A benzodioxanhydroxyethylpiperidine derivative with an acute central hypotensive action, different from that of clonidine. A comparison with neuroleptic agents.

Ertyhro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidazolinone (R28935), a new benzodioxanhydroxyethylpiperidyl derivative that is chemically but not pharmacologically related to pimozide, proved to possess potent central hypotensive activity when injected into the left vertebral artery of anaesthetized cats. Although almost as potent as clonidine, its hypotensive action is more prolonged. The central hypotensive effect is dose-dependent and stereospecific, the threo-isomer being much less effective than the erythro-form. In contrast to the effect of clonidine, the centrally induced hypotensive action of R 28935 is not diminished after pretreatment with piperoxane, yohimbine or desipramine. Accordingly, central alpha-adrenergic receptors are probably not involved in the central hypotensive action of R 28935. The following surgical interventions did not diminish the central hypotensive action of R 28935: bilateral vagotomy, bilateral cervical sympathectomy, bilateral extirpation of the stellate ganglia. Neuroleptic agents like pimozide, haloperidol, chlorpromazine and promazine were far less potent hypotensive agents. Promazine showed some central hypotensive action but the blood pressure-lowering effects of the other neuroleptic drugs are of peripheral origin and probably reflect the alpha-sympatholytic properties. From the results it si concluded that R 28935 depresses peripheral sympathetic tone via a centrally induced primary effect. Central alpha-adrenergic receptors do not play a role in this primary effect of R 28935, whereas they do play their part in that of clonidine or alpha-methyl-DOPA. As such, R 28935 is an example of a new class of centrally acting hypotensive compounds. Moreover, this compound provesthat it has been possible to separate the neuroleptic and hypotensive properties in benzimidazolinone derivatives.