Benperidol

{{Infobox drug

| Verifiedfields = changed

| verifiedrevid = 459533587

| IUPAC_name = 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one

| image = Benperidol.svg

| image_class = skin-invert-image

| alt = Skeletal formula of benperidol

| width = 240

| image2 = Benperidol 3D ball.png

| alt2 = Ball-and-stick model of the benperidol molecule

| width2 = 250

| tradename = Anquil, Frenactil

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

| pregnancy_AU =

| pregnancy_US =

| pregnancy_category =

| legal_AU = S4 (Prescription only)

| legal_UK =

| legal_US = Rx-only

| legal_status =

| routes_of_administration = Oral

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life = 8 hours

| excretion =

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

| CAS_number = 2062-84-2

| ATC_prefix = N05

| ATC_suffix = AD07

| PubChem = 16363

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

| DrugBank = DB12867

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

| ChemSpiderID = 15521

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

| UNII = 97O6X78C53

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

| ChEMBL = 297302

| KEGG = D02627

| ChEBI = 93403

| C = 22

| H = 24

| F = 1

| N = 3

| O = 2

| smiles = Fc1ccc(cc1)C(=O)CCCN4CCC(N3c2ccccc2NC3=O)CC4

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

| StdInChI = 1S/C22H24FN3O2/c23-17-9-7-16(8-10-17)21(27)6-3-13-25-14-11-18(12-15-25)26-20-5-2-1-4-19(20)24-22(26)28/h1-2,4-5,7-10,18H,3,6,11-15H2,(H,24,28)

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

| StdInChIKey = FEBOTPHFXYHVPL-UHFFFAOYSA-N

| drug_name =

| caption =

| type =

| MedlinePlus =

| licence_EU =

| licence_US =

}}

Benperidol, sold under the trade name Anquil{{Cite journal | vauthors = Council A, Kuenssberg V | title = Benperidol - a drug for sexual offenders? | journal = Drug and Therapeutics Bulletin | volume = 12 | issue = 3 | pages = 12 | date = 1974-02-01 | pmid = 4457302 | doi = 10.1136/dtb.12.3.12 | publisher = BMJ Publishing Group Ltd | s2cid = 44581451 }} among others, is a typical antipsychotic primarily used to treat hypersexuality syndromesBritish National Formulary (49th), British Medical Association 2005 p 183 and can be used to treat schizophrenia.{{cite journal | vauthors = Bobon J, Collard J, Lecoq R | title = [Benperidol and promazine: a "double blind" comparative study in mental geriatrics] | journal = Acta Neurologica et Psychiatrica Belgica | volume = 63 | pages = 839–843 | date = October 1963 | pmid = 14092279 | language = fr }} It is a highly potent butyrophenone derivative and is the most potent neuroleptic in the European market, with chlorpromazine equivalency as high as 75 to 100 (about 150 to 200% the potency per dose of haloperidol).{{cite book | vauthors = Möller HJ, Müller WE, Bandelow | title = Neuroleptika: pharmakologische Grundlagen, klinisches Wissen und therapeutisches Vorgehen; mit 136 Tabellen. | date = 2001 | publisher = Wiss. Verlag-Ges. | language = de | isbn = 978-3-8047-1773-2 }} It is sometimes prescribed to sex offenders as a condition of their parole, as an alternative to anti-androgen drugs such as cyproterone acetate.{{cite journal | vauthors = Murray MA, Bancroft JH, Anderson DC, Tennent TG, Carr PJ | title = Endocrine changes in male sexual deviants after treatment with anti-androgens, oestrogens or tranquillizers | journal = The Journal of Endocrinology | volume = 67 | issue = 2 | pages = 179–188 | date = November 1975 | pmid = 1107462 | doi = 10.1677/joe.0.0670179 }}

Benperidol was discovered by Janssen Pharmaceutica in 1961 and has been marketed since 1966. It is mainly used in Germany, but it is also available in Belgium, Greece, the Netherlands, and the United Kingdom.{{Cite web | title = NCATS Inxight Drugs — BENPERIDOL | access-date = 13 March 2022 | url = https://drugs.ncats.io/drug/97O6X78C53 }}

Pharmacology

= Pharmacodynamics =

Benperidol is a strong dopamine receptor antagonist (D₂ (K_i 0.027 nM) and D₄ (K_i 0.066 nM)) with weaker serotonin receptor antagonism (5-HT_2A (K_i 3.75 nM)). In high doses, it has antihistaminergic and alpha-adrenergic{{Which|date=April 2025}} properties. It possesses minimal anticholinergic properties.{{cite journal | vauthors = Leucht S, Hartung B | title = Benperidol for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2005 | issue = 2 | pages = CD003083 | date = April 2005 | pmid = 15846648 | pmc = 7017029 | doi = 10.1002/14651858.CD003083.pub2 }}

class="wikitable" \|+Benperidol{{cite web \| vauthors = Roth BL, Driscol J \| title = PDSP K_i Database \| work = Psychoactive Drug Screening Program (PDSP) \| author1-link = Bryan Roth \| publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health \| access-date = 11 March 2022 \| url = https://pdsp.unc.edu/databases/pdsp.php?recDDRadio=recDDRadio&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Benperidol&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query }} ! Site !! K_i (nM) !! Action !! Ref
5-HT_2A	3.75	Antagonist	{{cite journal \| vauthors = Li P, Snyder GL, Vanover KE \| title = Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future \| journal = Current Topics in Medicinal Chemistry \| volume = 16 \| issue = 29 \| pages = 3385–3403 \| date = December 2016 \| pmid = 27291902 \| pmc = 5112764 \| doi = 10.2174/1568026616666160608084834 }}
D₁	4,100	Antagonist
D₂	0.027	Antagonist
D₄	0.06	Antagonist

