o-Methoxy-sila-hexocyclium: a new quaternary M1-selective muscarinic antagonist

Abstract

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

Selective antagonists provide evidence that M1 muscarinic receptors may mediate carbachol-induced drinking in the rat

“…In the present study 60 p.g/rat was the highest dose of methoctramine tested, as we observed that administration of 100 p.gjrat plus carbachol 1 p.g pro- Melchiorre et al (1987), c Lambrecht et al (1988a). d Lambrecht et al (1988c). c Lambrecht et al (1988b), r Eltze (1988), and 1 Eglen and Whiting (1986).…”

Binding and functional properties of antimuscarinics of the hexocyclium/sila‐hexocyclium and hexahydro‐diphenidol/hexahydro‐sila‐diphenidol type to muscarinic receptor subtypes

“…M1 receptors are above all found in the nervous system and are characterized by a high affinity for pirenzepine Birdsall et al, 1980;Brown et al, 1980;Hammer & Giachetti, 1982;Lambrecht et al, 1988b). M2 receptors, which show low affinity for pirenzepine, have been further subdivided into cardiac type and glandular/ smooth muscle subtypes by use of selective antago-1 Author for correspondence.…”

Characterization of the muscarinic receptor subtype mediating contractions of the guinea‐pig uterus

“…The M1 subtype exhibits a high affinity toward pirenzepine and o-methoxy-silahexocyclium (see Eglen & Whiting, 1986 for review;Lambrecht et al, 1988); the M2 subtype exhibits a high affinity toward methoctramine (Michel & Whiting, 1988) and the M3 subtype exhibits a high affinity toward hexahydrosiladiphenidol and silahexocyclium (Mutschler et al, 1987). The anatomical location of these subtypes suggest that the cerebral cortex, heart and salivary gland possess a preponderance of M1, M2 and M3 receptors respectively (Doods et al, 1987).…”