Hypotensive properties of benzodioxane derivatives structurally related to R 28935. Comparison of activity with some receptor affinities.

Hypotensive activities were determined of some derivatives of erythro 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]-4-piperidyl)-2-benzimidazolinone (R 28935) following intravenous administration to anaesthetized normotensive rats. Introduction of chlorine into the benzimidazolinone part of R 28935 negatively influenced the hypotensive potency as did opening of the dioxane ring. An appropriate substituent restored the hypotensive effectiveness of the "opened" structures. In general, the compounds were weak inhibitors of the specific binding of (3H)-prazosin (alpha 1-adrenoceptors), (3H)-clonidine (alpha 2-adrenoceptors) and (3H)-dihydromorphine (opiate-receptors) to rat brain membranes. The relative order of affinity for either receptor did not correspond with that of the hypotensive activity. Previous (-15 min) intravenous treatment with phentolamine (0.2 mg/kg) abolished the depressor effect of prazosin and diminished that of the threo form R 29814 as well as of all "opened" congeners, but did not significantly reduce the hypotensive response to R 28935 and the other erythro structures. It is concluded that neither alpha 1- and alpha 2- nor opiate-receptors are involved as the primary targets for R 28935 and its congeneric drugs to induce hypotension. The exact mechanism of action remains therefore unsolved. Erythro R 28935 and the other racemic erythro mixtures are centrally acting hypotensive agents. A peripheral alpha-sympatholytic component may contribute to the overall depressor effect of threo R 29814 and the "opened" derivatives.