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants . Chemical Reviews . 124 . 1 . 124–163 . January 2024 . 38033123 . 10.1021/acs.chemrev.3c00375 . 265512698 .
3. Ennis MD, Hoffman RL, Ghazal NB, Olson RM, Knauer CS, Chio CL, Hyslop DK, Campbell JE, Fitzgerald LW, Nichols NF, Svensson KA, McCall RB, Haber CL, Kagey ML, Dinh DM . 6 . 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 . 12824036 . 10.1016/s0960-894x(03)00403-7 .
4. Smith BM, Smith JM, Tsai JH, Schultz JA, Gilson CA, Estrada SA, Chen RR, Park DM, Prieto EB, Gallardo CS, Sengupta D, Thomsen WJ, Saldana HR, Whelan KT, Menzaghi F, Webb RR, Beeley NR . 6 . 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 . 15713408 . 10.1016/j.bmcl.2004.12.080 .
5. Compounds with activity at the 5-ht2c receptor . Slassi A, Isaac M, Xin T, Higgins G, He Z, Sun G, Quach T . Cascade Therapeutics Inc. . WO . 2009/079765 . 2 July 2009 .
6. Jensen AA, Plath N, Pedersen MH, Isberg V, Krall J, Wellendorph P, Stensbøl TB, Gloriam DE, Krogsgaard-Larsen P, Frølund B . 6 . 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 . 23301527 . 10.1021/jm301656h .
7. Ergoline-like compounds for promoting neural plasticity . Olson DE, Dunlap L, Wagner F, Chytil M, Powell NA . The Regents Of The University Of California . Delix Therapeutics, Inc. . 22 April 2021 . WO . 2021/076572.
8. Orr MJ, Cao AB, Wang CT, Gaisin A, Csakai A, Friswold AP, Meltzer HY, McCorvy JD, Scheidt KA . 6 . Discovery of Highly Potent Serotonin 5-HT₂ Receptor Agonists Inspired by Heteroyohimbine Natural Products . ACS Medicinal Chemistry Letters . 13 . 4 . 648–657 . April 2022 . 35450369 . 9014500 . 10.1021/acsmedchemlett.1c00694 .
9. Yao R, Jensen AA, Bryce-Rogers HP, Schultz-Knudsen K, Zhou L, Hovendal NP, Pedersen H, Kubus M, Ulven T, Laraia L . 6 . 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 . 37566000 . 10.1021/acs.jmedchem.3c01059 . 260806387 .
10. Diarylamine and arylheteroarylamine pyrazole derivatives as modulators of 5ht2a. . Teegarden B, Jayakumar H, Strah-Pleynet S . Arena Pharmaceuticals, Inc. . WO . 2004/058722 . 15 July 2004 .
11. 5-HT2A Agonists for Use in Treatment of Depression. . Kristensen JL, Jensen AA, Märcher-Rørsted E . US . 2021/0137908 . Lophora ApS . 13 May 2021 . . .
12. Book: Evans-Brown M, Gallegos A, Christie R, Jorge R, De Morais J, Almeida A, Sedefov R . New Psychoactive Substances: Global Markets, Glocal Threats and the COVID-19 Pandemic. An update from the EU Early Warning System . December 2020 . 10.2810/921262 . 978-92-9497-557-7 . European Monitoring Center for Drugs and Drug Addiction . Luxembourg . Publications Office of the European Union .
13. Glennon RA, Bondarev ML, Khorana N, Young R, May JA, Hellberg MR, McLaughlin MA, Sharif NA . 6 . Beta-oxygenated analogues of the 5-HT2A serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane . Journal of Medicinal Chemistry . 47 . 24 . 6034–41 . November 2004 . 15537358 . 10.1021/jm040082s .
14. Arias HR, Rudin D, Hines DJ, Contreras A, Gulsevin A, Manetti D, Anouar Y, De Deurwaerdere P, Meiler J, Romanelli MN, Liechti ME, Chagraoui A . The novel non-hallucinogenic compound DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and anxiolytic-like activity in mice by a mechanism involving 5-HT2A receptor activation . European Journal of Pharmacology . 966 . 176329 . March 2024 . 38253116 . 10.1016/j.ejphar.2024.176329 . 2158/1354752 . free .
