Binding and functional properties of hexocyclium and sila-hexocyclium derivatives to muscarinic receptor subtypes

Br J Pharmacol. 1994 Jun;112(2):505-14. doi: 10.1111/j.1476-5381.1994.tb13102.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cattle
  • Female
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Male
  • N-Methylscopolamine
  • Parasympatholytics / pharmacokinetics
  • Parasympatholytics / pharmacology*
  • Piperazines / pharmacokinetics*
  • Piperazines / pharmacology*
  • Pirenzepine / pharmacology
  • Rabbits
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism*
  • Scopolamine Derivatives / pharmacology
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Vas Deferens / drug effects


  • Parasympatholytics
  • Piperazines
  • Receptors, Muscarinic
  • Scopolamine Derivatives
  • silahexocyclium
  • Pirenzepine
  • hexocyclium
  • N-Methylscopolamine