5-HT6 receptor

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

The 5HT6 receptor is a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5HT).[1] It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission.[1] HTR6 denotes the human gene encoding for the receptor.[2]

## Contents

* 1 Distribution
* 2 Function
* 2.1 As a drug target for antagonists
* 2.2 As a drug target for agonists
* 3 Ligands
* 3.1 Agonists
* 3.1.1 Full agonists
* 3.1.2 Partial agonists
* 3.2 Antagonists and inverse agonists
* 4 Genetics
* 5 See also
* 6 References
* 7 Further reading
* 8 External links

## Distribution

The 5HT6 receptor is expressed almost exclusively in the brain.[3] It is distributed in various areas including, but not limited to, the olfactory tubercle, cerebral cortex (frontal and entorhinal regions), nucleus accumbens, striatum, caudate nucleus, hippocampus, and the molecular layer of the cerebellum.[1][4][5] Based on its abundance in extrapyramidal, limbic, and cortical regions it can be suggested that the 5HT6 receptor plays a role in functions like motor control, emotionality, cognition, and memory.[3][5][6]

## Function

Blockade of central 5HT6 receptors has been shown to increase glutamatergic and cholinergic neurotransmission in various brain areas,[7][8][9][10] whereas activation enhances GABAergic signaling in a widespread manner.[11] Antagonism of 5HT6 receptors also facilitates dopamine and norepinephrine release in the frontal cortex,[10][12] while stimulation has the opposite effect.[11]

### As a drug target for antagonists

Despite the 5HT6 receptor having a functionally excitatory action, it is largely co-localized with GABAergic neurons and therefore produces an overall inhibition of brain activity.[11] In parallel with this, 5HT6 antagonists are hypothesized to improve cognition, learning, and memory.[13] Agents such as latrepirdine, idalopirdine (Lu AE58054), and intepirdine (SB-742,457/RVT-101) were evaluated as novel treatments for Alzheimer's disease and other forms of dementia.[10][14][15] However, phase III trials of latrepirdine, idalopirdine, and intepirdine have failed to demonstrate efficacy.

5HT6 antagonists have also been shown to reduce appetite and produce weight loss, and as a result, PRX-07034, BVT-5,182, and BVT-74,316 are being investigated for the treatment of obesity.[16][17]

### As a drug target for agonists

Recently, the 5HT6 agonists WAY-181,187 and WAY-208,466 have been demonstrated to be active in rodent models of depression, anxiety, and obsessive-compulsive disorder (OCD), and such agents may be useful treatments for these conditions.[11][18] Additionally, indirect 5HT6 activation may play a role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).[citation needed]

## Ligands

A large number of selective 5HT6 ligands have now been developed.[19][20][21][22][23][24][25][26][27]

### Agonists

#### Full agonists

* 2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)[28]
* WAY-181,187
* WAY-208,466
* N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): Ki = 4.5nM, EC50 = 0.9nM, Emax = 98%[29]
* E-6837 – Full agonist at human 5HT6 receptors

#### Partial agonists

* E-6801[30]
* E-6837 - partial agonist at rat 5-HT6 receptors. Orally active in rats, and caused weight loss with chronic administration[31]
* EMD-386,088 - potent partial agonist (EC50 = 1 nM) but non-selective[32][33]
* LSD - Emax = 60%[34]

### Antagonists and inverse agonists

* ALX-1161
* AVN-211
* BVT-5182[35]
* BVT-74316[16]
* Cerlapirdine – selective
* EGIS-12233 – mixed 5HT6 / 5HT7 antagonist
* Idalopirdine (Lu AE58054) – selective
* Intepirdine (SB-742,457/RVT-101) – selective antagonist
* Landipirdine (RO-5025181, SYN-120)
* Latrepirdine[36] (non-selective) and analogues[37]
* MS-245
* PRX-07034
* SB-258,585
* SB-271,046
* SB-357,134
* SB-399,885
* SGS 518 Fb: [445441-26-9]
* Ro 04-6790
* Ro-4368554[38]
* Atypical antipsychotics (sertindole, olanzapine, asenapine, clozapine)
* WAY-255315 / SAM-315: Ki = 1.1 nM, IC50 = 13 nM[39]
* Rosa rugosa extract[40]

## Genetics

Polymorphisms in the HTR6 gene are associated with neuropsychiatric disorders. For example, an association between the C267T (rs1805054) polymorphism and Alzheimer's disease has been shown.[41] Others have studied the polymorphism in relation to Parkinson's disease.[42]

## See also

* 5-HT receptor
* 5-HT1 receptor
* 5-HT2 receptor
* 5-HT3 receptor
* 5-HT4 receptor
* 5-HT5 receptor

