Lisbeth Nilvebrant

Dicyclomine, benzhexol and oxybutynine distinguish between subclasses of muscarinic binding sites☆

The interactions of various unlabelled antimuscarinic drugs with the muscarinic receptors in the cerebral cortex, heart and urinary bladder were studied by a receptor binding technique, using (-)[3H]QNB as radioligand. In contrast to the other drugs examined, dicyclomine, benzhexol, oxybutynine and pirenzepine were bound with a significantly higher affinity in the cortex than in the heart and bladder. Furthermore, not only pirenzepine, but also dicyclomine and benzhexol were capable of distinguishing between two populations of muscarinic binding sites in the cortex. The low affinity sites for these drugs in the cortex were characterised by dissociation constants which were similar to those determined in the heart and the bladder, respectively. It was concluded that dicyclomine and benzhexol, like pirenzepine, are selective antagonists at the putative M1-receptor. Oxybutynine exhibited the same affinity profile but the tissue selectivity of this drug was less pronounced.

Receptor binding profiles of some selective muscarinic antagonists

The binding of hexahydrosiladifenidol, procyclidine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine) and AF-DX 116 to muscarinic receptors in the heart, ileum, urinary bladder, parotid gland and cerebral cortex from guinea pig was studied in competition experiments with (-)-[3H]QNB. The affinity of AF-DX 116 was higher in the heart than in the cortex and it was extremely low in the parotid gland. The affinities of hexahydrosiladefinidol, procyclidine and 4-DAMP were higher in the cortex and parotid gland than in the heart, bladder and ileum. Hexahydrosiladifenidol and 4-DAMP recognized two classes of muscarinic binding sites in the cortex. However, in contrast to functional data, binding results showed that 4-DAMP hexahydrosiladifenidol and procyclidine did not distinguish between the sites in the smooth muscles and those in the heart. Nevertheless, the present data support the view that the putative M2-receptors are heterogeneous, since the four drugs examined were found to distinguish between the muscarinic binding sites in the parotid gland and those in smooth muscles and heart.