6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (azaprophen), a highly potent antimuscarinic agent.
The synthesis and antimuscarinic properties of 6-methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate (1, azaprophen) are described. Azaprophen is 50 times more potent than atropine as an antimuscarinic agent as measured by the inhibition of acetylcholine-induced contraction of guinea pig ileum and is more than 1000 times better than atropine in its ability to block alpha-amylase release from pancreatic acini cells induced by carbachol. In addition, azaprophen is 27 times more potent than atropine as an inhibitor of binding of [N-methyl-3H]scopolamine to muscarinic receptors, with human IMR-30 neuroblastoma cells. The potencies of azaprophen and atropine in altering operant behavior were similar. The structural features of 1 are compared to the standard anticholinergic drugs atropine and quinuclidinyl benzilate by using energy calculations and molecular modelling studies. A modification of the pharmacophore model hypothesis for cholinergic agents is suggested.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012601:Scopolamine / Q000378:metabolism; D014326:Tropanes / Q000138:chemical synthesis / Q000494:pharmacology*; D000516:alpha-Amylases / Q000378:metabolism
D010666:Phenylpropionates; D011976:Receptors, Muscarinic; D014326:Tropanes; C052339:azaprophen; D002217:Carbachol; D012601:Scopolamine; D000516:alpha-Amylases; D000109:Acetylcholine