## References

1. ↑ 1.0 1.1 1.2 "Cloning, characterization, and chromosomal localization of a human 5HT6 serotonin receptor". Journal of Neurochemistry 66 (1): 47–56. Jan 1996. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
2. ↑ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3362.
3. ↑ 3.0 3.1 "5HT6 receptors". Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79. Feb 2004. doi:10.2174/1568007043482561. PMID 14965245.
4. ↑ "A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation". Biochemical and Biophysical Research Communications 193 (1): 268–76. May 1993. doi:10.1006/bbrc.1993.1619. PMID 8389146.
5. ↑ 5.0 5.1 "Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system". Brain Research 746 (1–2): 207–19. Jan 1997. doi:10.1016/S0006-8993(96)01224-3. PMID 9037500.
6. ↑ "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5HT6 receptors". Neuropsychopharmacology 21 (2 Suppl): 68S–76S. Aug 1999. doi:10.1016/S0893-133X(99)00044-5. PMID 10432491.
7. ↑ "In vivo effects of the 5HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5HT, glutamate and aspartate". British Journal of Pharmacology 130 (1): 23–6. May 2000. doi:10.1038/sj.bjp.0703288. PMID 10780993.
8. ↑ "The 5HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus". Neuropsychopharmacology 25 (5): 662–8. Nov 2001. doi:10.1016/S0893-133X(01)00265-2. PMID 11682249.
9. ↑ "5HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism". Neuropharmacology 47 (2): 195–204. Aug 2004. doi:10.1016/j.neuropharm.2004.03.012. PMID 15223298.
10. ↑ 10.0 10.1 10.2 "5HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease". Neurotherapeutics 5 (3): 458–69. Jul 2008. doi:10.1016/j.nurt.2008.05.008. PMID 18625457.
11. ↑ 11.0 11.1 11.2 11.3 "Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466". Neuropsychopharmacology 33 (6): 1323–35. May 2008. doi:10.1038/sj.npp.1301503. PMID 17625499.
12. ↑ "5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex". Synapse 51 (2): 158–64. Feb 2004. doi:10.1002/syn.10288. PMID 14618683.
13. ↑ "A role for the 5HT(1A), 5HT4 and 5HT6 receptors in learning and memory". Trends in Pharmacological Sciences 29 (9): 482–92. Sep 2008. doi:10.1016/j.tips.2008.07.001. PMID 19086256.
14. ↑ "Serotonin 5HT6 receptor antagonists for the treatment of Alzheimer's disease". Current Topics in Medicinal Chemistry 8 (12): 1035–48. 2008. doi:10.2174/156802608785161420. PMID 18691131. http://www.bentham-direct.org/pages/content.php?CTMC/2008/00000008/00000012/0004R.SGM.
15. ↑ "The serotonin 5-HT6 receptor: a viable drug target for treating cognitive deficits in Alzheimer's disease". Expert Review of Neurotherapeutics 9 (7): 1073–85. Jul 2009. doi:10.1586/ern.09.51. PMID 19589055.
16. ↑ 16.0 16.1 "Selective 5-HT6 receptor ligands: progress in the development of a novel pharmacological approach to the treatment of obesity and related metabolic disorders". Pharmacology & Therapeutics 117 (2): 207–31. Feb 2008. doi:10.1016/j.pharmthera.2007.08.006. PMID 18068807.
17. ↑ "Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor". Brain Research 1236: 140–4. Oct 2008. doi:10.1016/j.brainres.2008.08.012. PMID 18755168.
18. ↑ "Antidepressant and anxiolytic effects of selective 5HT6 receptor agonists in rats". Psychopharmacology 213 (2–3): 499–507. Feb 2011. doi:10.1007/s00213-010-1798-7. PMID 20217056.
19. ↑ "Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 18 (20): 5698–700. Oct 2008. doi:10.1016/j.bmcl.2008.08.010. PMID 18793848.
20. ↑ "Identification of a series of benzoxazoles as potent 5-HT6 ligands". Bioorganic & Medicinal Chemistry Letters 19 (4): 1115–7. Feb 2009. doi:10.1016/j.bmcl.2008.12.107. PMID 19152787.
21. ↑ "1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands". Bioorganic & Medicinal Chemistry Letters 15 (6): 1707–11. Mar 2005. doi:10.1016/j.bmcl.2005.01.031. PMID 15745826.
22. ↑ "Binding of sulfonyl-containing arylalkylamines at human 5HT6 serotonin receptors". Journal of Medicinal Chemistry 49 (17): 5217–25. Aug 2006. doi:10.1021/jm060469q. PMID 16913710.
23. ↑ "Serotonin 5-HT6 receptor antagonists for the treatment of cognitive deficiency in Alzheimer's disease". J. Med. Chem. 57 (17): 7160–81. 2014. doi:10.1021/jm5003952. PMID 24850589. https://figshare.com/articles/journal_contribution/2255221.
24. ↑ "Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket". Bioorg. Med. Chem. Lett. 26 (6): 1605–11. 2016. doi:10.1016/j.bmcl.2016.02.001. PMID 26876931.
25. ↑ "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 15 (21): 4867–71. Nov 2005. doi:10.1016/j.bmcl.2005.06.107. PMID 16143522.
26. ↑ "Indene-based scaffolds. Design and synthesis of novel serotonin 5HT6 receptor ligands". Organic & Biomolecular Chemistry 6 (20): 3795–810. Oct 2008. doi:10.1039/b808641a. PMID 18843410.
27. ↑ "4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands". Bioorganic & Medicinal Chemistry Letters 15 (5): 1393–6. Mar 2005. doi:10.1016/j.bmcl.2005.01.005. PMID 15713394.
28. ↑ "2-Substituted tryptamines: agents with selectivity for 5HT(6) serotonin receptors". Journal of Medicinal Chemistry 43 (5): 1011–8. Mar 2000. doi:10.1021/jm990550b. PMID 10715164.
29. ↑ "Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists". Journal of Medicinal Chemistry 52 (3): 675–87. Feb 2009. doi:10.1021/jm8009469. PMID 19159187.
30. ↑ "Efficacy of selective 5-HT6 receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways". British Journal of Pharmacology 148 (8): 1133–43. Aug 2006. doi:10.1038/sj.bjp.0706827. PMID 16865095.
31. ↑ "Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats". British Journal of Pharmacology 148 (7): 973–83. Aug 2006. doi:10.1038/sj.bjp.0706807. PMID 16783408.
32. ↑ "2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists". Bioorganic & Medicinal Chemistry Letters 15 (19): 4230–4. Oct 2005. doi:10.1016/j.bmcl.2005.06.067. PMID 16055331.
33. ↑ "Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT6 partial agonist in rats". Naunyn Schmiedebergs Arch. Pharmacol. 389 (8): 839–49. 2016. doi:10.1007/s00210-016-1245-3. PMID 27106213.
34. ↑ "Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells". Neuropharmacology 36 (4–5): 713–20. 1997. doi:10.1016/s0028-3908(97)00019-1. PMID 9225298.
35. ↑ "Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT(6) receptor antagonist". Drug Development and Industrial Pharmacy 32 (2): 185–96. Feb 2006. doi:10.1080/03639040500466122. PMID 16537199.
36. ↑ "Evaluation of Dimebon in cellular model of Huntington's disease". Molecular Neurodegeneration 3: 15. 2008. doi:10.1186/1750-1326-3-15. PMID 18939977.
37. ↑ "Synthesis and biological evaluation of novel gamma-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists". Bioorganic & Medicinal Chemistry Letters 19 (12): 3183–7. Jun 2009. doi:10.1016/j.bmcl.2009.04.128. PMID 19443217.
38. ↑ "Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity". Behav Pharmacol 22 (2): 122–35. 2011. doi:10.1097/FBP.0b013e328343d804. PMID 21301322.
39. ↑ "5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists". Journal of Medicinal Chemistry 53 (21): 7639–46. Nov 2010. doi:10.1021/jm1007825. PMID 20932009.
40. ↑ "Antistress Effects of Rosa rugosa Thunb. on Total Sleep Deprivation-Induced Anxiety-Like Behavior and Cognitive Dysfunction in Rat: Possible Mechanism of Action of 5-HT6 Receptor Antagonist". J Med Food 19 (9): 870–81. 2016. doi:10.1089/jmf.2016.3660. PMID 27331439.
41. ↑ "Association of the HTR6 polymorphism C267T with late-onset Alzheimer's disease in Chinese". Neuroscience Letters 372 (1–2): 27–9. Nov 2004. doi:10.1016/j.neulet.2004.09.007. PMID 15531082.
42. ↑ "Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease". Neurology 58 (5): 828–9. Mar 2002. doi:10.1212/wnl.58.5.828. PMID 11889255. http://www.neurology.org/cgi/content/citation/58/5/828.

