5-HT6 receptor

From Wikipedia, the free encyclopedia

5-hydroxytryptamine (serotonin) receptor 6, G protein-coupled

Identifiers

HTR6; 5-HT6; 5-HT6R

External IDs

OMIM: 601109 MGI: 1196627 HomoloGene: 673 IUPHAR: 5-HT₆ ChEMBL: 3371 GeneCards: HTR6 Gene

Gene Ontology
Molecular function	• histamine receptor activity • serotonin receptor activity • protein binding
Cellular component	• plasma membrane • integral to plasma membrane • dendrite
Biological process	• G-protein coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger • synaptic transmission • brain development • learning • negative regulation of glutamate secretion • negative regulation of gamma-aminobutyric acid secretion • positive regulation of gamma-aminobutyric acid secretion • negative regulation of acetylcholine secretion • positive regulation of cAMP metabolic process • response to estradiol stimulus • positive regulation of dopamine secretion • response to drug • regulation of hormone secretion • long-term synaptic potentiation
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 1:
19.99 – 20.01 Mb

Chr 4:
139.06 – 139.08 Mb

PubMed search

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

Distribution

The 5-HT₆ 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 5-HT₆ receptor plays a role in functions like motor control, emotionality, cognition, and memory.^[3]^[5]^[6]

Function

Blockade of central 5-HT₆ 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 5-HT₆ receptors also facilitates dopamine and norepinephrine release in the frontal cortex,^[10]^[12] while stimulation has the opposite effect.^[11]

Despite the 5-HT₆ 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, 5-HT₆ antagonists improve cognition, learning, and memory,^[13] and agents such as latrepirdine, Lu AE58054, and SB-742,457 are being developed as novel treatments for Alzheimer's disease and other forms of dementia.^[10]^[14]^[15] 5-HT₆ 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]

Recently, the 5-HT₆ 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, it can be inferred that 5-HT₆ activation likely plays a major role in the therapeutic benefits of serotonergic antidepressants like the selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

Ligands

A large number of selective 5-HT₆ ligands have now been developed and this is a productive current area of research.^[19]^[20]^[21]^[22]^[23]^[24]^[25]

Full agonists

EMD-386,088 - potent and selective 5HT₆ agonist (EC₅₀ 1nM)^[26]
2-Ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT)^[27]
WAY-181,187^[11]
WAY-208,466^[11]
N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (compound 11q)^[28]
N-(inden-5-yl)imidazothiazole-5-sulfonamide (43): K_i = 4.5nM, EC₅₀ = 0.9nM, E_max = 98%^[29]
E-6837 - Full agonist at human 5-HT₆ 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]

Antagonists

BVT-5182^[32]
BVT-74316^[16]
Cerlapirdine
EGIS-12233 - mixed 5-HT₆ / 5-HT₇ antagonist
Latrepirdine (non-selective)^[33] and analogues^[34]
Lu AE58054
MS-245
PRX-07034
SB-258,585
SB-271,046
SB-357,134
SB-399,885
SB-742,457
Ro04-6790
Atypical antipsychotics (olanzapine, asenapine, clozapine)
WAY-255315 / SAM-315: Ki = 1.1nM, IC = 13nM^[35]

Genetics

The receptor is encoded by the HTR6 gene. As the protein is a neuroreceptor it is possible that genetic variations in the gene would have an effect on brain, and research studies have investigated whether polymorphisms is associated with brain-related variables, such as neuropsychiatric disorders. For example, in 2004 one Chinese study reported an association between the C267T (rs1805054) polymorphism and Alzheimer's disease.^[36] Others have studied the polymorphism in relation to Parkinson's disease.^[37]

