beta.-Adrenoceptor activity of the stereoisomers of the bufuralol alcohol and ketone metabolites

The stereoisomers of 2-[(tert-butylamino)methyl]-7-methyl-2,7-benzofurandimethanol (2) and 2-[2-(tert-butylamino)-1-hydroxyethyl]-7-benzofuranyl methyl ketone (3), the alcohol and ketone metabolites of bufuralol, have been prepared and examined for beta-adrenoceptor activity in rats. All the stereoisomers with the S configuration hydroxylamine side chain showed potent beta 2-antagonist activity comparable to (S)-bufuralol (1a). In contrast, a wide range of antagonist potencies was observed at the beta 1-receptor; only alcohol diastereomer 9a was more active than 1a. This suggests that the shape of the 7-substituent in these benzofurans influences the degree of interaction with the beta 1-receptor much more than with the beta 2-receptor. Partial beta 1-agonist activity was associated not only with all the stereoisomers with the S configuration hydroxylamine side chain but also with some of the R configuration derivatives, especially (R)-ketone 3b. The results suggest that the margin of difference in beta-adrenoceptor activity between compounds epimeric at the hydroxylamine side chain can be significantly influenced by a suitable substituent in the aromatic nucleus.