## Further reading

* "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacology Biochemistry and Behavior 71 (4): 533–54. Apr 2002. doi:10.1016/S0091-3057(01)00746-8. PMID 11888546.
* "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacology & Therapeutics 92 (2–3): 179–212. 2002. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537.
* "5-HT2A and 5-HT2C receptors and their atypical regulation properties". Life Sciences 72 (22): 2429–49. Apr 2003. doi:10.1016/S0024-3205(03)00141-3. PMID 12650852.
* "Family-based association study of the serotonin-6 receptor gene (C267T polymorphism) in schizophrenia". American Journal of Medical Genetics Part B 126B (1): 10–5. Apr 2004. doi:10.1002/ajmg.b.20120. PMID 15048641.
* "Expression of serotonin receptor mRNAs in blood vessels". FEBS Letters 370 (3): 215–21. Aug 1995. doi:10.1016/0014-5793(95)00828-W. PMID 7656980.
* "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". Journal of Neurochemistry 66 (1): 47–56. Jan 1996. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
* "Association study of the 5-hydroxytryptamine(6) receptor gene in Alzheimer's disease". Neuroscience Letters 325 (1): 13–6. May 2002. doi:10.1016/S0304-3940(02)00221-5. PMID 12023056.
* "Serotonergic genes and personality traits in the Korean population". Neuroscience Letters 354 (1): 2–5. Jan 2004. doi:10.1016/S0304-3940(03)00753-5. PMID 14698468.
* "1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands". Bioorganic & Medicinal Chemistry Letters 14 (22): 5499–502. Nov 2004. doi:10.1016/j.bmcl.2004.09.003. PMID 15482912.
* "Molecular analysis of the interaction between the intracellular loops of the human serotonin receptor type 6 (5-HT6) and the alpha subunit of GS protein". Biochemical and Biophysical Research Communications 329 (2): 684–92. Apr 2005. doi:10.1016/j.bbrc.2005.02.040. PMID 15737640.
* "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods 2 (8): 591–8. Aug 2005. doi:10.1038/nmeth776. PMID 16094384.
* "Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients". BMC Neuroscience 7: 36. 2006. doi:10.1186/1471-2202-7-36. PMID 16640790.
* "The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn". The Journal of Biological Chemistry 282 (8): 5496–505. Feb 2007. doi:10.1074/jbc.M606215200. PMID 17189269.

## External links

* "5-HT6". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2335.
* serotonin+6+receptor at the US National Library of Medicine Medical Subject Headings (MeSH)
* Human HTR6 genome location and HTR6 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

* v
* t
* e

Cell signaling / Signal transduction

Signaling pathways|

* GPCR
*   * Wnt
* RTK
* TGF beta
* MAPK/ERK
* Notch
* JAK-STAT
* Akt/PKB
* Fas apoptosis
* Hippo
* PI3K/AKT/mTOR pathway
* Integrin receptors

Agents|

| Receptor ligands|

* Hormones
* Neurotransmitters/Neuropeptides/Neurohormones
* Cytokines
* Growth factors
* Signaling molecules

|

Receptors|

* Cell surface
* Intracellular
* Co-receptor

Second messenger|

* cAMP-dependent pathway
* Ca2+ signaling
* Lipid signaling

Assistants:|

* Signal transducing adaptor protein
* Scaffold protein

Transcription factors|

* General
* Transcription preinitiation complex
* TFIID
* TFIIH

By distance|

* Juxtacrine
* Autocrine / Paracrine
* Endocrine

Other concepts|

* Intracrine action
* Neurocrine signaling
* Synaptic transmission
* Chemical synapse
* Neuroendocrine signaling
* Exocrine signalling
* Pheromones
* Mechanotransduction
* Phototransduction
* Ion channel gating
* Gap junction

