Pipamperone

{{Drugbox

| Verifiedfields = changed

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| verifiedrevid = 464207244

| IUPAC_name = 1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidin-1-ylpiperidine-4-carboxamide

| image = Pipamperone.svg

| image_class = skin-invert-image

| width = 250

| tradename = Dipiperon

| Drugs.com = {{drugs.com|international|pipamperone}}

| pregnancy_AU =

| pregnancy_US =

| legal_AU =

| legal_BR = C1

| legal_BR_comment = {{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}

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| legal_US =

| legal_EU =

| legal_UN =

| legal_status =

| routes_of_administration = Oral

| bioavailability =

| metabolism =

| elimination_half-life = 17-22 hours

| duration_of_action = 0.5-1 hour

| excretion =

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 1893-33-0

| ATC_prefix = N05

| ATC_suffix = AD05

| ATC_supplemental =

| PubChem = 4830

| IUPHAR_ligand = 92

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB09286

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 4664

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 5402501F0W

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D02622

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 440294

| synonyms = Carpiperone, floropipamide, fluoropipamide, floropipamide hydrochloride (JAN), McN-JR 3345; R-3345

| C=21 | H=30 | F=1 | N=3 | O=2

| smiles = Fc1ccc(cc1)C(=O)CCCN3CCC(C(=O)N)(N2CCCCC2)CC3

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C21H30FN3O2/c22-18-8-6-17(7-9-18)19(26)5-4-12-24-15-10-21(11-16-24,20(23)27)25-13-2-1-3-14-25/h6-9H,1-5,10-16H2,(H2,23,27)

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = AXKPFOAXAHJUAG-UHFFFAOYSA-N

|drug_name=|alt=|caption=|type=|MedlinePlus=|licence_EU=|pregnancy_category=|licence_US=}}

Pipamperone (INN, USAN, BAN), sold under the brand name Dipiperon, is a typical antipsychotic of the butyrophenone family used in the treatment of schizophrenia{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA222|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=222–}}{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA985|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=985–}} and as a sleep aid for depression.{{cite journal | vauthors = Ansoms C, Backer-Dierick GD, Vereecken JL | title = Sleep disorders in patients with severe mental depression: double-blind placebo-controlled evaluation of the value of pipamperone (Dipiperon) | journal = Acta Psychiatrica Scandinavica | volume = 55 | issue = 2 | pages = 116–122 | date = February 1977 | pmid = 320830 | doi = 10.1111/j.1600-0447.1977.tb00147.x | s2cid = 40758854 }} It is or has been marketed under brand names including Dipiperon, Dipiperal, Piperonil, Piperonyl, and Propitan. Pipamperone was discovered at Janssen Pharmaceutica in 1961, and entered clinical trials in the United States in 1963.{{cite book | vauthors = Healy D |title=The Creation of Psychopharmacology|url=https://books.google.com/books?id=6O2rPJnyhj0C&pg=PA251|date=1 July 2009|publisher=Harvard University Press|isbn=978-0-674-03845-5|pages=251–}}

Medical uses

Pipamperone was developed for use as an antipsychotic in the treatment of schizophrenia.

Pipamperone might be useful as a hallucinogen antidote or "trip killer" in blocking the effects of serotonergic psychedelics like psilocybin.{{cite journal | vauthors = Halman A, Kong G, Sarris J, Perkins D | title = Drug-drug interactions involving classic psychedelics: A systematic review | journal = J Psychopharmacol | volume = 38 | issue = 1 | pages = 3–18 | date = January 2024 | pmid = 37982394 | pmc = 10851641 | doi = 10.1177/02698811231211219 | url = }}