References

↑ 1.0 1.1 1.2 Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW (1996). "Cloning, characterization, and chromosomal localization of a human 5-HT₆ serotonin receptor". J. Neurochem. 66 (1): 47–56. doi:10.1046/j.1471-4159.1996.66010047.x. PMID 8522988.
↑ "Entrez Gene: HTR6 5-hydroxytryptamine (serotonin) receptor 6".
↑ 3.0 3.1 Woolley ML, Marsden CA, Fone KC (February 2004). "5-ht6 receptors". Current Drug Targets. CNS and Neurological Disorders 3 (1): 59–79. doi:10.2174/1568007043482561. PMID 14965245.
↑ Ruat M, Traiffort E, Arrang JM, et al. (May 1993). "A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation". Biochemical and Biophysical Research Communications 193 (1): 268–76. doi:10.1006/bbrc.1993.1619. PMID 8389146.
↑ 5.0 5.1 Gérard C, Martres MP, Lefèvre K, et al. (January 1997). "Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system". Brain Research 746 (1-2): 207–19. doi:10.1016/S0006-8993(96)01224-3. PMID 9037500.
↑ Hamon M, Doucet E, Lefèvre K, et al. (August 1999). "Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors". Neuropsychopharmacology 21 (2 Suppl): 68S–76S. doi:10.1016/S0893-133X(99)00044-5. PMID 10432491.
↑ Dawson LA, Nguyen HQ, Li P (May 2000). "In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate". British Journal of Pharmacology 130 (1): 23–6. doi:10.1038/sj.bjp.0703288. PMC 1572041. PMID 10780993.
↑ Dawson LA, Nguyen HQ, Li P (November 2001). "The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus". Neuropsychopharmacology 25 (5): 662–8. doi:10.1016/S0893-133X(01)00265-2. PMID 11682249.
↑ King MV, Sleight AJ, Woolley ML, Topham IA, Marsden CA, Fone KC (August 2004). "5-HT6 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. doi:10.1016/j.neuropharm.2004.03.012. PMID 15223298.
↑ 10.0 10.1 10.2 Upton N, Chuang TT, Hunter AJ, Virley DJ (July 2008). "5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease". Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 5 (3): 458–69. doi:10.1016/j.nurt.2008.05.008. PMID 18625457.
↑ 11.0 11.1 11.2 11.3 11.4 11.5 Schechter LE, Lin Q, Smith DL, et al. (May 2008). "Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466". Neuropsychopharmacology 33 (6): 1323–35. doi:10.1038/sj.npp.1301503. PMID 17625499.
↑ Lacroix LP, Dawson LA, Hagan JJ, Heidbreder CA (February 2004). "5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex". Synapse 51 (2): 158–64. doi:10.1002/syn.10288. PMID 14618683.
↑ King MV, Marsden CA, Fone KC (September 2008). "A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory". Trends in Pharmacological Sciences 29 (9): 482–92. doi:10.1016/j.tips.2008.07.001. PMID 19086256.
↑ Geldenhuys WJ, Van der Schyf CJ (2008). "Serotonin 5-HT6 receptor antagonists for the treatment of Alzheimer's disease". Current Topics in Medicinal Chemistry 8 (12): 1035–48. doi:10.2174/156802608785161420. PMID 18691131.
↑ Geldenhuys WJ, Van der Schyf CJ (July 2009). "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. doi:10.1586/ern.09.51. PMID 19589055.
↑ 16.0 16.1 Heal DJ, Smith SL, Fisas A, Codony X, Buschmann H (February 2008). "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. doi:10.1016/j.pharmthera.2007.08.006. PMID 18068807.
↑ Frassetto A, Zhang J, Lao JZ, et al. (October 2008). "Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor". Brain Research 1236: 140–4. doi:10.1016/j.brainres.2008.08.012. PMID 18755168.
↑ Carr GV, Schechter LE, Lucki I (March 2010). "Antidepressant and anxiolytic effects of selective 5-HT(6) receptor agonists in rats". Psychopharmacology 213 (2-3): 499–507. doi:10.1007/s00213-010-1798-7. PMC 2910165. PMID 20217056.
↑ Trani G, Baddeley SM, Briggs MA, Chuang TT, Deeks NJ, Johnson CN, Khazragi AA, Mead TL, Medhurst AD, Milner PH, Quinn LP, Ray AM, Rivers DA, Stean TO, Stemp G, Trail BK, Witty DR (October 2008). "Tricyclic azepine derivatives as selective brain penetrant 5-HT₆ receptor antagonists". Bioorg. Med. Chem. Lett. 18 (20): 5698–700. doi:10.1016/j.bmcl.2008.08.010. PMID 18793848.
↑ Liu KG, Lo JR, Comery TA, Zhang GM, Zhang JY, Kowal DM, Smith DL, Di L, Kerns EH, Schechter LE, Robichaud AJ (February 2009). "Identification of a series of benzoxazoles as potent 5-HT₆ ligands". Bioorg. Med. Chem. Lett. 19 (4): 1115–7. doi:10.1016/j.bmcl.2008.12.107. PMID 19152787.