* v
* t
* e

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

| Neurotransmitter|

| Adrenergic|

* α1 (A
* B
* D)
* α2 (A
* B
* C)
* β1
* β2
* β3

|

Purinergic|

* Adenosine (A1
* A2A
* A2B
* A3)
* P2Y (1
* 2
* 4
* 5
* 6
* 8
* 9
* 10
* 11
* 12
* 13
* 14)

Serotonin|

* (all but 5-HT3) 5-HT1 (A
* B
* D
* E
* F)
* 5-HT2 (A
* B
* C)
* 5-HT (4
* 5A
* 6
* 7)

Other|

* Acetylcholine (M1
* M2
* M3
* M4
* M5)
* Dopamine
* D1
* D2
* D3
* D4
* D5
* GHB receptor
* Histamine
* H1
* H2
* H3
* H4
* Melatonin (1A
* 1B
* 1C)
* TAAR (1
* 2
* 5
* 6
* 8
* 9)

Metabolites and
signaling molecules|

| Eicosanoid|

* CysLT (1
* 2)
* LTB4
* 1
* 2
* FPRL1
* OXE
* Prostaglandin
* DP (1
* 2), EP (1
* 2
* 3
* 4), FP
* Prostacyclin
* Thromboxane

|

Other|

* Bile acid
* Cannabinoid (CB1
* CB2, GPR (18
* 55
* 119))
* EBI2
* Estrogen
* Free fatty acid (1
* 2
* 3
* 4)
* Hydroxycarboxylic acids
* 1
* 2
* 3
* Lysophosphatidic acid (1
* 2
* 3
* 4
* 5
* 6)
* Lysophospholipid (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8)
* Oxoglutarate
* PAF
* Sphingosine-1-phosphate (1
* 2
* 3
* 4
* 5)
* Succinate

Peptide|

| Neuropeptide|

* B/W (1
* 2)
* FF (1
* 2)
* S
* Y (1
* 2
* 4
* 5)
* Neuromedin (B
* U (1
* 2))
* Neurotensin (1
* 2)

|

Other|

* Anaphylatoxin (C3a
* C5a)
* Angiotensin (1
* 2)
* Apelin
* Bombesin
* BRS3
* GRPR
* NMBR)
* Bradykinin (B1
* B2)
* Chemokine
* Cholecystokinin (A
* B)
* Endothelin
* A
* B
* Formyl peptide (1
* 2
* 3)
* FSH
* Galanin (1
* 2
* 3)
* Gonadotropin-releasing hormone (1
* 2)
* Ghrelin
* Kisspeptin
* Luteinizing hormone/choriogonadotropin
* MAS (1
* 1L
* D
* E
* F
* G
* X1
* X2
* X3
* X4)
* Melanocortin (1
* 2
* 3
* 4
* 5)
* MCHR (1
* 2)
* Motilin
* Opioid (Delta
* Kappa
* Mu
* Nociceptin & Zeta, but not Sigma)
* Orexin (1
* 2)
* Oxytocin
* Prokineticin (1
* 2)
* Prolactin-releasing peptide
* Relaxin (1
* 2
* 3
* 4)
* Somatostatin (1
* 2
* 3
* 4
* 5)
* Tachykinin (1
* 2
* 3)
* Thyrotropin
* Thyrotropin-releasing hormone
* Urotensin-II
* Vasopressin (1A
* 1B
* 2)

Miscellaneous|

| Taste, bitter|

* TAS2R
* 1
* 3
* 4
* 5
* 7
* 8
* 9
* 10
* 13
* 14
* 16
* 19
* 20
* 30
* 31
* 38
* 39
* 40
* 41
* 42
* 43
* 45
* 46
* 50
* 60
* Vomeronasal receptor type 1

|

Orphan|

* GPR (1
* 3
* 4
* 6
* 12
* 15
* 17
* 18
* 19
* 20
* 21
* 22
* 23
* 25
* 26
* 27
* 31
* 32
* 33
* 34
* 35
* 37
* 39
* 42
* 44
* 45
* 50
* 52
* 55
* 61
* 62
* 63
* 65
* 68
* 75
* 77
* 78
* 81
* 82
* 83
* 84
* 85
* 87
* 88
* 92
* 101
* 103
* 109A
* 109B
* 119
* 120
* 132
* 135
* 137B
* 139
* 141
* 142
* 146
* 148
* 149
* 150
* 151
* 152
* 153
* 160
* 161
* 162
* 171
* 173
* 174
* 176
* 177
* 182
* 183)

Other|

* Adrenomedullin
* Olfactory
* Opsin (3
* 4
* 5
* 1LW
* 1MW
* 1SW
* RGR
* RRH)
* Protease-activated (1
* 2
* 3
* 4)
* SREB (1
* 2
* 3)

Class B: Secretin-like

| Adhesion|

* ADGRG (1
* 2
* 3
* 4
* 5
* 6
* 7)

|

Orphan|

* GPR (56
* 64
* 97
* 98
* 110
* 111
* 112
* 113
* 114
* 115
* 116
* 123
* 124
* 125
* 126
* 128
* 133
* 143
* 144
* 155
* 157)

Other|

* Brain-specific angiogenesis inhibitor (1
* 2
* 3)
* Cadherin (1
* 2
* 3)
* Calcitonin
* CALCRL
* CD97
* Corticotropin-releasing hormone (1
* 2)
* EMR (1
* 2
* 3)
* Glucagon (GR
* GIPR
* GLP1R
* GLP2R)
* Growth-hormone-releasing hormone
* PACAPR1
* GPR
* Latrophilin (1
* 2
* 3
* ELTD1)
* Methuselah-like proteins
* Parathyroid hormone (1
* 2)
* Secretin
* Vasoactive intestinal peptide (1
* 2)

