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

Feifel, Roland; Miranda, Rodrigues de; Waelbroeck, Magalì; Christophe, Jean; Rafeiner, K.; Tacke, Reinhold; Wagner-Röder, Monika; Mutschler, E.; Lambrecht, Günter

doi:10.1016/0014-2999(90)92030-m

Cited by 2 publications

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“…Our current results with secoverine and tropicamide confirm the earlier finding in binding studies (Lazareno et al, 1990) that these antagonists have 2 to 3 fold overall selectivity for m4 receptors. OMSH was reported to have similar affinities to pirenzepine at M1-M3 receptors in functional studies, with a pA2 of 8.3 at rat superior cervical ganglion and 8.4 at rabbit vas deferens (two putative functional Ml preparations), but in binding studies at Ml sites its log affinity constant was only 7 (Lambrecht et al, 1988;Feifel et al, 1990). Our results at ml -m3 receptors are almost identical to the binding results at Ml and functional results at M2 and M3 receptors.…”

Section: Discussionsupporting

confidence: 81%

“…(Lazareno et al, 1990) or cloned human receptors (Dorje et al, 1991b) and the affinity estimates in the three studies were very similar (see also Mitchelson, 1988 andCaulfield, 1993). Our current results with secoverine and tropicamide confirm the earlier finding in binding studies (Lazareno et al, 1990) (Lambrecht et al, 1988;Feifel et al, 1990 (Dorje et al, 1991a).…”

Section: Experimental Design and Analysissupporting

confidence: 82%

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Pharmacological characterization of acetylcholine‐stimulated [³⁵S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies

Lazareno

Birdsall

1993

British J Pharmacology

157

101

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1 We have used dose-ratio analysis to estimate functionally the affinity constants (pKb) and Schild slope factors of a range of selective or atypical antagonists at human muscarinic ml-m4 receptors.2 The functional response was the stimulation by acetylcholine of [35S]-GTPyS binding to membranes from Chinese hamster ovary (CHO) cells stably expressing individual receptor subtypes. 3 A novel experimental design and analysis was used which allowed the estimation of affinity and Schild slope factor from a single antagonist inhibition curve, and the results were compared with other methods of analysis, both theoretically valid and invalid. 4 In general, the affinity estimates were very similar to previously reported values obtained in binding studies with animal tissues and cloned human receptors and the Schild slope factors were close to unity. 5 These results demonstrate the validity of the assay and provide no evidence for species differences in antagonist affinity for muscarinic receptor subtypes. 6 The results confirm both the utility of himbacine in distinguishing between ml and m4 receptors and a previously reported modest m4-selectivity for tropicamide and secoverine. 7 The cholinesterase inhibitor, tacrine (THA), had a potency profile similar to that of gallamine but with less selectivity. Its affinity could not be determined since it had Schild slope factors of about 2 at all subtypes. 8 o-Methoxy-sila-hexocyclium had only a modest selectivity for the ml subtype.

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Section: Discussionsupporting

confidence: 81%

Section: Experimental Design and Analysissupporting

confidence: 82%

Pharmacological characterization of acetylcholine‐stimulated [³⁵S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies

Lazareno

Birdsall

1993

British J Pharmacology

157

101

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“…Preliminary accounts of this study have been communicated to the German Society for Pharmacology and Toxicology, Hamburg, September 1988 and to the IUPHAR, Amsterdam, July 1990 (Feifel et al, 1990). …”

Section: Introductionmentioning

confidence: 99%

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

Waelbroeck

Camus

Tastenoy

et al. 1994

British J Pharmacology

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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.

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

Cited by 2 publications

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Pharmacological characterization of acetylcholine‐stimulated [³⁵S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies

Pharmacological characterization of acetylcholine‐stimulated [³⁵S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies

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

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

Cited by 2 publications

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Pharmacological characterization of acetylcholine‐stimulated [35S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies

Pharmacological characterization of acetylcholine‐stimulated [35S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies

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

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Pharmacological characterization of acetylcholine‐stimulated [³⁵S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies

Pharmacological characterization of acetylcholine‐stimulated [³⁵S]‐GTPγS binding mediated by human muscarinic m1–m4 receptors: antagonist studies