Comparative anticholinergic properties of thioridazine, mesoridazine and sulforidazine

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

Research output: Contribution to journalArticle

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Abstract

The anticholinergic properties of thioridazine (THD) and its metabolites mesoridazine (MES) and sulforidazine (SUL) were compared to the antimuscarinics atropine and quinuclidinylbenzilate (QNB). THD, MES and SUL were virtually inactive in antagonizing the carbachol-induced inhibition of evoked ACh release from perfused rabbit striatal slices. This lack of effect was seen even when dopamine influences were abolished by treatment with reserpine and α-methyl-p-tyrosine. The lack of functional anticholinergic potency contrasted with the affinity of THD for muscarinic receptors measured as competition for [3H]QNB binding sites in striatal homogenates (K(i) values: atropine, 2.7 nM; THD, 14 nM; SUL, 66 nM; and MES, 90 nM). Both atropine and QNB blocked carbachol-induced inhibition of ACh release in a dose-dependent manner (IC50 values vs. 3 μM carbachol: 0.5 nM for QNB; 1.25 nM for atropine). THD, only 5 times less potent than atropine in competing for [3H]QNB binding sites, was inactive in antagonizing carbachol-induced ACh release. At very high concentrations (3-30 μM), THD, MES and SUL did enhance dopamine efflux and inhibit ACh release. In summary, the lack of effect of THD on release modulatory muscarinic receptors suggest that THD is selective for the M1 subtype. Because the M2 subtype is a small fraction of the total population in the striatum, it is not surprising that they would escape recognition in the QNB binding assays. These data suggest that inhibition of ACh release may contribute to the actions of THD only at very high doses, or when drug accumulation is abnormal.

Original languageEnglish (US)
Pages (from-to)126-133
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume250
Issue number1
StatePublished - 1989

Fingerprint

Mesoridazine
Thioridazine
Cholinergic Antagonists
Atropine
Carbachol
Corpus Striatum
Muscarinic Receptors
Dopamine
Binding Sites
sulforidazine
Muscarinic Antagonists
Reserpine
Inhibitory Concentration 50
Tyrosine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Comparative anticholinergic properties of thioridazine, mesoridazine and sulforidazine",
abstract = "The anticholinergic properties of thioridazine (THD) and its metabolites mesoridazine (MES) and sulforidazine (SUL) were compared to the antimuscarinics atropine and quinuclidinylbenzilate (QNB). THD, MES and SUL were virtually inactive in antagonizing the carbachol-induced inhibition of evoked ACh release from perfused rabbit striatal slices. This lack of effect was seen even when dopamine influences were abolished by treatment with reserpine and α-methyl-p-tyrosine. The lack of functional anticholinergic potency contrasted with the affinity of THD for muscarinic receptors measured as competition for [3H]QNB binding sites in striatal homogenates (K(i) values: atropine, 2.7 nM; THD, 14 nM; SUL, 66 nM; and MES, 90 nM). Both atropine and QNB blocked carbachol-induced inhibition of ACh release in a dose-dependent manner (IC50 values vs. 3 μM carbachol: 0.5 nM for QNB; 1.25 nM for atropine). THD, only 5 times less potent than atropine in competing for [3H]QNB binding sites, was inactive in antagonizing carbachol-induced ACh release. At very high concentrations (3-30 μM), THD, MES and SUL did enhance dopamine efflux and inhibit ACh release. In summary, the lack of effect of THD on release modulatory muscarinic receptors suggest that THD is selective for the M1 subtype. Because the M2 subtype is a small fraction of the total population in the striatum, it is not surprising that they would escape recognition in the QNB binding assays. These data suggest that inhibition of ACh release may contribute to the actions of THD only at very high doses, or when drug accumulation is abnormal.",
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Comparative anticholinergic properties of thioridazine, mesoridazine and sulforidazine. / Niedzwiecki, D. M.; Cubeddu, L. X.; Mailman, Richard.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 250, No. 1, 1989, p. 126-133.

Research output: Contribution to journalArticle

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