Class C: Metabotropic glutamate / pheromone

| Taste, sweet|

* TAS1R
* 1
* 2
* 3
* Vomeronasal receptor, type 2

|

Other|

* Calcium-sensing receptor
* GABAB (1
* 2)
* Glutamate receptor (Metabotropic glutamate (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8))
* GPRC6A
* GPR (156
* 158
* 179)
* RAIG (1
* 2
* 3
* 4)

Class F: Frizzled & Smoothened

| Frizzled|

* Frizzled (1
* 2
* 3
* 4
* 5
* 6
* 7
* 8
* 9
* 10)

|

Smoothened|

* Smoothened

* v
* t
* e

Serotonin receptor modulators

5-HT1|

| 5-HT1A|

* Agonists: 8-OH-DPAT
* Adatanserin
* Amphetamine
* Antidepressants (e.g., etoperidone, hydroxynefazodone, nefazodone, trazodone, triazoledione, vilazodone, vortioxetine)
* Atypical antipsychotics (e.g., aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, lurasidone, quetiapine, ziprasidone)
* Azapirones (e.g., buspirone, eptapirone, gepirone, perospirone, tandospirone)
* Bay R 1531
* Befiradol
* BMY-14802
* Cannabidiol
* Dimemebfe
* Dopamine
* Ebalzotan
* Eltoprazine
* Enciprazine
* Ergolines (e.g., bromocriptine, cabergoline, dihydroergotamine, ergotamine, lisuride, LSD, methylergometrine (methylergonovine), methysergide, pergolide)
* F-11461
* F-12826
* F-13714
* F-14679
* F-15063
* F-15,599
* Flesinoxan
* Flibanserin
* Flumexadol
* Hypidone
* Lesopitron
* LY-293284
* LY-301317
* mCPP
* MKC-242
* Naluzotan
* NBUMP
* Osemozotan
* Oxaflozane
* Pardoprunox
* Piclozotan
* Rauwolscine
* Repinotan
* Roxindole
* RU-24,969
* S-14,506
* S-14671
* S-15535
* Sarizotan
* Serotonin (5-HT)
* SSR-181507
* Sunepitron
* Tryptamines (e.g., 5-CT, 5-MeO-DMT, 5-MT, bufotenin, DMT, indorenate, N-Me-5-HT, psilocin, psilocybin)
* TGBA01AD
* U-92,016-A
* Urapidil
* Vilazodone
* Xaliproden
* Yohimbine

* Antagonists: Atypical antipsychotics (e.g., iloperidone, risperidone, sertindole)
* AV965
* Beta blockers (e.g., alprenolol, carteolol, cyanopindolol, iodocyanopindolol, isamoltane, oxprenolol, penbutolol, pindobind, pindolol, propranolol, tertatolol)
* BMY-7,378
* CSP-2503
* Dotarizine
* Ergolines (e.g., metergoline)
* FCE-24379
* Flopropione
* GR-46611
* Isamoltane
* Lecozotan
* Mefway
* Metitepine (methiothepin)
* MIN-117 (WF-516)
* MPPF
* NAN-190
* Robalzotan
* S-15535
* SB-649,915
* SDZ 216-525
* Spiperone
* Spiramide
* Spiroxatrine
* UH-301
* WAY-100135
* WAY-100635
* Xylamidine

* Unknown/unsorted: Acetryptine
* Carvedilol
* Ergolines (e.g., ergometrine (ergonovine))

5-HT1B|

* Agonists: Anpirtoline
* CGS-12066A
* CP-93129
* CP-94253
* CP-122,288
* CP-135807
* Eltoprazine
* Ergolines (e.g., bromocriptine, dihydroergotamine, ergotamine, methylergometrine (methylergonovine), methysergide, pergolide)
* mCPP
* RU-24,969
* Serotonin (5-HT)
* Triptans (e.g., avitriptan, donitriptan, eletriptan, sumatriptan, zolmitriptan)
* TFMPP
* Tryptamines (e.g., 5-BT, 5-CT, 5-MT, DMT)
* Vortioxetine

* Antagonists: AR-A000002
* Beta blockers (e.g., alprenolol, carteolol, isamoltane, oxprenolol, penbutolol, propranolol, tertatolol)
* Elzasonan
* Ergolines (e.g., metergoline)
* GR-127935
* Isamoltane
* LY-393558
* Metitepine (methiothepin)
* SB-216641
* SB-224289
* SB-236057
* Yohimbine

* Unknown/unsorted: Ergolines (e.g., cabergoline, ergometrine (ergonovine), lisuride)

5-HT1D|

* Agonists: CP-122,288
* CP-135807
* CP-286601
* Ergolines (e.g., bromocriptine, cabergoline, dihydroergotamine, ergotamine, LSD, methysergide)
* Chemistry:GR-46611
* L-694247
* Chemistry:L-772405
* mCPP
* PNU-109291
* PNU-142633
* Serotonin (5-HT)
* TGBA01AD
* Triptans (e.g., almotriptan, avitriptan, donitriptan, [[Chemistry:Eleeletriptan, Frovatriptan|frovatriptan]], naratriptan, rizatriptan, sumatriptan, zolmitriptan)
* Tryptamines (e.g., 5-BT, 5-CT, 5-Et-DMT, 5-MT, 5-(nonyloxy)tryptamine, DMT)

