Heterocyclic compound containing a ring of four carbon, one nitrogen and one sulfur atom
Phenothiazine Names Preferred IUPAC name Other names Thiodiphenylamine Dibenzothiazine Dibenzoparathiazine 10H -dibenzo-[b ,e ]-1,4-thiazine PTZ
Identifiers 143237 ChEBI ChEMBL ChemSpider ECHA InfoCard 100.001.997 EC Number KEGG RTECS number UNII InChI=1S/C12H9NS/c1-3-7-11-9(5-1)13-10-6-2-4-8-12(10)14-11/h1-8,13H
Y Key: WJFKNYWRSNBZNX-UHFFFAOYSA-N
Y InChI=1/C12H9NS/c1-3-7-11-9(5-1)13-10-6-2-4-8-12(10)14-11/h1-8,13H
Key: WJFKNYWRSNBZNX-UHFFFAOYAI
Properties C12 H9 NS Molar mass 199.27 g/mol Appearance greenish-yellow rhombic leaflets or diamond-shaped plates Melting point 185 °C (365 °F; 458 K) Boiling point 371 °C (700 °F; 644 K) 0.00051 g/L (20 °C)[ 2] Solubility in other solvents benzene , ether , petroleum ether , chloroform , hot acetic acid , ethanol (slightly), mineral oil (slightly) Acidity (pK a ) approx 23 in DMSO −114.8·10−6 cm3 /mol Hazards GHS labelling : Warning H302 , H317 , H373 , H412 P260 , P261 , P264 , P270 , P272 , P273 , P280 , P301+P312 , P302+P352 , P314 , P321 , P330 , P333+P313 , P363 , P501 NIOSH (US health exposure limits): none[ 3] TWA 5 mg/m3 [skin] N.D.[ 3] Pharmacology QP52AX03 (WHO ) Except where otherwise noted, data are given for materials in their
standard state (at 25 °C [77 °F], 100 kPa).
Chemical compound
Phenothiazine , abbreviated PTZ , is an organic compound that has the formula S(C6 H4 )2 NH and is related to the thiazine -class of heterocyclic compounds . Derivatives of phenothiazine are highly bioactive and have widespread use and rich history.
The derivatives chlorpromazine and promethazine revolutionized the fields of psychiatry and allergy treatment, respectively. An earlier derivative, methylene blue , was one of the first antimalarial drugs , and derivatives of phenothiazine are currently under investigation as possible anti-infective drugs. Phenothiazine is a prototypical pharmaceutical lead structure in medicinal chemistry .
Phenothiazine itself is only of theoretical interest, but derivatives of it revolutionized psychiatry, other fields of medicine, and pest management. Other derivatives have been studied for possible use in advanced batteries and fuel cells.[ 4]
Phenothiazine-derived drugs [ edit ] In 1876, methylene blue , a derivative of phenothiazine, was synthesized by Heinrich Caro at BASF . The structure was deduced in 1885 by Heinrich August Bernthsen. Bernthsen synthesized phenothiazine in 1883.[ 4] In the mid 1880s, Paul Ehrlich began to use methylene blue in his cell staining experiments that led to pioneering discoveries about different cell types. He was awarded a Nobel Prize based in part on that work. He became particularly interested in its use to stain bacteria and parasites such as Plasmodiidae – the genus that includes the malaria pathogen – and found that it could be stained with methylene blue. He thought methylene blue could possibly be used in the treatment of malaria, tested it clinically, and by the 1890s methylene blue was being used for that purpose.[ 4]
For the next several decades, research on derivatives lapsed until phenothiazine itself came to market as an insecticide and deworming drug. In the 1940s, chemists working with Paul Charpentier at Rhone-Poulenc Laboratories in Paris (a precursor company to Sanofi ), began making derivatives. This work led to promethazine which had no activity against infective organisms, but did have good antihistamine activity, with a strong sedative effect. It went to market as a drug for allergies and for anesthesia . As of 2012 it was still on the market.[ 4] At the end of the 1940s the same lab produced chlorpromazine which had an even stronger sedative and soothing effect, and Jean Delay and Pierre Deniker attempted to use it on their psychiatric patients, publishing their results in the early 1950s. The strong effects they found opened the door of the modern field of psychiatry and led to a proliferation of work on phenothiazine derivatives.[ 4] The systematic research conducted by chemists to explore phenothiazine derivatives and their activity was a pioneering example of medicinal chemistry ; phenothiazine is often discussed as a prototypical example of a pharmaceutical lead structure .[ 4] [ 5]