↑ Lee M, Rangisetty JB, Pullagurla MR, et al (2005). "1-(1-Naphthyl)piperazine as a novel template for 5-HT6 serotonin receptor ligands". Bioorg. Med. Chem. Lett. 15 (6): 1707–11. doi:10.1016/j.bmcl.2005.01.031. PMID 15745826.
↑ Sikazwe D, Bondarev ML, Dukat M, Rangisetty JB, Roth BL, Glennon RA (2006). "Binding of sulfonyl-containing arylalkylamines at human 5-HT6 serotonin receptors". J. Med. Chem. 49 (17): 5217–25. doi:10.1021/jm060469q. PMID 16913710.
↑ Zhou P, Yan Y, Bernotas R, et al (2005). "4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands". Bioorg. Med. Chem. Lett. 15 (5): 1393–6. doi:10.1016/j.bmcl.2005.01.005. PMID 15713394.
↑ Ahmed M, Briggs MA, Bromidge SM, et al (2005). "Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists". Bioorg. Med. Chem. Lett. 15 (21): 4867–71. doi:10.1016/j.bmcl.2005.06.107. PMID 16143522.
↑ Alcalde E, Mesquida N, Frigola J, López-Pérez S, Mercè R (October 2008). "Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT₆ receptor ligands". Org. Biomol. Chem. 6 (20): 3795–810. doi:10.1039/b808641a. PMID 18843410.
↑ Mattsson C, Sonesson C, Sandahl A, Greiner HE, Gassen M, Plaschke J, Leibrock J, Böttcher H (October 2005). "2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT₆ receptor agonists". Bioorg. Med. Chem. Lett. 15 (19): 4230–4. doi:10.1016/j.bmcl.2005.06.067. PMID 16055331.
↑ Glennon RA, Lee M, Rangisetty JB, Dukat M, Roth BL, Savage JE, McBride A, Rauser L, Hufeisen S, Lee DK (2000). "2-Substituted tryptamines: agents with selectivity for 5-HT₆ serotonin receptors". J. Med. Chem. 43 (5): 1011–8. doi:10.1021/jm990550b. PMID 10715164.
↑ Cole DC, Stock JR, Lennox WJ, Bernotas RC, Ellingboe JW, Boikess S, Coupet J, Smith DL, Leung L, Zhang GM, Feng X, Kelly MF, Galante R, Huang P, Dawson LA, Marquis K, Rosenzweig-Lipson S, Beyer CE, Schechter LE (November 2007). "Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist". Journal of Medicinal Chemistry 50 (23): 5535–8. doi:10.1021/jm070521y. PMID 17948978.
↑ Alcalde E, Mesquida N, López-Pérez S, Frigola J, Mercè R (2009). "Indene-based scaffolds. 2. An indole-indene switch: discovery of novel indenylsulfonamides as 5-HT6 serotonin receptor agonists". J. Med. Chem. 52 (3): 675–87. doi:10.1021/jm8009469. PMID 19159187.
↑ Romero G, Sánchez E, Pujol M, Pérez P, Codony X, Holenz J, Buschmann H, Pauwels PJ (August 2006). "Efficacy of selective 5-HT₆ receptor ligands determined by monitoring 5-HT6 receptor-mediated cAMP signaling pathways". Br. J. Pharmacol. 148 (8): 1133–43. doi:10.1038/sj.bjp.0706827. PMC 1752021. PMID 16865095.
↑ Fisas A, Codony X, Romero G, Dordal A, Giraldo J, Mercé R, Holenz J, Vrang N, Sørensen RV, Heal D, Buschmann H, Pauwels PJ (August 2006). "Chronic 5-HT₆ receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats". Br. J. Pharmacol. 148 (7): 973–83. doi:10.1038/sj.bjp.0706807. PMC 1751931. PMID 16783408.
↑ Hugerth A, Brisander M, Wrange U, Kritikos M, Norrlind B, Svensson M, Bisrat M, Ostelius J (February 2006). "Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT₆ receptor antagonist". Drug Dev Ind Pharm 32 (2): 185–96. doi:10.1080/03639040500466122. PMID 16537199.
↑ Wu, J; Li, Q; Bezprozvanny, I (2008). "Evaluation of Dimebon in cellular model of Huntington's disease.". Molecular neurodegeneration 3: 15. doi:10.1186/1750-1326-3-15. PMC 2577671. PMID 18939977.
↑ Ivachtchenko AV, Frolov EB, Mitkin OD, Kysil VM, Khvat AV, Okun IM, Tkachenko SE (June 2009). "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. doi:10.1016/j.bmcl.2009.04.128. PMID 19443217.
↑ Liu KG, Robichaud AJ, Bernotas RC, et al. (November 2010). "5-Piperazinyl-3-sulfonylindazoles as potent and selective 5-hydroxytryptamine-6 antagonists". J. Med. Chem. 53 (21): 7639–46. doi:10.1021/jm1007825. PMID 20932009.
↑ Kan R, Wang B, Zhang C, Yang Z, Ji S, Lu Z, Zheng C, Jin F, Wang L (November 2004). "Association of the HTR6 polymorphism C267T with late-onset Alzheimer's disease in Chinese". Neurosci. Lett. 372 (1-2): 27–9. doi:10.1016/j.neulet.2004.09.007. PMID 15531082.
↑ Messina D, Annesi G, Serra P, Nicoletti G, Pasqua A, Annesi F, Tomaino C, Cirò-Candiano IC, Carrideo S, Caracciolo M, Spadafora P, Zappia M, Savettieri G, Quattrone A (12 March 2002). "Association of the 5-HT6 receptor gene polymorphism C267T with Parkinson's disease". Neurology 58 (5): 828–9. PMID 11889255.