* Antagonists: Alniditan
* BRL-15,572
* Elzasonan
* Ergolines (e.g., metergoline)
* GR-127935
* Ketanserin
* LY-310762
* LY-367642
* LY-393558
* LY-456219
* LY-456220
* Metitepine (methiothepin)
* Mianserin
* Ritanserin
* Yohimbine
* Ziprasidone

* Unknown/unsorted: Acetryptine
* Ergolines (e.g., lisuride, lysergol, pergolide)

5-HT1E|

* Agonists: BRL-54443
* Ergolines (e.g., methysergide)
* Serotonin (5-HT)
* Triptans (e.g., eletriptan)
* Tryptamines (e.g., tryptamine)

* Antagonists: Metitepine (methiothepin)

* Unknown/unsorted: ErgIrindaloneolines (e.g., ergometrine (ergonovine), lysergol, methylergometrine (methylergonovine)

5-HT1F|

* Agonists: BRL-54443
* CP-122,288
* Ergolines (e.g., bromocriptine, lysergol, methylergometrine (methylergonovine) methysergide)
* Lasmiditan
* LY-334370
* Serotonin (5-HT)
* Triptans (e.g., eletriptan, naratriptan, sumatriptan)
* Tryptamines (e.g., 5-MT)

* Antagonists: Metitepine (methiothepin)
* Mianserin

5-HT2|

| 5-HT2A|

* Agonists: 25H/NB series (e.g., 25I-NBF, 25I-NBMD, 25I-NBOH, 25I-NBOMe, 25B-NBOMe, 25C-NBOMe, 25TFM-NBOMe, 2CBCB-NBOMe, 25CN-NBOH, 2CBFly-NBOMe)
* 2Cs (e.g., 2C-B, 2C-E, 2C-I, 2C-T-2, 2C-T-7, 2C-T-21)
* 2C-B-FLY
* 2CB-Ind
* 5-Methoxytryptamines (5-MeO-DET, 5-MeO-DiPT, 5-MeO-DMT, 5-MeO-DPT, 5-MT)
* α-Alkyltryptamines (e.g., 5-Cl-αMT, 5-Fl-αMT, 5-MeO-αET, 5-MeO-αMT, α-Me-5-HT, αET, αMT)
* AL-34662
* AL-37350A
* Bromo-DragonFLY
* Dimemebfe
* DMBMPP
* DOx (e.g., DOB, DOC, DOI, DOM)
* Efavirenz
* Ergolines (e.g., 1P-LSD, ALD-52, bromocriptine, cabergoline, ergine (LSA), ergometrine (ergonovine), ergotamine, lisuride, LA-SS-Az, LSB, LSD, LSD-Pip, LSH, LSP, methylergometrine (methylergonovine), pergolide)
* Flumexadol
* IHCH-7113
* Jimscaline
* Lorcaserin
* MDxx (e.g., MDA (tenamfetamine), MDMA (midomafetamine), MDOH, MMDA)
* O-4310
* Oxaflozane
* PHA-57378
* PNU-22394
* PNU-181731
* RH-34
* SCHEMBL5334361
* Phenethylamines (e.g., lophophine, mescaline)
* Piperazines (e.g., BZP, quipazine, TFMPP)
* Serotonin (5-HT)
* TCB-2
* TFMFly
* Tryptamines (e.g., 5-BT, 5-CT, bufotenin, DET, DiPT, DMT, DPT, psilocin, psilocybin, tryptamine)

* Antagonists: 5-I-R91150
* 5-MeO-NBpBrT
* AC-90179
* Adatanserin
* Altanserin
* Antihistamines (e.g., cyproheptadine, hydroxyzine, ketotifen, perlapine)
* AMDA
* Atypical antipsychotics (e.g., amperozide, aripiprazole, asenapine, blonanserin, brexpiprazole, carpipramine, clocapramine, clorotepine, clozapine, fluperlapine, gevotroline, iloperidone, lurasidone, melperone, mosapramine, ocaperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zicronapine, ziprasidone, zotepine)
* Chlorprothixene
* Cinanserin
* CSP-2503
* Deramciclane
* Dotarizine
* Eplivanserin
* Ergolines (e.g., amesergide, LY-53857, LY-215,840, mesulergine, metergoline, methysergide, sergolexole)
* Fananserin
* Flibanserin
* Glemanserin
* Irindalone
* Ketanserin
* KML-010
* Landipirdine
* LY-393558
* mCPP
* Medifoxamine
* Metitepine (methiothepin)
* MIN-117 (WF-516)
* Naftidrofuryl
* Nantenine
* Nelotanserin
* Opiranserin (VVZ-149)
* Pelanserin
* Phenoxybenzamine
* Pimavanserin
* Pirenperone
* Pizotifen
* Pruvanserin
* Rauwolscine
* Ritanserin
* Roluperidone
* S-14671
* Sarpogrelate
* Serotonin antagonists and reuptake inhibitors (e.g., etoperidone, hydroxynefazodone, lubazodone, mepiprazole, nefazodone, triazoledione, trazodone)
* SR-46349B
* TGBA01AD
* Teniloxazine
* Temanogrel
* Tetracyclic antidepressants (e.g., amoxapine, aptazapine, esmirtazapine, maprotiline, mianserin, mirtazapine)
* Tricyclic antidepressants (e.g., amitriptyline)
* Typical antipsychotics (e.g., chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, pimozide, pipamperone, prochlorperazine, setoperone, spiperone, spiramide, thioridazine, thiothixene, trifluoperazine)
* Volinanserin
* Xylamidine
* Yohimbine

* Unknown/unsorted: Ergolines (e.g., dihydroergotamine, nicergoline)

