A cholinergic antagonist identifies a subclass of muscarinic receptors in isolated rat pancreatic acini.
Atropine, pirenzepine (PZ) and the novel antimuscarinic drug [11- [[2-(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) were used to subclassify the pancreatic muscarinic receptor by correlating their effects on carbachol-mediated amylase release with their actions on the binding of [3H]N-methylscopolamine in rat pancreatic acini. Maximal stimulation of amylase release occurred at 3 microM carbachol. Atropine, PZ and AF-DX 116 inhibited carbachol-mediated amylase release with the following pA2 values: atropine = 9.1, PZ = 6.5 and AF-DX 116 = 5.7. There was parallel inhibition of [3H]N-methylscopolamine binding, with the following inhibition constants: atropine = 2.38 nM, PZ = 426 nM and AF-DX 116 = 3660 nM. Using the same animals, these compounds inhibited [3H]N-methylscopolamine binding in homogenates from both cerebral cortex and heart. The order of potency was the same in the cerebral cortex as in the pancreas: atropine = 0.67 nM, PZ = 85 nM and AF-DX 116 = 440 nM. However, in the cortex, the binding data with PZ also exhibited a high-affinity site with a KH value of 11 nM. In the heart, the order of potency was shifted to atropine greater than AF-DX 116 greater than PZ, with inhibition constants of 1.55, 12 and 110 nM, respectively. Thus, the muscarinic receptors in the pancreas and the heart exhibited the characteristics of the putative M2 receptor subtype, having lower affinities for PZ than the muscarinic receptors in the cerebral cortex. However, the heart had a significantly higher affinity for AF-DX 116.(ABSTRACT TRUNCATED AT 250 WORDS)
D000681:Amylases / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism; D019832:N-Methylscopolamine; D010179:Pancreas / Q000032:analysis*; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000378:metabolism
D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D010890:Pirenzepine; D001285:Atropine; D002217:Carbachol; D000681:Amylases; C048593:otenzepad; D019832:N-Methylscopolamine