External links

"5-HT₆". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
serotonin 6 receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

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

Cell physiology: Cell signaling / Signal transduction

Signaling pathways

Agents

Receptor ligands

Receptors

2nd messenger

cAMP-dependent pathway Ca²⁺ signaling Lipid signaling

Assistants:	Signal transducing adaptor protein Scaffold protein

Transcription factors

By distance

Other concepts

Intracrine action
Synaptic transmission (Neurocrine signaling)
Neuroendocrine signaling
Exocrine signalling
- Pheromones
Mechanotransduction
Phototransduction
Ion channel gating
Gap junction

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

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) Histamine (H1 H2 H3 H4) Melatonin (1A 1B 1C) TAAR (1 2 3 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) Lactate Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Niacin (1 2) 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) GHB receptor 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

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

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	TAS1R (1 2 3) 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)

Other	Calcium-sensing receptor GABA B (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

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

Serotonergics

5-HT₁ receptor ligands

5-HT_1A	Agonists: Azapirones: Alnespirone Binospirone Buspirone Enilospirone Eptapirone Gepirone Ipsapirone Perospirone Revospirone Tandospirone Tiospirone Umespirone Zalospirone; Antidepressants: Etoperidone Nefazodone Trazodone Vortioxetine; Antipsychotics: Aripiprazole Asenapine Clozapine Quetiapine Ziprasidone; Ergolines: Dihydroergotamine Bromocriptine Ergotamine Lisuride Methysergide LSD; Tryptamines: 5-CT 5-MeO-DMT 5-MT Bufotenin DMT Indorenate Psilocin Psilocybin; Others: 8-OH-DPAT Adatanserin Bay R 1531 Befiradol BMY-14802 Cannabidiol Dimemebfe Ebalzotan Eltoprazine F-11,461 F-12,826 F-13,714 F-14,679 F-15,063 F-15,599 Flesinoxan Flibanserin Lesopitron LY-293,284 LY-301,317 MKC-242 Naluzotan NBUMP Osemozotan Oxaflozane Pardoprunox Piclozotan Rauwolscine Repinotan Roxindole RU-24,969 S 14,506 S-14,671 S-15,535 Sarizotan SSR-181,507 Sunepitron U-92,016-A Urapidil Vilazodone Xaliproden Yohimbine Antagonists: Antipsychotics: Iloperidone Risperidone Sertindole; Beta blockers: Alprenolol Cyanopindolol Iodocyanopindolol Oxprenolol Pindobind Pindolol Propranolol Tertatolol; Others: AV965 BMY-7,378 CSP-2503 Dotarizine Flopropione GR-46611 Isamoltane Lecozotan Mefway Metitepine/Methiothepin MPPF NAN-190 Robalzotan S-15535 SB-649,915 SDZ 216-525 Spiperone Spiramide Spiroxatrine UH-301 WAY-100,135 WAY-100,635 Xylamidine

