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The present study was designed to further eharaeterize the presynaptie musearlnie M 1 -reeeptor responsible for the inhibition of neuragenie eontraetions in the isolated rabbit vas deferens. Eleetrically induced twiteh eontraetions of this preparation were inhibited by the M 1 -agonist, MeN-A-343, and by some of its analogs: 4-ehloro-phenyl derivative> MeN-A-343 > trans-olefinie analog> cis-olefinie analog. The same rank order of potency was obserVed for these agonists to raise the blood pressure of pithed rats by stimulation of M 1 -receptors in sympathetie ganglia. A highly signifieant eorrelation was found between the antimusearinie potencies of atropine, pirenzepine and a series of 9 antagonists strueturally related to the ganglionie M 1 p-receptor selective compounds, hexocyclium and hexahydro-difenidol, to antagonize the MeN-A-343-indueed inhibition of twitch eontraetions in rabbit vas deferens or the musearine-indueed depolarization in rat isolated superior eerVieal ganglia. I t is suggested that the presynaptie musearlnie receptor that mediates inhibition of neuragenie contraetions in rabbit vas deferens is of the ganglionic M 1 p-type.Musearlnie receptor subtypes; Vas deferens (rabbit); Pithed rat; Ganglia (rat); Musearlnie aeetyleholine receptor agonists; Musearlnie aeetyleholine receptor antagonists; MeN-A-343 analogs

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Pilocarpine isosteres have been synthesized and characterized with regard to their in vitro muscarinic properties. The results indicate that the carbonyl oxygen of the lactone function of pilocarpine is of primary importance for agonist activity with the ether oxygen being of lesser or secondary importance. An X-ray structure determination for the hydrogen O,O'-ditoluoyltartrate salt of thiolactone pilocarpine isostere 2a has been performed. This compound has an unusual pharmacological profile exhibiting M1-agonist selectivity as well ass presynaptic antagonism. As a result this compound is also viewed as having therapeutic potential for Alzheimer's disease. A model for the binding of pilocarpine and other muscarinic agonists to the third transmembrane helix of the human m1 muscarinic receptor has been developed.

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