Benperidol

Last updated

Benperidol
Benperidol.svg
Benperidol 3D ball.png
Clinical data
Trade names Anquil, Frenactil
AHFS/Drugs.com International Drug Names
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 8 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 InfoCard 100.016.521 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H24FN3O2
Molar mass 381.451 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) Yes check.svgY
  • Key:FEBOTPHFXYHVPL-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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]

Contents

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

Pharmacodynamics

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]
SiteKi (nM)ActionRef
5-HT2A 3.75Antagonist [7]
D1 4,100Antagonist [7]
D2 0.027Antagonist [7]
D4 0.06Antagonist [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

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

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

Benperidol synthesis.svg

See also

References

  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. 1 2 3 4 5 6 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. 1 2 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.{{cite journal}}: CS1 maint: article number as page number (link)
  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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