A number of phenothiazines other than methylene blue have been shown to have antimicrobial effects. In particular, thioridazine has been shown to make extensively drug-resistant tuberculosis (XDR-TB) drug-susceptible again[ 6] [ 7] and make methicillin-resistant Staphylococcus aureus (MRSA) susceptible to beta-lactam antibiotics.[ 7] [ 8] The major reason why thioridazine has not been utilized as an antimicrobial agent is due to adverse effects on the central nervous system and cardiovascular system (particularly QT interval prolongation).[ 7]
The term "phenothiazines" describes the largest of the five main classes of antipsychotic drugs . These drugs have antipsychotic and, often, antiemetic properties, although they may also cause severe side effects such as extrapyramidal symptoms (including akathisia and tardive dyskinesia ), hyperprolactinaemia , and the rare but potentially fatal neuroleptic malignant syndrome , as well as substantial weight gain.[ 4] Use of phenothiazines has been associated with antiphospholipid syndrome , but no causal relationship has been established.[ 9]
Phenothiazine antipsychotics are classified into three groups that differ with respect to the substituent on nitrogen: the aliphatic compounds (bearing acyclic groups), the "piperidines" (bearing piperidine -derived groups), and the piperazine (bearing piperazine -derived substituents).[ 5]
Group Anticholinergic Example Sedation Extrapyramidal side effects Aliphatic compounds moderate Chlorpromazine (marketed as Thorazine, Aminazine, Chlor-PZ, Klorazine, Promachlor, Promapar, Sonazine, Chlorprom, Chlor-Promanyl, Largactil) strong moderate Promazine (trade name Sparine, Propazine) moderate moderate Triflupromazine (trade names Clinazine, Novaflurazine, Pentazine, Terfluzine, Triflurin, Vesprin) strong moderate/strong Levomepromazine in Germany, Russia, most American countries (e.g., Brazil) and methotrimeprazine in USA (trade names Nozinan, Levoprome, Tisercin) extremely strong low Piperidines strong Mesoridazine (trade name Serentil) strong weak Thioridazine (trade names Mellaril, Novoridazine, Thioril, Sonapax) strong weak Piperazines weak Fluphenazine (trade names Prolixin, Permitil, Modecate, Moditen) weak/moderate strong Perphenazine (sold as Trilafon, Etrafon, Triavil, Phenazine, Etaperazin) weak/moderate strong Prochlorperazine (trade names Compazine, Stemetil) Trifluoperazine (trade name Stelazine, Triphtazine) moderate strong
Nondrug applications [ edit ] The synthetic dye methylene blue , containing the structure, was described in 1876. Many water-soluble phenothiazine derivatives, such as methylene blue , methylene green , thionine , and others, can be electropolymerized into conductive polymers used as electrocatalysts for NADH oxidation in enzymatic biosensors and biofuel cells.[ 10] [ 11] [ 12]
Phenothiazine is used as an anaerobic inhibitor for acrylic acid polymerization, often used as an in-process inhibitor during the purification of acrylic acid.[ 13]
Like many commercially significant compounds, phenothiazine has numerous trade names, including AFI-Tiazin, Agrazine, Antiverm, Biverm, Dibenzothiazine, Orimon, Lethelmin, Souframine, Nemazene, Vermitin, Padophene, Fenoverm, Fentiazine, Contaverm, Fenothiazine, Phenovarm, Ieeno, ENT 38, Helmetina, Helmetine, Penthazine, XL-50, Wurm-thional, Phenegic, Phenovis, Phenoxur, and Reconox.[ 14]
Phenothiazine was formerly used as an insecticide and as a drug to treat infections with parasitic worms (anthelminthic ) in livestock and people, but its use for those purposes has been superseded by other chemicals.
