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Benperidol

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Benperidol
Skeletal formula of benperidol
Ball-and-stick model of the benperidol molecule
Clinical data
Trade namesAnquil, Frenactil
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life8 hours
Identifiers
  • 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.016.521 Edit this at Wikidata
Chemical and physical data
FormulaC22H24FN3O2
Molar mass381.451 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)C(=O)CCCN4CCC(N3c2ccccc2NC3=O)CC4
  • InChI=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) checkY
  • Key:FEBOTPHFXYHVPL-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Benperidol, sold under the trade name Anquil[1] among others, is a typical antipsychotic primarily used to treat hypersexuality syndromes[2] and can be used to treat schizophrenia.[3] 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).[4] It is sometimes prescribed to sex offenders as a condition of their parole, as an alternative to anti-androgen drugs such as cyproterone acetate.[5]

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.[6]

Pharmacology

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Pharmacodynamics

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Benperidol is a strong dopamine receptor antagonist (D2 (Ki 0.027 nM) and D4 (Ki 0.066 nM))[7] with weaker serotonin receptor antagonism (5-HT2A (Ki 3.75 nM)).[7] In high doses, it has antihistaminergic and alpha-adrenergic[which?] properties. It possesses minimal anticholinergic properties.[8]

Benperidol[9]
Site Ki (nM) Action Ref
5-HT2A 3.75 Antagonist [7]
D1 4,100 Antagonist [7]
D2 0.027 Antagonist [7]
D4 0.06 Antagonist [7]

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.[10][11] 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.[12][13] 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),[14] as well as from cariprazine, which demonstrates an even higher D3 affinity relative to D2 (D2–D3 ratio of 0.49–0.085).[15]

Pharmacokinetics

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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.[8]

Synthesis

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4-(2-Keto-1-benzimidazolinyl)piperidine (1) is alkylated with 4-chloro-4'-Fluorobutyrophenone (2) to produce benperidol (3).[16][17]

See also

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References

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  1. ^ Council A, Kuenssberg V (1974-02-01). "Benperidol - a drug for sexual offenders?". Drug and Therapeutics Bulletin. 12 (3). BMJ Publishing Group Ltd: 12. doi:10.1136/dtb.12.3.12. PMID 4457302. S2CID 44581451.
  2. ^ British National Formulary (49th), British Medical Association 2005 p 183
  3. ^ Bobon J, Collard J, Lecoq R (October 1963). "[Benperidol and promazine: a "double blind" comparative study in mental geriatrics]". Acta Neurologica et Psychiatrica Belgica (in French). 63: 839–843. PMID 14092279.
  4. ^ Möller HJ, Müller WE, Bandelow (2001). Neuroleptika: pharmakologische Grundlagen, klinisches Wissen und therapeutisches Vorgehen; mit 136 Tabellen (in German). Wiss. Verlag-Ges. ISBN 978-3-8047-1773-2.
  5. ^ Murray MA, Bancroft JH, Anderson DC, Tennent TG, Carr PJ (November 1975). "Endocrine changes in male sexual deviants after treatment with anti-androgens, oestrogens or tranquillizers". The Journal of Endocrinology. 67 (2): 179–188. doi:10.1677/joe.0.0670179. PMID 1107462.
  6. ^ "NCATS Inxight Drugs — BENPERIDOL". Retrieved 13 March 2022.
  7. ^ a b c d e f Li P, Snyder GL, Vanover KE (December 2016). "Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future". Current Topics in Medicinal Chemistry. 16 (29): 3385–3403. doi:10.2174/1568026616666160608084834. PMC 5112764. PMID 27291902.
  8. ^ a b Leucht S, Hartung B (April 2005). "Benperidol for schizophrenia". The Cochrane Database of Systematic Reviews. 2005 (2): CD003083. doi:10.1002/14651858.CD003083.pub2. PMC 7017029. PMID 15846648.
  9. ^ Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 11 March 2022.
  10. ^ Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL (2009). "Amisulpride is a potent 5-HT7 antagonist: Relevance for antidepressant actions in vivo". Psychopharmacology. 205 (1): 119–128. doi:10.1007/s00213-009-1521-8. PMC 2821721. PMID 19337725.
  11. ^ Li P, Snyder GL, Vanover KE (2016). "Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future". Current Topics in Medicinal Chemistry. 16 (29): 3385–3403. doi:10.2174/1568026616666160608084834. PMC 5112764. PMID 27291902.
  12. ^ Ramachandraiah CT, Subramaniam N, Tancer M (2009). "The story of antipsychotics: Past and present". Indian Journal of Psychiatry. 51 (4): 324–326. doi:10.4103/0019-5545.58304. PMC 2802385. PMID 20048463.
  13. ^ Calabrese F, Tarazi FI, Racagni G, Riva MA (2020). "The role of dopamine D(3) receptors in the mechanism of action of cariprazine". CNS Spectrums. 25 (3): 343–351. doi:10.1017/S109285291900083X. hdl:2434/706105. PMID 31010452.
  14. ^ Mohell N, Mikaels Å, Mohell N (1998). "Agonist and inverse agonist activity at the dopamine D3 receptor measured by guanosine 5'--gamma-thio-triphosphate--35S- binding". The Journal of Pharmacology and Experimental Therapeutics. 285 (1): 119–126. doi:10.1016/S0022-3565(24)37395-1. PMID 9536001.
  15. ^ Stahl SM (2016). "Mechanism of action of cariprazine". CNS Spectrums. 21 (2): 123–127. doi:10.1017/S1092852916000043. PMID 26956157.
  16. ^ "Benperidol". Pharmaceutical Substances. Thieme.
  17. ^ BE 626307, Janssen C, "1-(1-Aroylpropyl-4-piperidyl)-2-benzimidazolinones", issued 1963, assigned to N. V. Research Laboratorium  Chemical Abstracts 60, 10690c (1964), corresp. to GB 989755, "1-(1-Aroylpropyl-4-piperidyl)-2-benzimidazolinones and related compounds", published 1965-04-22, assigned to N.V. Research Laboratorium Dr. C. Janssen 
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