beta-adrenoreceptor blocking heterocyclic oximes and ethers

This paper reports synthesis and pharmacological properties of thienyl, pyrrol, indolyl and benzofuryl-O-(3-alkylamine-2-hydroxypropyl)oximes and some 3-(3-alkylamine-2-hydroxypropyl)alkyloxy indoles aiming to study the influence of five membered and condensed heterocyclic substituents on the beta-adrenoreceptor inhibiting potency. All heterocyclic derivatives synthesized (1-17) were less active than the reference propranolol on the rat heart, while showed a comparable potency on the guinea pig trachea, exibiting a significant beta(2)-selectivity. The low beta-blocking potency of the five membered derivatives seemed to confirm the negative influence of the polarization of the oximic carbon in the binding with non polar region of the beta-adrenoreceptor. Another important interaction could take place with the enzime adenyl-cyclase which is responsible of the signal of transduction. It could be hypothesized that the heteroatom of the heterocyclic nucleus acted as an electron-donor group and engaged a cohordinative bond with magnesium atom present on the adenylcyclase system; responsible of the agonist activity. The pharmacological in vivo experiments and the binding results were in accordance with the in vitro data.