Phenothiazine was introduced by DuPont as an insecticide in 1935.[ 15] About 3,500,000 pounds were sold in the US in 1944.[ 16] However, because it was degraded by sunlight and air, it was difficult to determine how much to use in the field, and its use waned in the 1940s with the arrival of new pesticides like DDT that were more durable.[ 17] : 161–162 As of July 2015 it is not registered for pesticide use in the US, Europe,[ 18] or Australia.[ 19]
It was introduced as anthelminthic in livestock in 1940 and is considered, with thiabendazole , to be the first modern anthelminthic.[ 20] The first instances of resistance were noted in 1961.[ 20] Among anthelmintics, Blizzard et al. 1990 found only paraherquamide to have similar activity to phenothiazine. It is possible that they share the same mode of action .[ 21] Uses for this purpose in the US are still described[ 22] but it has "virtually disappeared from the market."[ 23] : 369
In the 1940s it also was introduced as antihelminthic for humans; since it was often given to children, the drug was often sold in chocolate, leading to the popular name, "worm chocolate." Phenothiazine was superseded by other drugs in the 1950s.[ 4]
Structure and synthesis [ edit ] The central C4 SN ring is folded in phenothiazines.[ 24]
The compound was originally prepared by Bernthsen in 1883 via the reaction of diphenylamine with sulfur, but more recent syntheses rely on the cyclization of 2-substituted diphenyl sulfides. Few pharmaceutically significant phenothiazines are prepared from phenothiazine,[ 25] although some of them are.[ 26]
Phenothiazines are electron donors, forming charge-transfer salts with many acceptors.
^ "Front Matter". Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book) . Cambridge: The Royal Society of Chemistry . 2014. p. 216. doi :10.1039/9781849733069-FP001 (inactive 2024-05-14). ISBN 978-0-85404-182-4 . {{cite book }}
: CS1 maint: DOI inactive as of May 2024 (link ) ^ "Sigma-Aldrich catalog of Phenothiazine" . Retrieved 2022-02-28 . ^ a b NIOSH Pocket Guide to Chemical Hazards. "#0494" . National Institute for Occupational Safety and Health (NIOSH). ^ a b c d e f g h M. J. Ohlow; B. Moosmann (2011). "Phenothiazine: the seven lives of pharmacology's first lead structure". Drug Discov. Today . 16 (3–4): 119–31. doi :10.1016/j.drudis.2011.01.001 . PMID 21237283 . ^ a b Jaszczyszyn, A; et al. (2012). "Chemical structure of phenothiazines and their biological activity" (PDF) . Pharmacol. Rep . 64 (1): 16–23. doi :10.1016/s1734-1140(12)70726-0 . PMID 22580516 . ^ Amaral, L; Viveiros, M (May 2012). "Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections". International Journal of Antimicrobial Agents . 39 (5): 376–380. doi :10.1016/j.ijantimicag.2012.01.012 . PMID 22445204 . ^ a b c Thanacoody, HKR (November 2007). "Thioridazine: resurrection as an antimicrobial agent?" . British Journal of Clinical Pharmacology . 64 (5): 566–574. doi :10.1111/j.1365-2125.2007.03021.x . PMC 2203271 . PMID 17764469 . ^ Thorsing, M; Klitgaard, JK; Atilano, ML; Skov, MN; Kolmos, HJ; Filipe, SR; Kallipolitis, BH (May 2013). "Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300" . PLOS ONE . 8 (5): e64518. Bibcode :2013PLoSO...864518T . doi :10.1371/journal.pone.0064518 . PMC 3656896 . PMID 23691239 . ^ "Antiphospholipid Syndrome - Doctor's Information | Patient" . Patient . Retrieved 2015-07-25 . ^ Chi, Qijin; Dong, Shaojun (1994-01-20). "Electrocatalytic oxidation of reduced nicotinamide coenzymes at Methylene Green-modified electrodes and fabrication of amperometric alcohol biosensors". Analytica Chimica Acta . 285 (1–2): 125–133. Bibcode :1994AcAC..285..125C . doi :10.1016/0003-2670(94)85016-X . ^ Karyakin, Arkady A.; Karyakina, Elena E.; Schuhmann, Wolfgang; Schmidt, Hanns-Ludwig (1999). "Electropolymerized Azines: Part II. In a Search of the Best Electrocatalyst of NADH Oxidation". Electroanalysis . 