Charged Analogues of Chlorpromazine as Dopamine Antagonists

Marc W. Harrold, Yu An Chang, Rave Ann Wallace, Tahira Farooqui, Lane J. Wallace, Norman Uretsky, Duane Miller

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Chlorpromazine (1, CPZ) is a potent dopamine antagonist that has been used widely as an antipsychotic agent. Since dopaminergic antagonists, like dopaminergic agonists, exist in solution as the charged and uncharged molecular species, it is not clear which form of the amine is most important for interaction with the dopamine receptor. Previous work from our laboratory has indicated that a variety of permanently charged species could replace the amine/ ammonium moiety of dopamine and retain dopamine agonist activity. This paper describes the synthesis and dopamine antagonist activity of both the trimethylammonium iodide (2) and the dimethylsulfonium iodide (3) analogues of chlorpromazine. The permanently uncharged methyl sulfide analogue (4) was also synthesized; however, due to its lack of aqueous solubility, its pharmacological activity could not be evaluated. Binding of both the dimethylsulfonium iodide and the trimethylammonium iodide analogues to D-2 dopamine receptors of rat striatal tissue was observed. The observed relative order of binding was CPZ > CPZ sulfonium analogue > CPZ ammonium analogue. These compounds had a similar order of activity in antagonizing the apomorphine-induced inhibition of potassium-induced release of [3H]acetylcholine from mouse striatal slices.

Original languageEnglish (US)
Pages (from-to)1631-1635
Number of pages5
JournalJournal of Medicinal Chemistry
Volume30
Issue number9
DOIs
StatePublished - Sep 1 1987
Externally publishedYes

Fingerprint

Dopamine Antagonists
Chlorpromazine
Iodides
Corpus Striatum
Dopamine Agonists
Dopamine Receptors
Ammonium Compounds
Amines
Apomorphine
Sulfides
Solubility
Antipsychotic Agents
Acetylcholine
Dopamine
Potassium
Pharmacology

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Harrold, M. W., Chang, Y. A., Wallace, R. A., Farooqui, T., Wallace, L. J., Uretsky, N., & Miller, D. (1987). Charged Analogues of Chlorpromazine as Dopamine Antagonists. Journal of Medicinal Chemistry, 30(9), 1631-1635. https://doi.org/10.1021/jm00392a019

Charged Analogues of Chlorpromazine as Dopamine Antagonists. / Harrold, Marc W.; Chang, Yu An; Wallace, Rave Ann; Farooqui, Tahira; Wallace, Lane J.; Uretsky, Norman; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 30, No. 9, 01.09.1987, p. 1631-1635.

Research output: Contribution to journalArticle

Harrold, MW, Chang, YA, Wallace, RA, Farooqui, T, Wallace, LJ, Uretsky, N & Miller, D 1987, 'Charged Analogues of Chlorpromazine as Dopamine Antagonists', Journal of Medicinal Chemistry, vol. 30, no. 9, pp. 1631-1635. https://doi.org/10.1021/jm00392a019
Harrold MW, Chang YA, Wallace RA, Farooqui T, Wallace LJ, Uretsky N et al. Charged Analogues of Chlorpromazine as Dopamine Antagonists. Journal of Medicinal Chemistry. 1987 Sep 1;30(9):1631-1635. https://doi.org/10.1021/jm00392a019
Harrold, Marc W. ; Chang, Yu An ; Wallace, Rave Ann ; Farooqui, Tahira ; Wallace, Lane J. ; Uretsky, Norman ; Miller, Duane. / Charged Analogues of Chlorpromazine as Dopamine Antagonists. In: Journal of Medicinal Chemistry. 1987 ; Vol. 30, No. 9. pp. 1631-1635.
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