In an attempt to assess the structural requirements for the muscarinic receptor selectivity of hexahydro-diphenidol (hexahydro-difenidol) and hexahydro-sila-diphenidol (hexahydro-sila-difenidol), a series of structurally related C/Si pairs were investigated, along with atropine, pirenzepine and methoctramine, for their binding affinities in NB-OK 1 cells as well as in rat heart and pancreas.2 The action of these antagonists at muscarinic receptors mediating negative inotropic responses in guinea-pig atria and ileal contractions has also been assessed. 3 Antagonist binding data indicated that NB-OK 1 cells (M1 type) as well as rat heart (cardiac type) and pancreas (glandular/smooth muscle type) possess different muscarinic receptor subtypes. 4 A highly significant correlation was found between the binding affinities of the antagonists to muscarinic receptors in rat heart and pancreas, respectively, and the affinities to muscarinic receptors in guinea-pig atria and ileum. This implies that the muscarinic binding sites in rat heart and the receptors in guinea-pig atria are essentially similar, but different from those in pancreas and ileum. 5 The antimuscarinic potency of hexahydro-diphenidol and hexahydro-sila-diphenidol at the three subtypes was influenced differently by structural modifications (e.g. quaternization). Different selectivity profiles for the antagonists were obtained, which makes these compounds useful tools to investigate further muscarinic receptor heterogeneity. Indeed, the tertiary analogues hexahydrodiphenidol (HHD) and hexahydro-sila-diphenidol (HHSiD) had an M1 = glandular/smooth muscle > cardiac selectivity profile, whereas the quaternary analogues HHD methiodide and HHSiD methiodide were M1 preferring (M1 > glandular/smooth muscle, cardiac).

Sila-Procyclidin (1 b) sowie dessen Derivate 2 b (Sila-Trihexyphenidyl), 3 b und 4 b (Sila-Cycrimin) wurdenausgehend von C13SiCH2CIdurch eine neue, sechsstufige Synthese mit einer Gcsamtausbeute von 16 (lb). 19 (Zb), 8 (3b) bzw. 7% (4b) dargcstellt. -Verglcichende in-vivo-Untenuchungen (Maus, per-os-Applikation) hinsichtlich der peripheren und zentralen anticholinergen Wirkung haben gezcigt. daO die Silicium-Verbindung 1 b dem Kohlenstofl-Analogon 1 a (Procyclidin) iiberlegen ist.

AbstractThe trimethylsilylalkyl acetoacetates 1 b and 2 b as well as their carba analogues 1 a and 2 a have been reduced microbiologically by Kloeckera corticis (ATCC 20109), leading to the corresponding ( + )-3(S)-hydroxybutanoates 3b, 4b, 3a, and 4a. The enantiomeric purity was found to be 80% (3a, 3b, 4b) and 65% (4a), respectively. The reduction of lb and 2b is - to our knowledge - the first example for a controlled microbiological transformation of organosilicon substrates.

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Enantiomer and the Racemate of the Antimuscarinic Agent (Cyclohexy1)phenyl[Z-(pyrrolidin-I -yl)ethyl]silanol (Sila-Procyclidine) t