5-HT_1B	Agonists: Lysergamides: Dihydroergotamine Ergotamine Methysergide; Piperazines: Eltoprazine TFMPP; Triptans: Avitriptan Eletriptan Sumatriptan Zolmitriptan; Tryptamines: 5-CT 5-MT; Others: CGS-12066A Bromocriptine CP-93,129 CP-94,253 CP-135,807 RU-24,969 Vortioxetine Antagonists: Lysergamides: Metergoline; Others: AR-A000002 Elzasonan GR-127,935 Isamoltane Metitepine/Methiothepin SB-216,641 SB-224,289 SB-236,057 Yohimbine

5-HT_1D	Agonists: Lysergamides: Dihydroergotamine Methysergide; Triptans: Almotriptan Avitriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan; Tryptamines: 5-CT 5-Ethyl-DMT 5-MT 5-(Nonyloxy)tryptamine; Others: CP-135,807 Bromocriptine CP-286,601 GR-46611 L-694,247 L-772,405 PNU-109,291 PNU-142633 Antagonists: Lysergamides: Metergoline; Others: Alniditan BRL-15,572 Elzasonan GR-127,935 Ketanserin LY-310,762 LY-367,642 LY-456,219 LY-456,220 Metitepine/Methiothepin Ritanserin Yohimbine Ziprasidone

5-HT_1E	Agonists: Lysergamides: Methysergide; Triptans: Eletriptan; Tryptamines: BRL-54443 Tryptamine Antagonists: Metitepine/Methiothepin

5-HT_1F	Agonists: Triptans: Eletriptan Naratriptan Sumatriptan; Tryptamines: 5-MT; Others: BRL-54443 Bromocriptine Lasmiditan LY-334,370 Antagonists: Metitepine/Methiothepin

5-HT₂ receptor ligands

5-HT_2A	Agonists: Lysergamides: ALD-52 Ergometrine Lisuride LA-SS-Az LSD LSD-Pip Lysergic acid 2-butyl amide Lysergic acid 3-pentyl amide Methysergide; Phenethylamines: 25I-NBF 25I-NBMD 25I-NBOH 25I-NBOMe 2C-B 2C-B-FLY 2CB-Ind 25B-NBOMe 25C-NBOMe 2C-E 2C-I 25TFM-NBOMe 2C-T-2 2C-T-7 2C-T-21 2CBCB-NBOMe 2CBFly-NBOMe Juncosamine Bromo-DragonFLY DOB DOC DOI DOM MDA MDMA Mescaline 25CN-NBOH TCB-2 TFMFly; Piperazines: BZP Quipazine TFMPP; Tryptamines: 5-CT 5-MeO-α-ET 5-MeO-α-MT 5-MeO-DET 5-MeO-DiPT 5-MeO-DMT 5-MeO-DPT 5-MT α-ET α-Methyl-5-HT α-MT Bufotenin DET DiPT DMT DPT Psilocin Psilocybin; Others: AL-34662 AL-37350A Bromocriptine Dimemebfe Medifoxamine O-4310 Oxaflozane PHA-57378 PNU-22394 PNU-181731 RH-34 Antagonists: Atypical antipsychotics: Amperozide Aripiprazole Blonanserin Carpipramine Clocapramine Clorotepine Clozapine Gevotroline Iloperidone Melperone Mosapramine Olanzapine Paliperidone Quetiapine Risperidone Sertindole Zicronapine Ziprasidone Zotepine; Typical antipsychotics: Loxapine Pipamperone; Antidepressants: Amitriptyline Amoxapine Aptazapine Etoperidone Mianserin Mirtazapine Nefazodone Pimozide Teniloxazine Trazodone; Others: 5-I-R91150 5-MeO-NBpBrT AC-90179 Adatanserin Altanserin AMDA APD-215 Cinanserin CSP-2503 Cyproheptadine Deramciclane Dotarizine Eplivanserin Esmirtazapine Fananserin Flibanserin Glemanserin Ketanserin KML-010 Lubazodone Mepiprazole Metitepine/Methiothepin Nantenine Pimavanserin Pizotifen Pruvanserin Rauwolscine Ritanserin S-14,671 Sarpogrelate Setoperone Spiperone Spiramide SR-46349B Volinanserin Xylamidine Yohimbine

