The zwitterionic spirocyclic \(\lambda_5\) -Silicates bis(3,4,5,6-tetrabromo- 1,2-benzenediolato(2- ))[2-(pyrrolidinio)ethyl]silicate (5; and its monohydrate 5 · H\(_2\)O) and bis[1,2-benzenediolato(2- )][( dimethylammonio)methyl]silicate (6) were synthesized by various methods including Si-C bond cleavage reactions. The crystal structures of 5, 5 · H\(_2\)O, and 6 were investigated by Xray düfraction. Furthermore, 5, 5 · H\(_2\)O, 6, and the related zwitterionic \(\lambda_5\)-spirosilicates 1 · 1/4 CH\(_3\)CN, 2 · CH\(_3\)CN, 3 · CH\(_3\)CN, and 4 were characterized by solid-state NMR spectroscopy (\(^{29}\)Si and \(^{15}\)N CP/MAS). The pentacoordinate silicon atoms of 5, 5 · H\(_2\)O (two crystallographically independent ZWitterions and two crystallographically independent water molecules), and 6 (two crystallographically independent zwitterions) are surrounded by four oxygen atoms and one carbon atom. The coordination polyhedrons around the silicon atoms of 5 and 6 can be described as distorted (5) or nearly ideal (6) trigonal bipyramids, the carbon atoms being in equatorial positions. 5 forms intramolecular and 6 intermolecular (--+ formation of dimeric units) N- H···O hydrogen bonds. The coordination polyhedrons around the two crystallographically independent silicon atoms of 5 · H\(_2\)O can be described as a nearly ideal and slightly distorted square pyramid, respectively, the carbon atoms being in the apical positions. In the crystal lattice of 5 · H\(_2\)O, intermolecular N-H···O and 0-H···O hydrogen bonds between the zwitterions and water molecules are observed. The results obtained by X-ray diffraction and solid-state NMR spectroscopy are consistent for each compound studied.

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The synthesis of the potent and highly selective silicon-containing antimuscarinic agent o-methoxysila- hexocyclium methyl sulfate and its corresponding tertiary amine (isolated as the dihydrochloride) is described. The quarternary compound is an omethoxy derivative of sila-hexocyclium methyl sulfate, which represents one of the tools currently used in experimental pharmacology for the subclassification of muscarinic receptors. The omethoxy derivative, the pharmacological profile of which differs substantially from tbat of the nonmethoxy compound, is also recommended as a tool for the investigation of muscarinic receptor heterogeneity.

The goals of the present study were: (1) to investigate thc binding properlies oi (R)- and (S)-procyclidine and two aehiral derivatives of muscarinic M\(_1\)• M\(_2\) and M\(_4\) receptor subtypes and (2) to identify the interaetions which allow these receptors to diseriminate between the two stereoisomers. (R)-Procyclidine showed a higher affinity for human neuroblastoma NB-OK 1 muscarinie M\(_1\) and rat striatum musearinie M\(_4\) receptors. a~ compared to rat cardiac M\(_2\) receptors. (S)-Procyclidine had a 130-iold lower affinity than (R)-procyclidine for M\(_1\) and M\(_4\) receptors. and a 40-fold lower affinity for M\(_2\) receptors. Pyrrinol. the aehiral diphenyl derivative with the eyclohexyl g.roup of (S}-procyclidine replaeed by a phenyl group, has an eight-fold lower affinity for M\(_1\) and M\(_4\) receptors. as eompared to (R)-procyclidine, and a three-fold lower affinity for M\(_2\) receptors. Hexahydro-procyclidine. the eorresponding achiral dicyclohexyl compound, had a 10- to 20-fold lower affinity than (R)-procyclidine for the three reeeptors. The inerease in binding free energy, which is observed when the phenyl and eyclohexyl groups of procyelidine are separately replaeed by cyclohexyJ and phenyl groups, respectively. was additive in the ease of M\(_1\)• M\(_2\) and M\(_4\) receptcrs. This indicates that the musearinic reeeptor s!ereoseleetivity was based on the eoexistence of two binding sites, one preferring a phenylrather than eyclohexyl group and the seeond preferring a cyclohexyl rather than a phenyl group. In addition. there were aiso binding sites for the hydroxy moiety and the protonated amino group of the ligands. The greater affinity and stereoselectivity of M\(_1\) and M\(_4\) muscarinic receptors for (R)-procyelidine reflected the better fit of the eyclohexyl group of (R)-procyclidine to the subsite of M\(_1\) and M\(_4\) as compared to M\(_2\) receptors.