The musearlnie receptors are currently divided into at least three subtypes: M 1 , M 2 a and M 2 ß (for recent reviews, see Eglen and Whiting, 1986; Mutschier et al., 1987;1988). M 1 -Receptors are found in high density in neuronal tissues such as autonomic ganglia, cerebral cortex and hippocampus, whereas M 2 -receptors are mainly present in lower brain areas and in peripheral effector organs such as heart (M 2 a) and smooth musdes (M 2 ß) as weil as glands (M 2 ß). Their different affinities for selective muscarinic antagonists such as pirenzepine (M 1 >> M 2 a = M 2 ß; Hammer and Giachetti, 1982; Mutschier et al., 1987;1988) and methoctramine (M 2 a > M 1 > M 2 ß; Mutschier et al., 1988) are a major characteristic of these subtypes. Recent structure-selectivity relationship sturlies of a series of difenidol and hexocyclium analogues have led to the discovery of novel muscarinic antagonists, hexahydro-sila-difenidol (M 1 = M 2 ß >> M 2 a) and sila-hexocyclium (SiHC; M 1 ::::: M 2 ß > M 2 a) (Mutschler et al., 1987;1988), which display a high selectivity in blocking smooth muscle and glandular M 2 ß-receptors in comparison to cardiac M 2 a-receptors. We report here on the unique pharmacological profile of o-methoxysila-hexocyclium (o-MeSiHC; 4-{[cyclohexylhy-• To whom all correspondence should be addressed: Depart· ment of Phannacology, University of Frankfurt, TheodorStem.Kai 7, Gebäude 75A, 0·6000 FrankfurtjM, F.R.G.droxy(2-methoxyphenyl)silyl]methyl} -1, 1-dimethylpiperazinium methyl sulfate) which ex.hibits a spectrum of selectivity different from that of the parent compound (SiHC). To the best of our knowledge, o-MeSiHC is the first quaternary antimuscarinic agent which shows high M 1 -receptor selectivity.Experiments on ganglia were performed as described by Brown et al. (1980). Briefly, superior cervical ganglia were isolated from rats anaesthetised with urethane. The ganglia were suspended in separate heated chambers (36 ° C) and superfused with oxygenated (5% C0 2 , 95% 0 2 ) Krebs solution (composition in mmoljl: NaC1124; KCl 3; NaHC0 3 26; NaH 2 P0 4 1.25; CaC1 2 2; MgC1 2 2; ( + )-glucose 10). Muscarine-induced (pD 2 = 7.4) depolarisation was recorded differentially, via calomel electrodes, between the ganglion and its postganglionic trunk. Semicumulative dose-response curves for muscarine were obtained and the antagonists pirenzepine and o-MeSiHC were pre-equilibrated for 30 min. Left atria and strips of ileallongitudinal muscle from adult guinea-pigs were incubated under 0.5 g tension in 6 ml oxygenated (5% C0 2 , 95% 0 2 ) Tyrode solution (32°C; composition in mmoljl: NaCl 137; KCI 2.7; CaC1 2 1.8; MgC1 2 1.05; NaHC0 3 11.9; NaH 2 P0 4 0.42; ( + )-glucose 5.6). The atria were paced electrically at 120 beatsjmin. The ileum contractions and negative inotropic responses of the atria were recorded with a force-displacement 0014-2999/88/$03.50
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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