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Binding and functional properties of hexocyclium and sila‐hexocyclium derivatives to muscarinic receptor subtypes
Author(s) -
Waelbroeck M.,
Camus J.,
Tastenoy M.,
Feifel R.,
Mutschler E.,
Tacke R.,
Strohmann C.,
Rafeiner K.,
Miranda J.F. Rodrigues,
Lambrecht G.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13102.x
Subject(s) - muscarinic acetylcholine receptor , receptor , vas deferens , muscarinic acetylcholine receptor m1 , chemistry , endocrinology , medicine , agonist , oxotremorine , biology , stereochemistry , biochemistry
1 We have compared the binding properties of several hexocyclium and sila‐hexocyclium derivatives to muscarinic M 1 receptors (in rat brain, human neuroblastoma (NB‐OK 1) cells and calf superior cervical ganglia), rat heart M 2 receptors, rat pancreas M 3 receptors and M 4 receptors in rat striatum, with their functional antimuscarinic properties in rabbit vas deferens (M 1 /M 4 ‐like), guinea‐pig atria (M 2 ), and guinea‐pig ileum (M 3 ) 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 (M 1 = M 4 ≥ M 3 ≥ M 2 ) had a much lower affinity than sila‐hexocyclium for the four receptor subtypes, and discriminated the receptor subtypes more poorly than sila‐hexocyclium (M 1 = M 3 > M 4 > M 2 ). This is in marked contrast with the very clear selectivity of o ‐methoxy‐sila‐hexocyclium for the prejunctional M 1 /M 4 ‐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.