Binding affinities of hexahydro-difenidol and hexahydro-sila-difenidol analogues at four muscarinic receptor subtypes: constitutional and stereochemical aspects
| Autor: | Jean Christophe, Michèle Tastenoy, Jean Claude Camus, Ernst Mutschler, Carsten Strohmann, Reinhold Tacke, Günter Lambrecht, Magali Waelbroeck |
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| Jazyk: | angličtina |
| Rok vydání: | 1991 |
| Předmět: |
Stereochemistry
Substituent In Vitro Techniques Binding Competitive Structure-Activity Relationship chemistry.chemical_compound Piperidines Muscarinic acetylcholine receptor Tumor Cells Cultured Animals Humans Anorganische Chemie Binding site Methiodide Receptor Pancreas Pharmacology Myocardium Brain Rats Inbred Strains Stereoisomerism Receptors Muscarinic Affinities Rats Kinetics chemistry ddc:540 Stereoselectivity Selectivity |
| Popis: | Hexahydro-sila-difenidoJ and eight analogues behaved as simple cumpetitive inhibitors of eHJN·methyl·scopoJamine binding to homogenates frorn human neuroblastoma NB-OK 1 cells (MI sites), rat heart (M 2 sites), rat pancreas (M 3 sites), and rat striatum 'B' sites (M4 sites). Pyrrolidino- and hexamethyleneimino analogues showed the same sekctivity profile as the parent compound. Hexahydro-sila-difenidol methiodide and the methiodide of p-fluoro-hexahydro·sila-difenidol had a fugher affinity but a lower selectivity than the tertiary amines. Compounds containing a p·methoxy, p-chJoro or p-fluoro substituent in the phenyl ring of hexahydro-sila-difenidol showed a qualitative)y similar selectivity profile as the parent compound (i.e., MI= M 3 = ;"~ 4 ::;.. M 2 j, but up to 16-fold lower affinities. o-Methoxy-hexahydro-sila-difenidol has a lower affinity than hexahydro-sila-difeni.:!o! at the four binding sites. lts selectivity profile (M4 > M 1, M 3 > M 2 ) was different from hexahydro-sila-difenidol. Replacement of the centrat silicon atom of hexahydro-sila-difenidol, p-fluoro-hexahydro-sila-difenidol and thdr quatemary (N-methylated) analogues by a carbon atom did not change their binding affinities significantly. The iour 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. Musearlnie receptor subtypes (MIM 2 , M 3, and (putative) M 4 ); Muscarinic receptor antagonists (selective); Hexahydro-sila-difenidol analogues; p-Fluoro-hexahydro-sila-difenidol: Stereoselecti"·ity (at muscarinic receptors) |
| Databáze: | OpenAIRE |
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