β-Adrenoceptor Antagonistic Actions and Mutagenicities of R(+)- and S(-)-Enantiomers of N-Desisopropylpropranolol and Its N-Acetyl Conjugate

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Enantiospecific acetyl conjugation was examined in the rat liver 105000×g supernatant (cytosol) system using racemic 1-amino-3-(1-naphthyloxy)-2-propanol (NDP), a N-desisopropyl metabolite of propranolol. From the results of chiral separative determination of the samples by HPLC using a Chiralcel OD-R column, more remarkable enantiospecificity was observed in the R(+)-enantiomer on NDP elimination and N-acetyl conjugate (AcNDP) formation.Next, the strength of β-adrenoceptor antagonistic actions and mutagenicities was compared between R(+)- and S(-)-enantiomers of NDP and AcNDP, respectively. In the case of NDP, both enantiomers possessed weak β_1-adrenoceptor antagonistic effects on isoproterenol-induced positive inotropic and chronotropic actions in the left and right atria isolated from a guinea pig. These actions of R(+)- and S(-)-NDP were 1700-times and 100-times less potent, respectively, than those of propranolol. β_2-Adrenoceptor antagonistic actions of R(+)- and S(-)-NDP in the trachea were 1600-times and 200-times less potent, respectively, than those of propranolol. Enantiospecificity was observed in the β-adrenoceptor antagonistic action of S(-)-NDP, while R(+)-NDP and both enantiomers of AcNDP appeared to be negligible in this action.On the other hand, the mutagenicities of each enantiomer were examined by the Ames method using 13 kinds of Salmonella typhimurium strains. In the case of AcNDP, the numbers of colonies increased according to the substrate concentration only when rat liver 9000×g supernatant fraction (S-9 mixture) was added to the plates containing TA100,YG1029,TA104 and YG3003,and then enantiospecificity was observed in the mutagenicity of S(-)-AcNDP. Thus, the ultimate mutagen might be an active metabolite formed mainly from S(-)-AcNDP.Despite of the addition of rat liver S-9 mixture, R(+)-AcNDP and both enantiomers of NDP did not indicate mutagenicity.
公益社団法人日本薬学会の論文
1997-01-15

β-Adrenoceptor Antagonistic Actions and Mutagenicities of R(+)- and S(-)-Enantiomers of N-Desisopropylpropranolol and Its N-Acetyl Conjugate

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