11 (8): 553–557. doi :10.1002/(SICI)1521-4109(199906)11:8<553::AID-ELAN553>3.0.CO;2-6 . ^ Sokic-Lazic, Daria; Minteer, Shelley D. (December 2008). "Citric acid cycle biomimic on a carbon electrode". Biosensors and Bioelectronics . 24 (4): 939–944. doi :10.1016/j.bios.2008.07.043 . PMID 18774285 . ^ Levy, Leon B. (1992-03-30). "Inhibition of acrylic acid polymerization by phenothiazine and p-methoxyphenol. II. Catalytic inhibition by phenothiazine". Journal of Polymer Science Part A: Polymer Chemistry . 30 (4): 569–576. Bibcode :1992JPoSA..30..569L . doi :10.1002/pola.1992.080300407 . ^ "U.S. Department of Labor Occupational Safety & Health Administration Chemical Sampling Information Phenothiazine" . Archived from the original on 2007-08-08. Retrieved 2007-07-06 . ^ History of Insecticides and Control Equipment Clemson University Pesticide Information Program. ^ Robert Lee Metcalf. The Mode of Action of Organic Insecticides, Issues 1-5. National Academies, 1948, page 44 ^ G. Matolcsy, M. Nádasy, V. Andriska. Studies in Environmental Science: Pesticide Chemistry. Elsevier, 1989 ISBN 9780080874913 ^ ECHA phenothiazine at the European Chemicals Authority [permanent dead link ] Page accessed July 26, 2015. Note - Registered uses are only in manufacturing. ^ Australian Pesticides and Veterinary Medicine Authority Phenothiazine Chemical Review Page accessed July 26, 2015 ^ a b Nielsen, MK; et al. (Jul 2014). "Anthelmintic resistance in equine parasites--current evidence and knowledge gaps". Vet Parasitol . 204 (1–2): 55–63. doi :10.1016/j.vetpar.2013.11.030 . PMID 24433852 . ^ Monaghan, Richard L.; Tkacz, Jan S. (1990). "Bioactive Microbial Products: Focus upon Mechanism of Action". Annual Review of Microbiology . 44 (1). Annual Reviews : 271–331. doi :10.1146/annurev.mi.44.100190.001415 . ISSN 0066-4227 . PMID 2252385 . ^ The Texas A&M University System; Texas AgriLife Extension Service Integrated pest management of flies in Texas dairies Archived 2014-08-11 at the Wayback Machine ^ Heinz Mehlhorn, Philip M. Armstrong. Encyclopedic Reference of Parasitology: Diseases, Treatment, Therapy, Volume 2. Springer Science & Business Media, 2001 ISBN 9783540668299 ^ J. J. H. McDowell (1976). "The crystal and molecular structure of phenothiazine". Acta Crystallographica Section B . 32 (1): 5. Bibcode :1976AcCrB..32....5M . doi :10.1107/S0567740876002215 . ^ Gérard Taurand, "Phenothiazine and Derivatives" in Ullmann's Encyclopedia of Industrial Chemistry , Wiley-VCH, Weinheim, 2005.doi :10.1002/14356007.a19_387 ^ T. Kahl, K.-W. Schröder, F. R. Lawrence, W. J. Marshall, Hartmut Höke, Rudolf Jäckh, "Aniline" in Ullmann's Encyclopedia of Industrial Chemistry , 2005, Wiley-VCH: Weinheim.
α1
Agonists Antagonists Abanoquil Ajmalicine Alfuzosin Anisodamine Anisodine Atiprosin Atypical antipsychotics (e.g., brexpiprazole , clozapine , olanzapine , quetiapine , risperidone ) Benoxathian Beta blockers (e.g., adimolol , amosulalol , arotinolol , carvedilol , eugenodilol , labetalol ) Buflomedil Bunazosin Corynanthine Dapiprazole Domesticine Doxazosin Ergolines (e.g., acetergamine , ergotamine , dihydroergotamine , lisuride , nicergoline , terguride ) Etoperidone Fenspiride Hydroxyzine Indoramin Ketanserin L-765,314 mCPP Mepiprazole Metazosin Monatepil Moxisylyte Naftopidil Nantenine Neldazosin Niaprazine Niguldipine Pardoprunox Pelanserin Perlapine Phendioxan Phenoxybenzamine Phentolamine Phenylpiperazine antidepressants (e.g., hydroxynefazodone , nefazodone , trazodone , triazoledione ) Piperoxan Prazosin Quinazosin Quinidine Silodosin Spegatrine Spiperone Talipexole Tamsulosin Terazosin Tiodazosin Tolazoline Tetracyclic antidepressants (e.g., amoxapine , maprotiline , mianserin ) Tricyclic antidepressants (e.g., amitriptyline , clomipramine , doxepin , imipramine , trimipramine ) Trimazosin Typical antipsychotics (e.g., chlorpromazine , fluphenazine , loxapine , thioridazine ) Urapidil WB-4101 Zolertine
