Binding and functional properties of hexocyclium and sila-hexocyclium derivatives to muscarinic receptor subtypes.
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Waelbroeck M, Camus J, Tastenoy M, Feifel R, Mutschler E, Tacke R, Strohmann C, Rafeiner K, Rodrigues de Miranda JF, Lambrecht G
Binding and functional properties of hexocyclium and sila-hexocyclium derivatives to muscarinic receptor subtypes.
Br J Pharmacol. 1994 Jun;112(2):505-14.
- PubMed ID
- 8075869 [ View in PubMed]
- Abstract
1. We have compared the binding properties of several hexocyclium and sila-hexocyclium derivatives to muscarinic M1 receptors (in rat brain, human neuroblastoma (NB-OK 1) cells and calf superior cervical ganglia), rat heart M2 receptors, rat pancreas M3 receptors and M4 receptors in rat striatum, with their functional antimuscarinic properties in rabbit vas deferens (M1/M4-like), guinea-pig atria (M2), and guinea-pig ileum (M3) muscarinic receptors. 2. Sila-substitution (C/Si exchange) of hexocyclium (-->sila-hexocyclium) and demethyl-hexocyclium (-->demethyl-sila-hexocyclium) did not significantly affect their affinities for muscarinic receptors. By contrast, sila-substitution of o-methoxy-hexocyclium increased its affinity 2 to 3 fold for all the muscarinic receptor subtypes studied. 3. The p-fluoro- and p-chloro-derivatives of sila-hexocyclium had lower affinities than the parent compound at the four receptor subtypes, in binding and pharmacological studies. 4. In binding studies, o-methoxy-sila-hexocyclium (M1 = M4 > or = M3 > or = M2) had a much lower affinity than sila-hexocyclium for the four receptor subtypes, and discriminated the receptor subtypes more poorly than sila-hexocyclium (M1 = M3 > M4 > M2). This is in marked contrast with the very clear selectivity of o-methoxy-sila-hexocyclium for the prejunctional M1/M4-like heteroreceptors in rabbit vas deferens. 5. The tertiary amines demethyl-hexocyclium, demethyl-sila-hexocyclium and demethyl-o-methoxy-sila-hexocyclium had 10 to 30 fold lower affinities than the corresponding quaternary ammonium derivatives.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Hexocyclium Muscarinic acetylcholine receptor M1 Protein Humans UnknownAntagonistDetails Hexocyclium Muscarinic acetylcholine receptor M2 Protein Humans UnknownAntagonistDetails Hexocyclium Muscarinic acetylcholine receptor M3 Protein Humans YesAntagonistDetails Hexocyclium Muscarinic acetylcholine receptor M4 Protein Humans UnknownAntagonistDetails