5-HT2B|

* Agonists: 4-Methylaminorex
* Aminorex
* Amphetamines (e.g., chlorphentermine, cloforex, dexfenfluramine, fenfluramine, levofenfluramine, norfenfluramine)
* BW-723C86
* DOx (e.g., DOB, DOC, DOI, DOM)
* Ergolines (e.g., cabergoline, dihydroergocryptine, dihydroergotamine, ergotamine, methylergometrine (methylergonovine), methysergide, pergolide)
* Lorcaserin
* MDxx (e.g., MDA (tenamfetamine), MDMA (midomafetamine), MDOH, MMDA)
* Piperazines (e.g., TFMPP)
* PNU-22394
* Ro60-0175
* Serotonin (5-HT)
* Tryptamines (e.g., 5-BT, 5-CT, 5-MT, α-Me-5-HT, bufotenin, DET, DiPT, DMT, DPT, psilocin, psilocybin, tryptamine)

* Antagonists: Agomelatine
* Atypical antipsychotics (e.g., amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, N-desalkylquetiapine (norquetiapine), N-desmethylclozapine (norclozapine), olanzapine, pipamperone, quetiapine, risperidone, ziprasidone)
* Cyproheptadine
* EGIS-7625
* Ergolines (e.g., amesergide, bromocriptine, lisuride, LY-53857, LY-272015, mesulergine)
* Ketanserin
* LY-393558
* mCPP
* Metadoxine
* Metitepine (methiothepin)
* Pirenperone
* Pizotifen
* Propranolol
* PRX-08066
* Rauwolscine
* Ritanserin
* RS-127445
* Sarpogrelate
* SB-200646
* SB-204741
* SB-206553
* SB-215505
* SB-221284
* SB-228357
* SDZ SER-082
* Tegaserod
* Tetracyclic antidepressants (e.g., amoxapine, mianserin, mirtazapine)
* Trazodone
* Typical antipsychotics (e.g., chlorpromazine)
* TIK-301
* Yohimbine

* Unknown/unsorted: Ergolines (e.g., ergometrine (ergonovine))

5-HT2C|

* Agonists: 2Cs (e.g., 2C-B, 2C-E, 2C-I, 2C-T-2, 2C-T-7, 2C-T-21)
* 5-Methoxytryptamines (5-MeO-DET, 5-MeO-DiPT, 5-MeO-DMT, 5-MeO-DPT, 5-MT)
* α-Alkyltryptamines (e.g., 5-Cl-αMT, 5-Fl-αMT, 5-MeO-αET, 5-MeO-αMT, α-Me-5-HT, αET, αMT)
* A-372159
* AL-38022A
* Alstonine
* CP-809101
* Dimemebfe
* DOx (e.g., DOB, DOC, DOI, DOM)
* Ergolines (e.g., ALD-52, cabergoline, dihydroergotamine, ergine (LSA), ergotamine, lisuride, LA-SS-Az, LSB, LSD, LSD-Pip, LSH, LSP, pergolide)
* Flumexadol
* Lorcaserin
* MDxx (e.g., MDA (tenamfetamine), MDMA (midomafetamine), MDOH, MMDA)
* MK-212
* ORG-12962
* ORG-37684
* Oxaflozane
* PHA-57378
* Phenethylamines (e.g., lophophine, mescaline)
* Piperazines (e.g., aripiprazole, BZP, mCPP, quipazine, TFMPP)
* PNU-22394
* PNU-181731
* Ro60-0175
* Ro60-0213
* Serotonin (5-HT)
* Tryptamines (e.g., 5-BT, 5-CT, bufotenin, DET, DiPT, DMT, DPT, psilocin, psilocybin, tryptamine)
* Vabicaserin
* WAY-629
* WAY-161503
* YM-348

* Antagonists: Adatanserin
* Agomelatine
* Atypical antipsychotics (e.g., asenapine, clorotepine, clozapine, fluperlapine, iloperidone, melperone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, zotepine)
* Captodiame
* CEPC
* Cinanserin
* Cyproheptadine
* Deramciclane
* Desmetramadol
* Dotarizine
* Eltoprazine
* Ergolines (e.g., amesergide, bromocriptine, LY-53857, LY-215,840, mesulergine, metergoline, methysergide, sergolexole)
* Etoperidone
* Fluoxetine
* FR-260010
* Irindalone
* Ketanserin
* Ketotifen
* Latrepirdine (dimebolin)
* Medifoxamine
* Metitepine (methiothepin)
* Nefazodone
* Pirenperone
* Pizotifen
* Propranolol
* Ritanserin
* RS-102221
* S-14671
* SB-200646
* SB-206553
* SB-221284
* SB-228357
* SB-242084
* SB-243213
* SDZ SER-082
* Tedatioxetine
* Tetracyclic antidepressants (e.g., amoxapine, aptazapine, esmirtazapine, maprotiline, mianserin, mirtazapine)
* TIK-301
* Tramadol
* Trazodone
* Tricyclic antidepressants (e.g., amitriptyline, nortriptyline)
* Typical antipsychotics (e.g., chlorpromazine, loxapine, pimozide, pipamperone, thioridazine)
* Xylamidine

* Unknown/unsorted: Efavirenz
* Ergolines (e.g., ergometrine (ergonovine), methylergometrine (methylergonovine))

5-HT3–7|

| 5-HT3|

* Agonists: Alcohols (e.g., butanol, ethanol (alcohol), trichloroethanol)
* m-CPBG
* Phenylbiguanide
* Piperazines (e.g., BZP, mCPP, quipazine)
* RS-56812
* Serotonin (5-HT)
* SR-57227
* SR-57227A
* Tryptamines (e.g., 2-Me-5-HT, 5-CT, bufotenidine (5-HTQ))
* Volatiles/gases (e.g., halothane, isoflurane, toluene, trichloroethane)
* YM-31636