α2
Agonists Antagonists 1-PP Adimolol Amesergide Aptazapine Atipamezole Atypical antipsychotics (e.g., asenapine , brexpiprazole , clozapine , lurasidone , olanzapine , paliperidone , quetiapine , risperidone , zotepine ) Azapirones (e.g., buspirone , gepirone , ipsapirone , tandospirone ) BRL-44408 Buflomedil Cirazoline Efaroxan Esmirtazapine Fenmetozole Fluparoxan Idazoxan Ketanserin Lisuride mCPP Mianserin Mirtazapine NAN-190 Pardoprunox Phentolamine Phenoxybenzamine Piperoxan Piribedil Rauwolscine Rotigotine Setiptiline Spegatrine Spiroxatrine Sunepitron Terguride Tolazoline Typical antipsychotics (e.g., chlorpromazine , fluphenazine , loxapine , thioridazine ) Yohimbine
β
mAChRs Tooltip Muscarinic acetylcholine receptors
Agonists Antagonists 3-Quinuclidinyl benzilate 4-DAMP Aclidinium bromide (+formoterol ) Abediterol AF-DX 250 AF-DX 384 Ambutonium bromide Anisodamine Anisodine Antihistamines (first-generation) (e.g., brompheniramine , buclizine , captodiame , chlorphenamine (chlorpheniramine) , cinnarizine , clemastine , cyproheptadine , dimenhydrinate , dimetindene , diphenhydramine , doxylamine , meclizine , mequitazine , perlapine , phenindamine , pheniramine , phenyltoloxamine , promethazine , propiomazine , triprolidine ) AQ-RA 741 Atropine Atropine methonitrate Atypical antipsychotics (e.g., clozapine , fluperlapine , olanzapine (+fluoxetine ), rilapine , quetiapine , tenilapine , zotepine ) Benactyzine Benzatropine (benztropine) Benzilone Benzilylcholine mustard Benzydamine Bevonium BIBN 99 Biperiden Bornaprine Camylofin CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 Caramiphen Cimetropium bromide Clidinium bromide Cloperastine CS-27349 Cyclobenzaprine Cyclopentolate Darifenacin DAU-5884 Desfesoterodine Dexetimide DIBD Dicycloverine (dicyclomine) Dihexyverine Difemerine Diphemanil metilsulfate Ditran Drofenine EA-3167 EA-3443 EA-3580 EA-3834 Emepronium bromide Etanautine Etybenzatropine (ethybenztropine) Fenpiverinium Fentonium bromide Fesoterodine Flavoxate Glycopyrronium bromide (+beclometasone/formoterol , +indacaterol , +neostigmine ) Hexahydrodifenidol Hexahydrosiladifenidol Hexbutinol Hexocyclium Himbacine HL-031,120 Homatropine Imidafenacin Ipratropium bromide (+salbutamol ) Isopropamide J-104,129 Hyoscyamine Mamba toxin 3 Mamba toxin 7 Mazaticol Mebeverine Meladrazine Mepenzolate Methantheline Methoctramine Methylatropine Methylhomatropine Methylscopolamine Metixene Muscarinic toxin 7 N-Ethyl-3-piperidyl benzilate N-Methyl-3-piperidyl benzilate Nefopam Octatropine methylbromide (anisotropine methylbromide) Orphenadrine Otenzepad (AF-DX 116) Otilonium bromide Oxapium iodide Oxitropium bromide Oxybutynin Oxyphencyclimine Oxyphenonium bromide PBID PD-102,807 PD-0298029 Penthienate Pethidine pFHHSiD Phenglutarimide Phenyltoloxamine Pipenzolate bromide Piperidolate Pirenzepine Piroheptine Pizotifen Poldine Pridinol Prifinium bromide Procyclidine Profenamine (ethopropazine) Propantheline bromide Propiverine Quinidine 3-Quinuclidinyl thiochromane-4-carboxylate Revefenacin Rociverine RU-47,213 SCH-57,790 SCH-72,788 SCH-217,443 Scopolamine (hyoscine) Scopolamine butylbromide (hyoscine butylbromide) Silahexacyclium Sofpironium bromide Solifenacin SSRIs Tooltip Selective serotonin reuptake inhibitors (e.g., femoxetine , paroxetine ) Telenzepine Terodiline Tetracyclic antidepressants (e.g., amoxapine , maprotiline , mianserin , mirtazapine ) Tiemonium iodide Timepidium bromide Tiotropium