Greater potency of mesoridazine and sulforidazine compared with the parent compound, thioridazine, on striatal dopamine autoreceptors

D. M. Niedzwiecki, Richard Mailman, L. X. Cubeddu

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Abstract

The electrically evoked overflow of dopamine (DA) from perfused rabbit striatal slices was used to assess the relative functional potencies of thioridazine, a phenothiazine antipsychotic agent, and two of its major metabolites, mesoridazine (thioridazine-2-sulfoxide) and sulforidazine (thioridazine-2-sulfone). Thioridazine (1000 nM) enhanced the electrically evoked overflow of DA by 18.3 ± 4.6% (n = 4) at 0.3 Hz. Mesoridazine and sulforidazine likewise produced only small increases (5-20%) in evoked overflow of DA from slices stimulated at 0.3 Hz. At this frequency of stimulation, apomorphine (30 nM) inhibited the overflow of DA by 71.4 ± 8.43% (n = 40). All three drugs antagonized, in a concentration-dependent fashion, the inhibitory effect of apomorphine (30 nM) on electrically evoked DA release at 0.3 Hz. The IC50 for thioridazine for antagonizing the effect of apomorphine was 130 nM, whereas that for mesoridazine was 14.4 nM and for sulforidazine was 6.1 nM. These results indicate that thioridazine and its two clinically active metabolites can block striatal DA autoreceptors involved in modulatng DA release. The observation that mesoridazine and sulforidazine were significantly more potnt than the parent drug is consistent with the hypothesis that a major part of the pharmacologic responses to thioridazine may be a consequence of its metabolism to active compounds.

Original languageEnglish (US)
Pages (from-to)636-639
Number of pages4
JournalJournal of Pharmacology and Experimental Therapeutics
Volume228
Issue number3
StatePublished - 1984

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Mesoridazine
Thioridazine
Corpus Striatum
Autoreceptors
Dopamine
Apomorphine
sulforidazine
Pharmaceutical Preparations
Antipsychotic Agents
Inhibitory Concentration 50
Rabbits

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Greater potency of mesoridazine and sulforidazine compared with the parent compound, thioridazine, on striatal dopamine autoreceptors",
abstract = "The electrically evoked overflow of dopamine (DA) from perfused rabbit striatal slices was used to assess the relative functional potencies of thioridazine, a phenothiazine antipsychotic agent, and two of its major metabolites, mesoridazine (thioridazine-2-sulfoxide) and sulforidazine (thioridazine-2-sulfone). Thioridazine (1000 nM) enhanced the electrically evoked overflow of DA by 18.3 ± 4.6{\%} (n = 4) at 0.3 Hz. Mesoridazine and sulforidazine likewise produced only small increases (5-20{\%}) in evoked overflow of DA from slices stimulated at 0.3 Hz. At this frequency of stimulation, apomorphine (30 nM) inhibited the overflow of DA by 71.4 ± 8.43{\%} (n = 40). All three drugs antagonized, in a concentration-dependent fashion, the inhibitory effect of apomorphine (30 nM) on electrically evoked DA release at 0.3 Hz. The IC50 for thioridazine for antagonizing the effect of apomorphine was 130 nM, whereas that for mesoridazine was 14.4 nM and for sulforidazine was 6.1 nM. These results indicate that thioridazine and its two clinically active metabolites can block striatal DA autoreceptors involved in modulatng DA release. The observation that mesoridazine and sulforidazine were significantly more potnt than the parent drug is consistent with the hypothesis that a major part of the pharmacologic responses to thioridazine may be a consequence of its metabolism to active compounds.",
author = "Niedzwiecki, {D. M.} and Richard Mailman and Cubeddu, {L. X.}",
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T1 - Greater potency of mesoridazine and sulforidazine compared with the parent compound, thioridazine, on striatal dopamine autoreceptors

AU - Niedzwiecki, D. M.

AU - Mailman, Richard

AU - Cubeddu, L. X.

PY - 1984

Y1 - 1984

N2 - The electrically evoked overflow of dopamine (DA) from perfused rabbit striatal slices was used to assess the relative functional potencies of thioridazine, a phenothiazine antipsychotic agent, and two of its major metabolites, mesoridazine (thioridazine-2-sulfoxide) and sulforidazine (thioridazine-2-sulfone). Thioridazine (1000 nM) enhanced the electrically evoked overflow of DA by 18.3 ± 4.6% (n = 4) at 0.3 Hz. Mesoridazine and sulforidazine likewise produced only small increases (5-20%) in evoked overflow of DA from slices stimulated at 0.3 Hz. At this frequency of stimulation, apomorphine (30 nM) inhibited the overflow of DA by 71.4 ± 8.43% (n = 40). All three drugs antagonized, in a concentration-dependent fashion, the inhibitory effect of apomorphine (30 nM) on electrically evoked DA release at 0.3 Hz. The IC50 for thioridazine for antagonizing the effect of apomorphine was 130 nM, whereas that for mesoridazine was 14.4 nM and for sulforidazine was 6.1 nM. These results indicate that thioridazine and its two clinically active metabolites can block striatal DA autoreceptors involved in modulatng DA release. The observation that mesoridazine and sulforidazine were significantly more potnt than the parent drug is consistent with the hypothesis that a major part of the pharmacologic responses to thioridazine may be a consequence of its metabolism to active compounds.

AB - The electrically evoked overflow of dopamine (DA) from perfused rabbit striatal slices was used to assess the relative functional potencies of thioridazine, a phenothiazine antipsychotic agent, and two of its major metabolites, mesoridazine (thioridazine-2-sulfoxide) and sulforidazine (thioridazine-2-sulfone). Thioridazine (1000 nM) enhanced the electrically evoked overflow of DA by 18.3 ± 4.6% (n = 4) at 0.3 Hz. Mesoridazine and sulforidazine likewise produced only small increases (5-20%) in evoked overflow of DA from slices stimulated at 0.3 Hz. At this frequency of stimulation, apomorphine (30 nM) inhibited the overflow of DA by 71.4 ± 8.43% (n = 40). All three drugs antagonized, in a concentration-dependent fashion, the inhibitory effect of apomorphine (30 nM) on electrically evoked DA release at 0.3 Hz. The IC50 for thioridazine for antagonizing the effect of apomorphine was 130 nM, whereas that for mesoridazine was 14.4 nM and for sulforidazine was 6.1 nM. These results indicate that thioridazine and its two clinically active metabolites can block striatal DA autoreceptors involved in modulatng DA release. The observation that mesoridazine and sulforidazine were significantly more potnt than the parent drug is consistent with the hypothesis that a major part of the pharmacologic responses to thioridazine may be a consequence of its metabolism to active compounds.

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