Rapid communication o-Methoxy-sila-hexocyclium: a new quatemary M 1-selective muscarinic antagonist

The musearlnie receptors are currently divided into at least three subtypes: M1, M 2a and M 2ß (for recent reviews, see Eglen and Whiting, 1986; Mutschier et al., 1987; 1988). M1-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 2a) and smooth musdes (M 2ß) as weil as glands (M 2ß). Their different affinities for selective muscarinic antagonists such as pirenzepine (M1 >> M 2a = M 2ß; Hammer and Giachetti, 1982; Mutschier et al., 1987; 1988) and methoctramine (M 2 a > M 1 > M 2ß; 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 (M1 = M2ß >> M 2 a) and sila-hexocyclium (SiHC; M1 ::::: M 2ß > M 2a) (Mutschler et al., 1987; 1988), which display a high selectivity in blocking smooth muscle and glandular M 2ß-receptors in comparison to cardiac M 2a-receptors. We report here on the unique pharmacological profile of o-methoxysila-hexocyclium (o-MeSiHC; 4-{[cyclohexylhy-