bromide Tiquizium bromide Tofenacin Tolterodine Tricyclic antidepressants (e.g., amitriptyline (+perphenazine ), amitriptylinoxide , butriptyline , cidoxepin , clomipramine , desipramine , desmethyldesipramine , dibenzepin , dosulepin (dothiepin) , doxepin , imipramine , lofepramine , nitroxazepine , northiaden (desmethyldosulepin) , nortriptyline , protriptyline , quinupramine , trimipramine ) Tridihexethyl Trihexyphenidyl Trimebutine Tripitamine (tripitramine) Tropacine Tropatepine Tropicamide Trospium chloride Typical antipsychotics (e.g., chlorpromazine , chlorprothixene , cyamemazine (cyamepromazine) , loxapine , mesoridazine , thioridazine ) Umeclidinium bromide (+vilanterol ) WIN-2299 Xanomeline Zamifenacin
Precursors (and prodrugs )
nAChRs Tooltip Nicotinic acetylcholine receptors
Agonists (and PAMs Tooltip positive allosteric modulators ) 5-HIAA 6-Chloronicotine A-84,543 A-366,833 A-582,941 A-867,744 ABT-202 ABT-418 ABT-560 ABT-894 Acetylcholine Altinicline Anabasine Anatabine Anatoxin-a AR-R17779 Bephenium hydroxynaphthoate Butinoline Butyrylcholine Carbachol Choline Cotinine Cytisine Decamethonium Desformylflustrabromine Dianicline Dimethylphenylpiperazinium Epibatidine Epiboxidine Ethanol (alcohol) Ethoxysebacylcholine EVP-4473 EVP-6124 Galantamine GTS-21 Ispronicline Ivermectin JNJ-39393406 Levamisole Lobeline MEM-63,908 (RG-3487) Morantel Nicotine (tobacco ) NS-1738 PHA-543,613 PHA-709,829 PNU-120,596 PNU-282,987 Pozanicline Pyrantel Rivanicline RJR-2429 Sazetidine A SB-206553 Sebacylcholine SIB-1508Y SIB-1553A SSR-180,711 Suberyldicholine Suxamethonium (succinylcholine) Suxethonium (succinyldicholine) TC-1698 TC-1734 TC-1827 TC-2216 TC-5214 TC-5619 TC-6683 Tebanicline Tribendimidine Tropisetron UB-165 Varenicline WAY-317,538 XY-4083 Antagonists (and NAMs Tooltip negative allosteric modulators )
Precursors (and prodrugs )
H1
Agonists Antagonists Others: Atypical antipsychotics (e.g., aripiprazole , asenapine , brexpiprazole , brilaroxazine , clozapine , iloperidone , olanzapine , paliperidone , quetiapine , risperidone , ziprasidone , zotepine ) Phenylpiperazine antidepressants (e.g., hydroxynefazodone , nefazodone , trazodone , triazoledione ) Tetracyclic antidepressants (e.g., amoxapine , loxapine , maprotiline , mianserin , mirtazapine , oxaprotiline ) Tricyclic antidepressants (e.g., amitriptyline , butriptyline , clomipramine , desipramine , dosulepin (dothiepin) , doxepin , imipramine , iprindole , lofepramine , nortriptyline , protriptyline , trimipramine ) Typical antipsychotics (e.g., chlorpromazine , flupenthixol , fluphenazine , loxapine , perphenazine , prochlorperazine , thioridazine , thiothixene )
H2
H3
H4
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-11,461 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
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
5-HT1D
Agonists: CP-122,288 CP-135807 CP-286601 Ergolines (e.g., bromocriptine , cabergoline , dihydroergotamine , ergotamine , LSD , methysergide ) GR-46611 L-694247 L-772405 mCPP PNU-109291 PNU-142633 Serotonin (5-HT) TGBA01AD Triptans (e.g., almotriptan , avitriptan , donitriptan , eletriptan , frovatriptan , naratriptan , rizatriptan , sumatriptan , zolmitriptan ) Tryptamines (e.g., 5-BT , 5-CT , 5-Et-DMT , 5-MT , 5-(nonyloxy)tryptamine , DMT )
5-HT1E
5-HT1F
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
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
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
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 Anpirtoline 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
5-HT4
5-HT5A
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 )
5-HT7
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 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