TY  - JOUR
A1  - Waelbroeck, M.
A1  - Camus, J.
A1  - Tastenoy, M.
A1  - Feifel, R.
A1  - Mutschler, E.
A1  - Tacke, R.
A1  - Strohmann, C.
A1  - Rafeiner, K.
A1  - Rodrigues de Miranda, J. F.
A1  - Lambrecht, G.
T1  - Binding and functional properties of hexocyclium and sila-hexocyclium derivatives to muscarinic receptor suhtypes
JF  - British Journal of Pharmacology
N2  - 1 We have compared the binding properties of several hexocyclium and sila-hexocyclium derivatives to muscarinic Ml receptors (in rat brain, human neuroblastoma (NB-OK I) 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 (Ml/M4-like), guinea-pig atria (M2), and guinea-pig ileum (M3) muscarinic receptors.
2 Si la-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 demethoxy-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 (Ml = 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 (Ml = M3> M4> M2)' This is in marked contrast with the very clear selectivity of demethoxy-sila-hexocyclium for the prejunctional MtlM4-like heteroreceptors in rabbit vas deferens.
5 The tertiary amines demethyl-hexocyclium, demethyl-sila-hexocyclium and demethyl-o-methoxy-silahexocyclium had 10 to 30 fold lower affinities than the corresponding quaternary ammonium derivatives.
KW  - Hexocyclium/sila-hexocyclium derivatives
KW  - o-methoxy-sila-hexocyclium
KW  - muscarinic receptor subtypes
KW  - structure/ affinity relationships
KW  - binding/functional correlations
KW  - muscarinic receptor antagonists
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128265
VL  - 112
ER  -