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

Abstract

1 We have compared the binding properties of several hexocyclium and sila-hexocyclium derivatives to muscarinic M, 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 (MI/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 (MI = M4 > M3 > M2) had a much lower affinity than sila-hexocyclium for the four receptor subtypes, and discriminated the receptor subtypes more poorly than sila-hexocyclium (MI = 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-hexocycium, demethyl-sila-hexocyclium and demethyl-o-methoxy-silahexocychum had 10 to 30 fold lower affinities than the corresponding quaternary ammonium derivatives.

M2 Receptor Binding of the Selective Antagonist AF-DX 384: Possible Involvement of the Common Allosteric Site

“…Tissues were isolated from adult guinea pigs of either sex or from male New Zealand White rabbits previously killed by cervical dislocation or intravenous injection of 120 mg/kg pentobarbitone sodium, respectively. The methods used have been described in detail previously (Waelbroeck et al, 1994(Waelbroeck et al, , 1996.…”

“…W84 was synthesized by Dr. Joachim Pfeffer (University of Kiel, Germany) according to Wassermann (1970). APE and 4-Cl-McN-A-343 were synthesized by Dr. Ulrich Moser (University of Frankfurt, Germany) according to Waelbroeck et al (1994).…”

Simultaneous determination of enantiomers of structurally related anticholinergic analogs in human serum by liquid chromatography–electrospray ionization mass spectrometry with on-line sample cleanup

“…Quantitation is done other has serious adverse drug reactions [8]. It was by ESI-MS in the selected ion monitoring (SIM) indicated by previously published studies [7,[9][10][11][12][13][14][15] mode. The entire analysis can be automated and that (R)-enantiomers of THP and procyclidine have requires little operator skill.…”

“…subtypes whereas (2)-enantiomer was nearly devoid of such selectivity [16]. However, these studies showed no conclusions about the potency of the ''high affinity'' enantiomer because no correlation Experimental was observed between its potency and the affinity ratios of the two enantiomers [7,10]. This situation Materials was in part due to the lack of sensitive stereoselective analytical methodology for the determination of DL-Trihexyphenidyl hydrochloride, DL-procycthese enantiomers in biological fluids.…”