Desethylaprophen: a metabolite of aprophen with antimuscarinic activities.
The metabolic fate of aprophen hydrochloride (2-diethylaminoethyl 2,2-diphenylpropionate) was studied in rats after intravenous administration. Both 14C-labeled and unlabeled aprophen were used in these studies. Blood samples were collected and analyzed to determine the identities of the metabolites formed. Utilizing high-performance liquid chromatography, desethylaprophen was identified as a major metabolite in ether-extracted samples from rats, and could be detected in blood samples 1 min after intravenous administration. It was most likely formed by N-de-ethylation of aprophen by a cytochrome P-450-dependent monooxygenase. Synthetic desethylaprophen was found to possess cholinolytic activity (i.e., it functioned as a muscarinic antagonist by blocking the contraction of acetylcholine-stimulated guinea pig ileum, the release of alpha-amylase from pancreatic acinar cells stimulated by carbachol, and also by inhibiting the binding of [3H]N-methyl scopolamine to the muscarinic receptors of guinea pig ileum). It was interesting that although the biological effects of desethylaprophen were 100-fold lower than those of aprophen, it was equally able to compete for the binding sites of muscarinic receptors of the guinea pig ileum.
Brown
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ND
Department of Applied Biochemistry, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Smejkal
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RM
Breuer
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Doctor
B P
BP
Chiang
P K
PK
D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D010276:Parasympatholytics; D010666:Phenylpropionates / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism; D000516:alpha-Amylases / Q000378:metabolism
D010276:Parasympatholytics; D010666:Phenylpropionates; D011976:Receptors, Muscarinic; C055647:desethylaprophen; D000516:alpha-Amylases; C006615:aprofen