Benperidol is a strong dopaminereceptor 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]
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]
^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. PMID4457302. S2CID44581451.
^British National Formulary (49th), British Medical Association 2005 p 183
^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. PMID14092279.
^Möller HJ, Müller WE, Bandelow (2001). Neuroleptika: pharmakologische Grundlagen, klinisches Wissen und therapeutisches Vorgehen; mit 136 Tabellen (in German). Wiss. Verlag-Ges. ISBN978-3-8047-1773-2.
^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. PMID1107462.
^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.
^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. PMID31010452.
^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