* Antagonists: Alosetron
* Chemistry:Arazasetron
* AS-8112
* Atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine)
* Azasetron
* Batanopride
* Bemesetron (MDL-72222)
* Bupropion
* Cilansetron
* CSP-2503
* Dazopride
* Dolasetron
* Galanolactone
* Granisetron
* Hydroxybupropion
* Lerisetron
* Memantine
* Ondansetron
* Palonosetron
* Ramosetron
* Renzapride
* Ricasetron
* Tedatioxetine
* Tetracyclic antidepressants (e.g., amoxapine, mianserin, mirtazapine)
* Thujone
* Tropanserin
* Tropisetron
* Typical antipsychotics (e.g., loxapine)
* Volatiles/gases (e.g., nitrous oxide, sevoflurane, xenon)
* Vortioxetine
* Zacopride
* Zatosetron

* Unknown/unsorted: LY-53857
* Piperazines (e.g., naphthylpiperazine)

5-HT4|

* Agonists: 5-MT
* BIMU8
* Capeserod
* Cinitapride
* Cisapride
* CJ-033466
* Dazopride
* Metoclopramide
* Minesapride
* Mosapride
* Prucalopride
* PRX-03140
* Renzapride
* RS-67,333
* RS-67,506
* Serotonin (5-HT)
* Tegaserod
* Usmarapride
* Velusetrag
* Zacopride

* Antagonists: GR-113808
* GR-125487
* L-Lysine
* Piboserod
* RS-39604
* RS-67532
* SB-203186
* SB-204070

5-HT5A|

* Agonists: Ergolines (e.g., 2-Br-LSD (BOL-148), ergotamine, LSD)
* Serotonin (5-HT)
* Tryptamines (e.g., 5-CT)
* Valerenic acid

* Antagonists: Asenapine
* Latrepirdine (dimebolin)
* Metitepine (methiothepin)
* Ritanserin
* SB-699551

* Unknown/unsorted: Ergolines (e.g., metergoline, methysergide)
* Piperazines (e.g., naphthylpiperazine)

5-HT6|

* Agonists: Ergolines (e.g., dihydroergocryptine, dihydroergotamine, ergotamine, lisuride, LSD, mesulergine, metergoline, methysergide)
* Hypidone
* Serotonin (5-HT)
* Tryptamines (e.g., 2-Me-5-HT, 5-BT, 5-CT, 5-MT, Bufotenin, E-6801, E-6837, EMD-386088, EMDT, LY-586713, N-Me-5-HT, ST-1936, tryptamine)
* WAY-181187
* WAY-208466

* Antagonists: ABT-354
* Atypical antipsychotics (e.g., aripiprazole, asenapine, clorotepine, clozapine, fluperlapine, iloperidone, olanzapine, tiospirone)
* AVN-101
* AVN-211
* AVN-322
* AVN-397
* BGC20-760
* BVT-5182
* BVT-74316
* Cerlapirdine
* EGIS-12,233
* GW-742457
* Idalopirdine
* Ketanserin
* Landipirdine
* Latrepirdine (dimebolin)
* Masupirdine
* Metitepine (methiothepin)
* MS-245
* PRX-07034
* Ritanserin
* Ro 04-6790
* Ro 63-0563
* SB-258585
* SB-271046
* SB-357134
* SB-399885
* SB-742457
* Tetracyclic antidepressants (e.g., amoxapine, mianserin)
* Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, nortriptyline)
* Typical antipsychotics (e.g., chlorpromazine, loxapine)

* Unknown/unsorted: Ergolines (e.g., 2-Br-LSD (BOL-148), bromocriptine, lergotrile, pergolide)
* Piperazines (e.g., naphthylpiperazine)

5-HT7|

* Agonists: 8-OH-DPAT
* AS-19
* Bifeprunox
* E-55888
* Ergolines (e.g., LSD)
* LP-12
* LP-44
* LP-211
* RU-24,969
* Sarizotan
* Serotonin (5-HT)
* Triptans (e.g., frovatriptan)
* Tryptamines (e.g., 5-CT, 5-MT, bufotenin, N-Me-5-HT)

* Antagonists: Atypical antipsychotics (e.g., amisulpride, aripiprazole, asenapine, brexpiprazole, clorotepine, clozapine, fluperlapine, olanzapine, risperidone, sertindole, tiospirone, ziprasidone, zotepine)
* Butaclamol
* DR-4485
* EGIS-12,233
* Ergolines (e.g., 2-Br-LSD (BOL-148), amesergide, bromocriptine, cabergoline, dihydroergotamine, ergotamine, LY-53857, LY-215,840, mesulergine, metergoline, methysergide, sergolexole)
* JNJ-18038683
* Ketanserin
* LY-215,840
* Metitepine (methiothepin)
* Ritanserin
* SB-258719
* SB-258741
* SB-269970
* SB-656104
* SB-656104A
* SB-691673
* SLV-313
* SLV-314
* Spiperone
* Chemistry:SSR-181507
* Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin, mirtazapine)
* Tricyclic antidepressants (e.g., amitriptyline, clomipramine, imipramine)
* Typical antipsychotics (e.g., acetophenazine, chlorpromazine, chlorprothixene, fluphenazine, loxapine, pimozide)
* Vortioxetine

* Unknown/unsorted: Ergolines (e.g., lisuride, pergolide)
* Piperazines (e.g., naphthylpiperazine)

* See also: Receptor/signaling modulators
* Adrenergics
* Dopaminergics
* Melatonergics
* Monoamine reuptake inhibitors and releasing agents
* Monoamine metabolism modulators
* Monoamine neurotoxins

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