Preferential blockade of alpha 1-adrenoceptors in the rabbit pulmonary artery by derivatives of beta-phenylethylamine chemically related to BE 2254 (heat).

We investigated the antagonistic properties of several derivatives of beta-phenylethylamine at pre- and postsynaptic alpha-adrenoceptors (alpha 2 and alpha 1, respectively) using strips of rabbit pulmonary arteries preincubated with [3H]noradrenaline. The parent compound, BE 1726 [2-(beta-phenylethyl-aminomethyl)-tetralone], produced an increase in electrically evoked 3H overflow and in inhibition of the electrically evoked increase in tension; both effects occurred in the same concentration range. Substitution on the benzene ring of the beta-phenylethylamine moiety with a hydroxy (e.g., BE 2254, a well-characterized alpha 1-adrenoceptor antagonist) and/or methoxy group did not substantially alter the presynaptic potency, but considerably increased the potency at postsynaptic sites (some of the derivatives were as potent as prazosin). beta-Hydroxy substitution on the aliphatic chain selectively decreased the presynaptic potency. Hence, these changes in structure resulted in a marked preference for action at postsynaptic sites which was, however, less pronounced than that of prazosin. The increasing effect of the drugs on 3H overflow was attenuated by clonidine, and the compounds produced parallel shifts to the right of the concentration-response curve of noradrenaline for its contractile action, suggesting that the pre- and postsynaptic effects were mediated via alpha-adrenoceptors. In conclusion, strong and preferential blockade of alpha 1-adrenoceptors can be achieved by derivatives of beta-phenylethylamine, N-substituted with methyl-alpha-tetralone.