title: Binding affinities of hexahydro-difenidol and hexahydro-sila-difenidol analogues at four muscarinic receptor subtypes: constitutional and stereochemical aspects.
abstract: 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.
authors.affiliation: Department of Biochemistry and Nutrition, Medical School, Free University of Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Waelbroeck
authors.forename: J
authors.initials: J
authors.lastname: Camus
authors.forename: M
authors.initials: M
authors.lastname: Tastenoy
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: C
authors.initials: C
authors.lastname: Strohmann
authors.forename: R
authors.initials: R
authors.lastname: Tacke
authors.forename: G
authors.initials: G
authors.lastname: Lambrecht
authors.forename: J
authors.initials: J
authors.lastname: Christophe
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000145:classification / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D010880:Piperidines; D011976:Receptors, Muscarinic; C060685:hexahydrodifenidol; C046773:hexahydrosiladifenidol