Pharmacology

File:Pipamperon neuraxpharm 40mg by Danny S. - 001.JPG{{clear left}}

Pipamperone acts as an antagonist of the 5-HT_2A,{{cite journal | vauthors = Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE | display-authors = 6 | title = Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding | journal = Psychopharmacology | volume = 124 | issue = 1–2 | pages = 57–73 | date = March 1996 | pmid = 8935801 | doi = 10.1007/bf02245606 | s2cid = 12028979 }} 5-HT_2B,{{cite journal | vauthors = Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL | title = Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 276 | issue = 2 | pages = 720–727 | date = February 1996 | pmid = 8632342 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8632342 }} 5-HT_2C{{cite journal | vauthors = Prinssen EP, Koek W, Kleven MS | title = The effects of antipsychotics with 5-HT(2C) receptor affinity in behavioral assays selective for 5-HT(2C) receptor antagonist properties of compounds | journal = European Journal of Pharmacology | volume = 388 | issue = 1 | pages = 57–67 | date = January 2000 | pmid = 10657547 | doi = 10.1016/s0014-2999(99)00859-6 }} D₂, D₃,{{cite book | vauthors = Leyson JE | chapter = Receptor profile of antipsychotics | veditors = Ellenbroek BA, Cools AR |title=Atypical Antipsychotics| chapter-url = https://books.google.com/books?id=08kGCAAAQBAJ&pg=PA62 |date=6 December 2012|publisher=Birkhäuser|isbn=978-3-0348-8448-8|pages=62–}} D₄,{{cite journal | vauthors = Van Craenenbroeck K, Gellynck E, Lintermans B, Leysen JE, Van Tol HH, Haegeman G, Vanhoenacker P | title = Influence of the antipsychotic drug pipamperone on the expression of the dopamine D4 receptor | journal = Life Sciences | volume = 80 | issue = 1 | pages = 74–81 | date = December 2006 | pmid = 16978659 | doi = 10.1016/j.lfs.2006.08.024 }} α₁-adrenergic, and α₂-adrenergic receptors. It shows much higher affinity for the 5-HT_2A and D₄ receptors over the D₂ receptor (15-fold in the case of the D₄ receptor, and even higher in the case of the 5-HT_2A receptor),{{cite journal | vauthors = Wade AG, Crawford GM, Nemeroff CB, Schatzberg AF, Schlaepfer T, McConnachie A, Haazen L, Buntinx E | display-authors = 6 | title = Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response | journal = Psychological Medicine | volume = 41 | issue = 10 | pages = 2089–2097 | date = October 2011 | pmid = 21349239 | doi = 10.1017/S0033291711000158 | s2cid = 19189492 | url = https://eprints.gla.ac.uk/57374/1/id57374.pdf }} being regarded as "highly selective" for the former two sites at low doses.{{cite book| vauthors = Abi-Dargham A, Krystal J | chapter = Serotonin Receptors as Targets of Antipsychotic Medications | veditors = Lidow MS |title=Neurotransmitter Receptors in Actions of Antipsychotic Medications| chapter-url=https://books.google.com/books?id=HIHLBQAAQBAJ&pg=PA88|date=22 June 2000|publisher=CRC Press|isbn=978-1-4200-4177-4|pages=88–}} Pipamperone has low and likely insignificant affinity for the H₁ and mACh receptors, as well as for other serotonin and dopamine receptors.

Pipamperone is considered to have been a forerunner to the atypical antipsychotics, if not an atypical antipsychotic itself, due to its prominent serotonin antagonism.{{cite journal | vauthors = Awouters FH, Lewi PJ | title = Forty years of antipsychotic Drug research--from haloperidol to paliperidone--with Dr. Paul Janssen | journal = Arzneimittel-Forschung | volume = 57 | issue = 10 | pages = 625–632 | year = 2007 | pmid = 18074755 | doi = 10.1055/s-0031-1296660 | s2cid = 5713281 }}{{cite journal | vauthors = Vanden Bussche G, Gelders YG, Heylen SL | title = [Development of new antipsychotic drugs] | language = es | journal = Acta Psiquiatrica y Psicologica de America Latina | volume = 36 | issue = 1–2 | pages = 13–25 | year = 1990 | pmid = 2127339 }}{{cite journal | vauthors = Niemegeers CJ, Awouters F, Janssen PA | title = [Serotonin antagonism involved in the antipsychotic effect. Confirmation with ritanserine and risperidone] | language = fr | journal = L'Encéphale | volume = 16 | issue = 2 | pages = 147–151 | year = 1990 | pmid = 1693560 }} It is also used to normalise mood and sleep patterns and has antianxiety effects in neurotic patients.{{Cite book|url=https://books.google.com/books?id=oK7tCAAAQBAJ&q=pipamperone+mania&pg=PA36|title=Psychotropic Agents: Part I: Antipsychotics and Antidepressants|date=2012-12-06|publisher=Springer Science & Business Media|isbn=9783642675386|language=en}}

Site	{{Tooltip\|pKi\|2=pKi: pKi = -log Ki → -pKi = log Ki → 10-pKi = Ki; higher pKi values correspond to lower Ki values, and vice versa}}
class="wikitable" \|+ AffinityBart A. Ellenbroek, Alexander R. Cools (eds.) (6 December 2012). Atypical Antipsychotics. Basel: Birkhäuser, pp. 62 f. {{ISBN\|978-3-0348-8448-8}}.
D₁	5.61
D₂	6.71
D₃	6.58
D₄	7.95
5 HT_1A	5.46
5 HT_1B	5.54
5 HT_1D	6.14
5 HT_1E	5.44
5 HT_1F	<5
5-HT_2A	8.19
5 HT₅	5.35
5 HT₇	6.26
α₁	7.23
α_2A	6.15
α_2B	7.08
α_2C	6.25

Antidepressant effects

Low-dose pipamperone (5 mg twice daily) has been found to accelerate and enhance the antidepressant effect of citalopram (40 mg once daily), in a combination (citalopram/pipamperone) referred to as PipCit (code name PNB-01).{{cite journal | vauthors = Kirk R | title = Clinical trials in CNS--SMi's eighth annual conference | journal = IDrugs | volume = 13 | issue = 2 | pages = 66–69 | date = February 2010 | pmid = 20127552 }}