Although benperidol was developed relatively early in the history of antipsychotic drugs, it exhibits a uniquely high and selective affinity for the human dopamine D₂ receptor when compared with all other human dopamine receptor subtypes. This is evident from its nanomolar binding affinities, which stand out even among both typical and atypical antipsychotics. Benperidol is also considered to possess one of the greatest selectivity ratios for dopamine receptors over 5-HT₂A serotonin receptors, although this distinction is surpassed by certain neuroleptics such as amisulpride and sulpiride.{{cite journal | vauthors = Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL | title = Amisulpride is a potent 5-HT7 antagonist: Relevance for antidepressant actions in vivo | journal = Psychopharmacology | volume = 205 | issue = 1 | pages = 119–128 | date = 2009 | pmid = 19337725 | pmc = 2821721 | doi = 10.1007/s00213-009-1521-8 }}{{cite journal | vauthors = Li P, Snyder GL, Vanover KE | title = Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future | journal = Current Topics in Medicinal Chemistry | volume = 16 | issue = 29 | pages = 3385–3403 | date = 2016 | pmid = 27291902 | pmc = 5112764 | doi = 10.2174/1568026616666160608084834 }} Dopamine receptors play central roles not only in cognition, emotion, and motor control—key domains affected in schizophrenia—but also in various unconscious biological processes. The emphasis on D₂ receptor blockade in antipsychotic drug design stems from its critical role in these functions and its dense expression in brain regions implicated in schizophrenia, such as the striatum and frontal cortex.{{cite journal | vauthors = Ramachandraiah CT, Subramaniam N, Tancer M | title = The story of antipsychotics: Past and present | journal = Indian Journal of Psychiatry | volume = 51 | issue = 4 | pages = 324–326 | date = 2009 | pmid = 20048463 | pmc = 2802385 | doi = 10.4103/0019-5545.58304 | doi-access = free }}{{cite journal | vauthors = Calabrese F, Tarazi FI, Racagni G, Riva MA | title = The role of dopamine D(3) receptors in the mechanism of action of cariprazine | journal = CNS Spectrums | volume = 25 | issue = 3 | pages = 343–351 | date = 2020 | pmid = 31010452 | doi = 10.1017/S109285291900083X | url = https://pubmed.ncbi.nlm.nih.gov/31010452/ | hdl = 2434/706105 | hdl-access = free }} Benperidol’s preferential binding to the D₂ receptor—over other dopamine receptor subtypes such as D₃ and D₄—is also unusually strong, with approximately a twofold greater selectivity. This distinguishes it from antipsychotics like haloperidol and perphenazine, which show more balanced D₂/D₃ binding ratios (e.g., 0.7–0.3 or 0.13),{{cite journal | vauthors = Mohell N, Mikaels Å, Mohell N | title = Agonist and inverse agonist activity at the dopamine D3 receptor measured by guanosine 5'--gamma-thio-triphosphate--35S- binding | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 285 | issue = 1 | pages = 119–126 | date = 1998 | pmid = 9536001 | doi = 10.1016/S0022-3565(24)37395-1 | url = https://jpet.aspetjournals.org/article/S0022-3565(24)37395-1/abstract | url-access = subscription }} as well as from cariprazine, which demonstrates an even higher D₃ affinity relative to D₂ (D₂–D₃ ratio of 0.49–0.085).{{cite journal | vauthors = Stahl SM | title = Mechanism of action of cariprazine | journal = CNS Spectrums | volume = 21 | issue = 2 | pages = 123–127 | date = 2016 | pmid = 26956157 | doi = 10.1017/S1092852916000043 | url = https://www.cambridge.org/core/journals/cns-spectrums/article/mechanism-of-action-of-cariprazine/BE9B7B7A373A80A0B5BC8C47B47ACC12 }}

= Pharmacokinetics =

Benperidol is absorbed well and undergoes extensive first pass metabolism. One percent of benperidol is excreted in urine. The half-life of benperidol is 8 hours.

Synthesis

4-(2-Keto-1-benzimidazolinyl)piperidine (1) is alkylated with 4-chloro-4'-Fluorobutyrophenone (2) to produce benperidol (3).{{cite web | title = Benperidol | work = Pharmaceutical Substances | publisher = Thieme | url = https://pharmaceutical-substances.thieme.com/lexicon/KD-02-0036?searchterm=benperidol&context=search }}{{cite patent | number = 626307 | country = BE | gdate = 1963 | inventor = Janssen C | assign1 = N. V. Research Laboratorium | title = 1-(1-Aroylpropyl-4-piperidyl)-2-benzimidazolinones }} Chemical Abstracts 60, 10690c (1964), corresp. to {{cite patent | title = 1-(1-Aroylpropyl-4-piperidyl)-2-benzimidazolinones and related compounds | number = 989755 | country = GB | pubdate = 1965-04-22 | assign1 = N.V. Research Laboratorium Dr. C. Janssen }}

File:Benperidol synthesis.svg