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. [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 | [3] | |
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 | [10] | ||
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 (ibogaminalog) | 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] | ||
GM-2505 | [22] | |||||
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 | [23] | ||
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] | ||
? | ITI-1549 | ? | 10.2 | ? | ? | [24] |
NDTDI | N,N-diethyl-3-[methyl(1,3,4,5-tetrahydrobenzo[cd]indol-4-yl)amino]propanamide | 163192742 | [25] | |||
Mefloquine | 2,8-bis(trifluoromethyl)quinolin-4-yl-(2-piperidyl)methanol | 40692 | 53230-10-7 | [26] | ||
ORG-12962 | 1-(5-trifluoromethyl-6-chloropyridin-2-yl)piperazine | 9796408 | 210821-63-9 | [27] | ||
ORG-37684 | (3S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]pyrrolidine | 9794656 | 213007-95-5 | [28] | ||
OSU-6162 | (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine | 9795741 | 156907-84-5 | [29] | ||
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 | [3] | |
P-54 | 2-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)-N,N-dimethylethanamine | 168946740 | [30] | |||
I-28 | N-[2-(8-methoxynaphthalen-1-yl)ethyl]-N-methylpropan-2-amine | 170604481 | [31] | |||
(R)-69 | 3-[(5R)-5-methyl-1,2,5,6-tetrahydropyridin-3-yl]-1H-pyrrolo[2,3-b]pyridine | 164513426 | [32] | |||
RS134-49 | 4-methyl-3-(1,2,3,6-tetrahydropyridin-5-yl)-1H-indole | 168941768 | [33] [34] | |||
RH-34 | 3-[2-(2-methoxybenzylamino)ethyl]-1H-quinazoline-2,4-dione | 10041987 | 1028307-48-3 | [35] | ||
SCHEMBL5334361 | 7-[(3-methoxyphenoxy)methyl]-2,3,4,5-tetrahydro-1H-3-benzazepine | (0.4) | 59027940 | 959867-47-1 | [36] | |
Tabernanthalog | 8-methoxy-3-methyl-2,4,5,6-tetrahydro-1H-azepino[4,5-b]indole | 146026994 | 2483829-59-8 | [37] | ||
TKU-II-100 | [(1S,2S)-2-(2-fluorophenyl)cyclopropyl]methanamine | 0.62 | 44572747 | [38] | ||
WAY-470 | 1,16-diazatetracyclo[8.8.1.02,9.014,19]nonadeca-2(9),10,12,14(19)-tetraene | 36 | 10037962 | [39] | ||
WXVL_BT0793LQ2118 | 6-fluoro-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole | [40] | ||||
Z2825713589 | (4-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-(6-methoxypyrazin-2-yl)methanone | 167788805 | [40] | |||
Z2876442907 | ethyl 2-[[2-(4-methyl-1H-indol-3-yl)ethylamino]methyl]-1,3-thiazole-5-carboxylate | 167850865 | [40] | |||
Z3517967757 | 4-[1-(1-pyrimidin-2-ylethyl)piperidin-3-yl]phenol | 167949972 | [40] | |||
Z3881312504 | 2-bromo-4-[2-[methyl-[2-(1,3-thiazol-2-yl)ethyl]amino]ethyl]phenol | 167904469 | [40] | |||
Z4154032166 | 2,2,2-trifluoro-1-[6-(1,2,3,6-tetrahydropyridin-5-yl)pyridin-2-yl]ethanol | 167878716 | [40] | |||
Z5247692566 | 4-[(3,3-dimethyloxolan-2-yl)methyl]-3-[(1H-indol-3-yl)methyl]morpholine | [40] | ||||
Z5247692629 | 1-(1-bicyclo[1.1.1]pentanyl)-4-[[5-(4-chlorophenyl)-1H-pyrazol-4-yl]methyl]piperazine | 166358273 | [40] | |||
Psilocin, also known as 4-hydroxy-N,N-dimethyltryptamine (4-OH-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocybin. Psilocin is a Schedule I drug under the Convention on Psychotropic Substances. Acting on the serotonin 5-HT2A receptors, psilocin's psychedelic effects are directly correlated with the drug's occupancy at these receptor sites. The subjective mind-altering effects of psilocin are highly variable and are said to resemble those of lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT).
2C-B-FLY is a psychedelic phenethylamine and designer drug of the 2C family. It was first synthesized in 1996 by Aaron Monte, Professor of Chemistry at UW-La Crosse.
The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations.
A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.
Ariadne, also known chemically as 4C-D or 4C-DOM, by its developmental code name BL-3912, and by its former tentative brand name Dimoxamine, is a little-known psychoactive drug of the phenethylamine, amphetamine, and phenylisobutylamine families. It is a homologue of the psychedelics 2C-D and DOM.
Norfenfluramine, or 3-trifluoromethylamphetamine, is a never-marketed drug of the amphetamine family that behaves as a serotonin and norepinephrine releasing agent and potent 5-HT2A, 5-HT2B, and 5-HT2C agonist. The action of norfenfluramine on 5-HT2B receptors on heart valves leads to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve, known as cardiac fibrosis. This side effect led to the withdrawal of fenfluramine as an anorectic agent worldwide, and to the withdrawal of benfluorex in Europe, as both fenfluramine and benfluorex form norfenfluramine as an active metabolite. It is a human TAAR1 agonist.
5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.