5-HT_2B	Agonists: Oxazolines: 4-Methylaminorex Aminorex; Phenethylamines: Chlorphentermine Cloforex DOB DOC DOI DOM Fenfluramine (Dexfenfluramine, Levofenfluramine) MDA MDMA Norfenfluramine; Tryptamines: 5-CT 5-MT α-Methyl-5-HT; Others: BW-723C86 Bromocriptine Cabergoline mCPP Pergolide PNU-22394 Ro60-0175 Antagonists: Agomelatine Asenapine EGIS-7625 Ketanserin Lisuride LY-272,015 Metitepine/Methiothepin PRX-08066 Rauwolscine Ritanserin RS-127,445 Sarpogrelate SB-200,646 SB-204,741 SB-206,553 SB-215,505 SB-221,284 SB-228,357 SDZ SER-082 Tegaserod Yohimbine

5-HT_2C	Agonists: Phenethylamines: 2C-B 2C-E 2C-I 2C-T-2 2C-T-7 2C-T-21 DOB DOC DOI DOM MDA MDMA Mescaline; Piperazines: Aripiprazole mCPP TFMPP; Tryptamines: 5-CT 5-MeO-α-ET 5-MeO-α-MT 5-MeO-DET 5-MeO-DiPT 5-MeO-DMT 5-MeO-DPT 5-MT α-ET α-Methyl-5-HT α-MT Bufotenin DET DiPT DMT DPT Psilocin Psilocybin; Others: A-372,159 AL-38022A Alstonine Bromocriptine CP-809,101 Dimemebfe Lorcaserin Medifoxamine MK-212 Org 12,962 ORG-37,684 Oxaflozane PHA-57378 PNU-22394 PNU-181731 Ro60-0175 Ro60-0213 Vabicaserin WAY-629 WAY-161,503 YM-348 Antagonists: Atypical antipsychotics: Clorotepine Clozapine Iloperidone Melperone Olanzapine Paliperidone Quetiapine Risperidone Sertindole Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine Pimozide Pipamperone; Antidepressants: Agomelatine Amitriptyline Amoxapine Aptazapine Etoperidone Fluoxetine Mianserin Mirtazapine Nefazodone Nortriptyline Tedatioxetine Trazodone; Others: Adatanserin CEPC Cinanserin Cyproheptadine Deramciclane Dotarizine Eltoprazine Esmirtazapine FR-260,010 Ketanserin Ketotifen Latrepirdine Metitepine/Methiothepin Methysergide Pizotifen Ritanserin RS-102,221 S-14,671 SB-200,646 SB-206,553 SB-221,284 SB-228,357 SB-242,084 SB-243,213 SDZ SER-082 Xylamidine

5-HT₃	Agonists: Piperazines: BZP Quipazine; Tryptamines: 2-Methyl-5-HT 5-CT; Others: Chlorophenylbiguanide Butanol Ethanol Halothane Isoflurane RS-56812 SR-57,227 SR-57,227-A Toluene Trichloroethane Trichloroethanol Trichloroethylene YM-31636 Antagonists: Antiemetics: AS-8112 Alosetron Azasetron Batanopride Bemesetron Cilansetron Dazopride Dolasetron Galanolactone Granisetron Lerisetron Ondansetron Palonosetron Ramosetron Renzapride Tropisetron Zacopride Zatosetron; Atypical antipsychotics: Clozapine Olanzapine Quetiapine; Tetracyclic antidepressants: Amoxapine Mianserin Mirtazapine; Others: CSP-2503 ICS-205,930 MDL-72,222 Memantine Nitrous Oxide Ricasetron Sevoflurane Tedatioxetine Thujone Tropanserin Vortioxetine Xenon

