Binding affinities of hexahydro-difenidol and hexahydro-sila-difenidol analogues at four muscarinic receptor subtypes: constitutional and stereochemical aspects

Hexahydro-sila-difenidol and eight analogues behaved as simple competitive inhibitors of [3H]N-methyl-scopolamine binding to homogenates from human neuroblastoma NB-OK 1 cells (M1 sites), rat heart (M2 sites), rat pancreas (M3 sites), and rat striatum 'B' sites (M4 sites). Pyrrolidino- and hexamethyleneimino analogues showed the same selectivity profile as the parent compound. Hexahydro-sila-difenidol methiodide and the methiodide of p-fluoro-hexahydro-sila-difenidol had a higher affinity but a lower selectivity than the tertiary amines. Compounds containing a p-methoxy, p-chloro or p-fluoro substituent in the phenyl ring of hexahydro-sila-difenidol showed a qualitatively similar selectivity profile as the parent compound (i.e., M1 = M3 = M4 greater than M2), but up to 16-fold lower affinities. o-Methoxy-hexahydro-sila-difenidol has a lower affinity than hexahydro-sila-difenidol at the four binding sites. Its selectivity profile (M4 greater than M1, M3 greater than M2) was different from hexahydro-sila-difenidol. Replacement of the central silicon atom of hexahydro-sila-difenidol, p-fluoro-hexahydro-sila-difenidol and their quaternary (N-methylated) analogues by a carbon atom did not change their binding affinities significantly. The four muscarinic receptors showed a higher affinity for the (R)- than for the (S)-enantiomers of hexahydro-difenidol, p-fluorohexahydro-difenidol and their methiodides. The stereoselectivity varied depending on the receptor subtype and drug considered.