AL-34662 is an indazole derivative drug that is being developed for the treatment of glaucoma. It acts as a selective serotonin 5-HT2 receptor agonist, including of the 5-HT2A, 5-HT2B, and 5-HT2C receptors (affinity (IC50Tooltip half-maximal inhibitory concentration) = 14.5, 8.1, and 3.0 nM, respectively). The serotonin 5-HT2A receptor is the same target as that of psychedelic drugs like psilocin. Unlike these drugs however, AL-34662 was designed specifically as a peripherally selective drug, which does not cross the blood–brain barrier. This means that AL-34662 can exploit a useful side effect of the hallucinogenic 5-HT2A receptor agonists, namely reduction in intra-ocular pressure and hence relief from the symptoms of glaucoma, but without causing the psychedelic effects that make centrally active serotonin 5-HT2A receptor agonists unsuitable for clinical use. In animal studies, AL-34662 has been shown to be potent and effective in the treatment of symptoms of glaucoma, with minimal side effects.
SB-206553 is a drug which acts as a mixed antagonist for the 5-HT2B and 5-HT2C serotonin receptors. It has anxiolytic properties in animal studies and interacts with a range of other drugs. It has also been shown to act as a positive allosteric modulator of α7 nicotinic acetylcholine receptors. Modified derivatives of SB-206553 have been used to probe the structure of the 5-HT2B receptor.
Substituted tryptamines, or simply tryptamines, also known as serotonin analogues (i.e., 5-hydroxytryptamine analogues), are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all tryptamines contain an indole ring, joined to an amino (NH2) group via an ethyl (−CH2–CH2−) sidechain. In substituted tryptamines, the indole ring, sidechain, and/or amino group are modified by substituting another group for one of the hydrogen (H) atoms.
5-MeO-NBpBrT is a N-substituted member of the methoxytryptamine family of compounds. Like other such compounds it acts as an antagonist for the 5-HT2A receptor, with a claimed 100x selectivity over the closely related 5-HT2C receptor. While N-benzyl substitution of psychedelic phenethylamines often results in potent 5-HT2A agonists, it had been thought that N-benzyl tryptamines show much lower efficacy and are either very weak partial agonists or antagonists at 5-HT2A, though more recent research has shown stronger agonist activity for 3-substituted benzyl derivatives. Extending the benzyl group to a substituted phenethyl can also recover agonist activity in certain cases.
PNU-181731 is a drug which acts as an agonist at serotonin 5-HT2 receptors, with strongest binding affinity for the 5-HT2C subtype at 4.8nM, and weaker 5-HT2A affinity of 18nM. It has anxiolytic effects in animal studies with around one tenth the potency of alprazolam and no significant ataxia or other side effects noted.
PHA-57378 is a drug which acts as an agonist at serotonin 5-HT2 receptors, having a binding affinity of 4.1 nM at the 5-HT2A subtype and 4.3 nM at 5-HT2C. It has anxiolytic effects in animal studies.
25CN-NBOH is a compound indirectly derived from the phenethylamine series of hallucinogens, which was discovered in 2014 at the University of Copenhagen. This compound is notable as one of the most selective agonist ligands for the 5-HT2A receptor yet discovered, with a pKi of 8.88 at the human 5-HT2A receptor and with 100x selectivity for 5-HT2A over 5-HT2C, and 46x selectivity for 5-HT2A over 5-HT2B. A tritiated version of 25CN-NBOH has also been accessed and used for more detailed investigations of the binding to 5-HT2 receptors and autoradiography.
1-Methylpsilocin (developmental code names CMY, CMY-16) is a tryptamine derivative developed by Sandoz which acts as a selective agonist of the serotonin 5-HT2C receptor (IC50Tooltip half-maximal inhibitory concentration of 12 nM, vs. 633 nM at 5-HT2A), and an inverse agonist at 5-HT2B (Ki of 38 nM). While 1-methylpsilocin does have higher affinity for 5-HT2C than 5-HT2A, it does produce a head-twitch response in mice that is dependent on 5-HT2A, so it is not entirely free of effects on 5-HT2Ain vivo. In contrast to psilocin, 1-methylpsilocin did not activate 5-HT1A receptors in mice.
The 25-NB (25x-NBx) series, sometimes alternatively referred to as the NBOMe compounds, is a family of serotonergic psychedelics. They are substituted phenethylamines and were derived from the 2C family. They act as selective agonists of the serotonin 5-HT2A receptor. The 25-NB family is unique relative to other classes of psychedelics in that they are, generally speaking, extremely potent and relatively selective for the 5-HT2A receptor. Use of NBOMe series drugs has caused many deaths and hospitalisations since the drugs popularisation in the 2010s. This is primarily due to their high potency, unpredictable pharmacokinetics, and sellers passing off the compounds in the series as LSD.
DOB-FLY is a recreational designer drug with psychedelic effects. It can be regarded as the alpha-methyl derivative of 2C-B-FLY or the partially saturated counterpart of bromo-dragonfly. Unlike bromo-dragonfly, DOB-FLY is only slightly more potent than DOB itself, with an active dose in humans of around 1 mg.
CYB210010, also known as 2C-T-TFM, is a lesser-known psychedelic drug of the phenethylamine family related to compounds such as 2C-T and 2C-T-21.
ITI-1549 is a putatively non-hallucinogenic serotonin 5-HT2A receptor agonist which is under development for the treatment of mood disorders and other psychiatric disorders. In addition to acting at the serotonin 5-HT2A receptor, it is also an antagonist of the serotonin 5-HT2B receptor and an agonist of the serotonin 5-HT2C receptor. The drug's route of administration has not been specified.
α-Methylisotryptamine is a synthetic compound belonging to the tryptamine class, known for its psychoactive properties. As a structural analog of α-methyltryptamine (αMT), isoAMT exhibits entactogenic and psychedelic effects.