15. Rorsted EM, Jensen AA, Smits G, Frydenvang K, Kristensen JL . Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists . Journal of Medicinal Chemistry . 67 . 9 . 7224–7244 . May 2024 . 38648420 . 11089506 . 10.1021/acs.jmedchem.4c00082 .
16. Lyon RA, Titeler M, McKenney JD, Magee PS, Glennon RA . Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergic agents . Journal of Medicinal Chemistry . 29 . 5 . 630–634 . May 1986 . 3701781 . 10.1021/jm00155a008 .
17. Walterscheid JP, Nghiem DX, Kazimi N, Nutt LK, McConkey DJ, Norval M, Ullrich SE . Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor . Proceedings of the National Academy of Sciences of the United States of America . 103 . 46 . 17420–17425 . November 2006 . 10.1073/pnas.0603119103 . free . 17085585 . 1859944 .
18. Shen L, Ji HF . Molecular basis for cis-urocanic acid as a 5-HT(2A) receptor agonist . Bioorganic & Medicinal Chemistry Letters . 19 . 18 . 5307–5309 . September 2009 . 10.1016/j.bmcl.2009.07.143 . 19683920 .
19. Menezes AC, Raposo S, Simões S, Ribeiro H, Oliveira H, Ascenso A . Prevention of Photocarcinogenesis by Agonists of 5-HT1A and Antagonists of 5-HT2A Receptors . Molecular Neurobiology . 53 . 2 . 1145–1164 . March 2016 . 10.1007/s12035-014-9068-z . 25589005 . 14282500 .
20. Ahmed A, Choo H, Cho YS, Park WK, Pae AN . Identification of novel serotonin 2C receptor ligands by sequential virtual screening . Bioorganic & Medicinal Chemistry . 17 . 13 . 4559–4568 . July 2009 . 19464901 . 10.1016/j.bmc.2009.05.003 .
21. Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA . 6 . The HIV antiretroviral drug efavirenz has LSD-like properties . Neuropsychopharmacology . 38 . 12 . 2373–2384 . November 2013 . 23702798 . 3799056 . 10.1038/npp.2013.135 .
22. Cao D, Yu J, Wang H, Luo Z, Liu X, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J, Wang S . 6 . Structure-based discovery of nonhallucinogenic psychedelic analogs . Science . 375 . 6579 . 403–411 . January 2022 . 35084960 . 10.1126/science.abl8615 . 2022Sci...375..403C . 246360313 .
23. Cao D, Yu J, Wang H, Luo Z, Liu X, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J, Wang S . 6 . Structure-based discovery of nonhallucinogenic psychedelic analogs . Science . 375 . 6579 . 403–411 . January 2022 . 35084960 . 10.1126/science.abl8615 . 2022Sci...375..403C . 246360313 .
24. Web site: Analytical Report NDTDI . Nacionalni Forenzični Laboratorij . Slovenia . June 2017 .
25. Janowsky A, Eshleman AJ, Johnson RA, Wolfrum KM, Hinrichs DJ, Yang J, Zabriskie TM, Smilkstein MJ, Riscoe MK . 6 . Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro . Psychopharmacology . 231 . 14 . 2771–2783 . July 2014 . 24488404 . 4097020 . 10.1007/s00213-014-3446-0 .
26. Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ . 6 . 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 . 10498829 . 1571597 . 10.1038/sj.bjp.0702751 .
27. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M . 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 . 15322733 . 10.1007/s00210-004-0951-4 . 8938111 .
28. Carlsson ML, Burstein ES, Kloberg A, Hansson S, Schedwin A, Nilsson M, Rung JP, Carlsson A . 6 . 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 . 21874578 . 10.1007/s00702-011-0704-8 . 43580367 .
