Binding and functional properties of antimuscarinics of the hexocyclium/sila‐hexocyclium and hexahydro‐diphenidol/hexahydro‐sila‐diphenidol type to muscarinic receptor subtypes

1 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 me...

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Bibliographic Details
Published in:	British journal of pharmacology Vol. 98; no. 1; pp. 197 - 205
Main Authors:	Waelbroeck, M., Tastenoy, M., Camus, J., Christophe, J., Strohmann, C., Linoh, H., Zilch, H., Tacke, R., Mutschier, E., Lambrecht, G.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-09-1989 Nature Publishing
Subjects:	Animals Biological and medical sciences Cells, Cultured Cholinergic system Guinea Pigs Humans Ileum - drug effects Ileum - metabolism In Vitro Techniques Male Medical sciences Muscle, Smooth - drug effects Muscle, Smooth - metabolism Myocardium - metabolism Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pancreas - drug effects Pancreas - metabolism Parasympatholytics - metabolism Parasympatholytics - pharmacology Pharmacology. Drug treatments Piperazines - metabolism Piperazines - pharmacology Piperidines - metabolism Piperidines - pharmacology Rats Rats, Inbred Strains Receptors, Muscarinic - drug effects Receptors, Muscarinic - metabolism Stereoisomerism Structure-Activity Relationship Heart Rat Rodentia Tissue specificity Selectivity Neuroblast In vitro Vertebrata Biological fixation Mammalia Animal Affinity Muscarinic receptor Antagonist Pancreas
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Summary:	1 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).
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0007-1188 1476-5381
DOI:	10.1111/j.1476-5381.1989.tb16882.x