5-HT₄	Agonists: Gastroprokinetic Agents: Cinitapride Cisapride Dazopride Metoclopramide Mosapride Prucalopride Renzapride Tegaserod Velusetrag Zacopride; Others: 5-MT BIMU8 CJ-033,466 PRX-03140 RS-67333 RS-67506 SL65.0155 Antagonists: GR-113,808 GR-125,487 L-Lysine Piboserod RS-39604 RS-67532 SB-203,186 SB-204,070

5-HT_5A	Agonists: Lysergamides: Ergotamine LSD; Tryptamines: 5-CT; Others: Valerenic Acid Antagonists: Asenapine Latrepirdine Metitepine/Methiothepin Ritanserin SB-699,551 * Note that the 5-HT_5B receptor is not functional in humans.

5-HT₆	Agonists: Lysergamides: Dihydroergotamine Ergotamine Lisuride LSD Mesulergine Metergoline Methysergide; Tryptamines: 2-Methyl-5-HT 5-BT 5-CT 5-MT Bufotenin E-6801 E-6837 EMD-386,088 EMDT LY-586,713 N-Methyl-5-HT Tryptamine; Others: WAY-181,187 WAY-208,466 Antagonists: Antidepressants: Amitriptyline Amoxapine Clomipramine Doxepin Mianserin Nortriptyline; Atypical antipsychotics: Aripiprazole Asenapine Clorotepine Clozapine Fluperlapine Iloperidone Olanzapine Tiospirone; Typical antipsychotics: Chlorpromazine Loxapine; Others: BGC20-760 BVT-5182 BVT-74316 Cerlapirdine EGIS-12,233 GW-742,457 Ketanserin Latrepirdine Lu AE58054 Metitepine/Methiothepin MS-245 PRX-07034 Ritanserin Ro04-6790 Ro 63-0563 SB-258,585 SB-271,046 SB-357,134 SB-399,885 SB-742,457

5-HT₇	Agonists: Lysergamides: LSD; Tryptamines: 5-CT 5-MT Bufotenin; Others: 8-OH-DPAT AS-19 Bifeprunox E-55888 LP-12 LP-44 RU-24,969 Sarizotan Antagonists: Lysergamides: 2-Bromo-LSD Bromocriptine Dihydroergotamine Ergotamine Mesulergine Metergoline Methysergide; Antidepressants: Amitriptyline Amoxapine Clomipramine Imipramine Maprotiline Mianserin; Atypical antipsychotics: Amisulpride Aripiprazole Asenapine Clorotepine Clozapine Olanzapine Risperidone Sertindole Tiospirone Ziprasidone Zotepine; Typical antipsychotics: Chlorpromazine Loxapine; Pimozide; Others: Butaclamol EGIS-12,233 Ketanserin LY-215,840 Metitepine/Methiothepin Ritanserin SB-258,719 SB-258,741 SB-269,970 SB-656,104 SB-656,104-A SB-691,673 SLV-313 SLV-314 Spiperone SSR-181,507 Vortioxetine

Reuptake inhibitors

SERT	Selective serotonin reuptake inhibitors (SSRIs): Alaproclate Citalopram Dapoxetine Desmethylcitalopram Desmethylsertraline Escitalopram Femoxetine Fluoxetine Fluvoxamine Indalpine Ifoxetine Litoxetine Lubazodone Omiloxetine Panuramine Paroxetine Pirandamine RTI-353 Seproxetine Sertraline Vilazodone Vortioxetine Zimelidine; Serotonin-norepinephrine reuptake inhibitors (SNRIs): Bicifadine Desvenlafaxine Duloxetine Eclanamine Levomilnacipran Milnacipran Sibutramine Venlafaxine; Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs): Brasofensine Diclofensine DOV-102,677 DOV-21,947 DOV-216,303 NS-2359 SEP-225289 SEP-227,162 Tedatioxetine Tesofensine; Tricyclic antidepressants (TCAs): Amitriptyline Butriptyline Cianopramine Clomipramine Desipramine Dosulepin Doxepin Imipramine Lofepramine Nortriptyline Pipofezine Protriptyline Trimipramine; Tetracyclic antidepressants (TeCAs): Amoxapine; Piperazines: Nefazodone Trazodone; Antihistamines: Brompheniramine Chlorphenamine Diphenhydramine Mepyramine/Pyrilamine Pheniramine Tripelennamine; Opioids: Pethidine Methadone Propoxyphene; Others: Cocaine CP-39,332 Cyclobenzaprine Dextromethorphan Dextrorphan EXP-561 Fezolamine Mesembrine Nefopam PIM-35 Pridefine Roxindole SB-649,915 Tofenacin Ziprasidone