29. Compounds . WO . 2023115165 . Banister S, Jorgensen W, Jinlong T . Psylo Pty Ltd. . 29 June 2023 .
30. Compounds . WO . 2023230649 . Banister S, Jorgensen W, Jinlong T, Whish L . Psylo Pty Ltd. . 7 December 2023 .
31. Kaplan AL, Confair DN, Kim K, Barros-Álvarez X, Rodriguiz RM, Yang Y, Kweon OS, Che T, McCorvy JD, Kamber DN, Phelan JP, Martins LC, Pogorelov VM, DiBerto JF, Slocum ST, Huang XP, Kumar JM, Robertson MJ, Panova O, Seven AB, Wetsel AQ, Wetsel WC, Irwin JJ, Skiniotis G, Shoichet BK, Roth BL, Ellman JA . 6 . Bespoke library docking for 5-HT_2A receptor agonists with antidepressant activity . Nature . 610 . 7932 . 582–591 . October 2022 . 36171289 . 9996387 . 10.1038/s41586-022-05258-z . 252598838 . 2022Natur.610..582K .
32. Kargbo RB . Small-Molecule Heterocyclic Compounds: Gq-Biased Agonists for the 5-HT2A Receptor in Neuropsychiatric Treatment . ACS Medicinal Chemistry Letters . 14 . 11 . 1498–1500 . November 2023 . 37974947 . 10.1021/acsmedchemlett.3c00444 . 10641896 . November 9, 2024 .
33. https://patents.google.com/patent/WO2023114472A1/ . WO . 2023114472 . Manish J, Slocum S, Skiniotis G, Barros X, Jin J, Kaniskan HU, Sun N, Xiong Y, Shen Y, Xu Z, Qui X, Qian C, Song X, Deng Z, Roth B, Biberto J, Kuglae K, Suomivuori CM, Daemgen MA, Dror R, Shoichet B, Kaplan AL . Icahn School Of Medicine at Mount Sinai, The University Of North Carolina at Chapel Hill, The Board of Trustees of The Leland Stanford Junior University, The Regents Of The University Of California . 22 June 2023 title = Heterocyclic compounds as 5ht2a biased agonists. .
34. Silva ME, Heim R, Strasser A, Elz S, Dove S . 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 . 21088982 . 10.1007/s10822-010-9400-2 . 3103050 . 10.1.1.688.2670 . 2011JCAMD..25...51S .
35. WO . 2007149728 . Aryl and heteroaryl tetrahydrobenzazepine derivatives and their use for treating glaucoma . Mohapatra S, Hellberg MR, Feng Z . Alcon Manufacturing, Ltd. .
36. Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, Vargas MV, McCarroll MN, Taylor JC, Myers-Turnbull D, Liu T, Yaghoobi B, Laskowski LJ, Anderson EI, Zhang G, Viswanathan J, Brown BM, Tjia M, Dunlap LE, Rabow ZT, Fiehn O, Wulff H, McCorvy JD, Lein PJ, Kokel D, Ron D, Peters J, Zuo Y, Olson DE . 6 . A non-hallucinogenic psychedelic analogue with therapeutic potential . Nature . 589 . 7842 . 474–479 . January 2021 . 33299186 . 7874389 . 10.1038/s41586-020-3008-z . 2021Natur.589..474C .
37. 5-ht2c receptor agonists as anorectic agents . Kozikowski A, Kurome T, Setola V, Roth B . WO . 2007/025144 . University Of Illinois - Chicago . 1 March 2007 .
38. Sabb AL, Vogel RL, Welmaker GS, Sabalski JE, Coupet J, Dunlop J, Rosenzweig-Lipson S, Harrison B . Cycloalkyl[b][1,4]benzodiazepinoindoles are agonists at the human 5-HT2C receptor . Bioorganic & Medicinal Chemistry Letters . 14 . 10 . 2603–7 . May 2004 . 15109661 . 10.1016/j.bmcl.2004.02.100 .
39. 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 . 6 . AlphaFold2 structures template ligand discovery . bioRxiv . December 2023 . 38187536 . 10769324 . 10.1101/2023.12.20.572662 .