VMAT	Ibogaine Reserpine Tetrabenazine

Releasing agents

Aminoindanes: 5-IAI
AMMI
ETAI
MDAI
MDMAI
MMAI
TAI; Aminotetralins: 6-CAT
8-OH-DPAT
MDAT
MDMAT; Oxazolines: 4-Methylaminorex
Aminorex
Clominorex
Fluminorex; Phenethylamines (also Amphetamines, Cathinones, Phentermines, etc): 2-Methyl-MDA
4-CAB
4-FA
4-FMA
4-HA
4-MTA
5-APDB
5-Methyl-MDA
6-APDB
6-Methyl-MDA
AEMMA
Amiflamine
BDB
BOH
Brephedrone
Butylone
Chlorphentermine
Cloforex
Amfepramone
Metamfepramone
DCA
DFMDA
DMA
DMMA
EBDB
EDMA
Ethylone
Etolorex
Fenfluramine (Dexfenfluramine, Levofenfluramine)
Flephedrone
IAP
IMP
Iofetamine
Lophophine
MBDB
MDA
MDEA
MDHMA
MDMA
MDMPEA
MDOH
MDPEA
Mephedrone
Methedrone
Methylone
MMA
MMDA
MMDMA
MMMA
NAP
Norfenfluramine
4-TFMA
pBA
pCA
pIA
PMA
PMEA
PMMA
TAP; Piperazines: 2C-B-BZP
3-MeOPP
BZP
DCPP
MBZP
mCPP
MDBZP
MeOPP
Mepiprazole
pCPP
pFPP
pTFMPP
TFMPP; Tryptamines: 4-Methyl-αET
4-Methyl-αMT
5-CT
5-MeO-αET
5-MeO-αMT
5-MT
αET
αMT
DMT
Tryptamine (itself); Others: Indeloxazine
Tramadol
Viqualine

Enzyme inhibitors

Anabolism

TPH	AGN-2979 Fenclonine

AAAD	Benserazide Carbidopa Genistein Methyldopa

Catabolism

MAO

Nonselective: Benmoxin
Caroxazone
Echinopsidine
Furazolidone
Hydralazine
Indantadol
Iproclozide
Iproniazid
Isocarboxazid
Isoniazid
Linezolid
Mebanazine
Metfendrazine
Nialamide
Octamoxin
Paraxazone
Phenelzine
Pheniprazine
Phenoxypropazine
Pivalylbenzhydrazine
Procarbazine
Safrazine
Tranylcypromine; MAO-A Selective: Amiflamine
Bazinaprine
Befloxatone
Brofaromine
Cimoxatone
Clorgiline
Eprobemide
Esuprone
Harmala alkaloids (Harmine
Harmaline
Tetrahydroharmine
Harman
Norharman, etc)
Methylene Blue
Metralindole
Minaprine
Moclobemide
Pirlindole
Sercloremine
Tetrindole
Toloxatone
Tyrima

Others

Precursors	L-Tryptophan → 5-HTP

Cofactors	Ferrous iron (Fe²⁺) Magnesium (Mg²⁺) Tetrahydrobiopterin Vitamin B₃ (Niacin Nicotinamide → NADPH) Vitamin B₆ (Pyridoxine Pyridoxamine Pyridoxal → Pyridoxal phosphate) Vitamin B₉ (Folic Acid → Tetrahydrofolic acid) Vitamin C (Ascorbic acid) Zinc (Zn²⁺)

Others	Activity enhancers: BPAP * PPAP; Reuptake enhancers: Tianeptine; Steroids: Anabolic-androgenic steroids

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