Mezilamine, a new dopamine antagonist, blocks presynaptic but stimulates postsynaptic alpha-adrenoceptors.

Mezilamine (2-methylamino-4-N-methylpiperazino-5-methylthio-6-chloropyrimidine), a new antidopaminergic agent, induced a concentration dependent increase in the electrically stimulated overflow of ³-H-noradrenaline from rat cortical slices, without affecting the basal overflow. The mezilamine effect of ³H overflow was antagonized by clonidine. It could not be related to noradrenaline uptake inhibition firstly because mezilamine is a weak inhibitor of noradrenaline uptake and secondly because of the presence in the medium of cocaine, a potent noradrenaline uptake inhibitor. In the same way, mezilamine increased the electrically induced contraction of the rat vas deferens and clonidine reversed this effect. Clonidine and mezilamine induced contractions of the rat anococcygeus muscle. On the contrary, classical neuroleptics such as chlorpromazine or UK 177, another antidopaminergic agent of the same chemical class as mezilamine, antagonized as did yohimbine and phenoxybenzamine the anococcygeus muscle contraction induced by noradrenaline. In the pithed rat, contrary to chlorpromazine and UK 177 which, like yohimbine, antagonizezd the hypertensive effect of clonidine, mezilamine, like clonidine, increased the blood pressure. But, like chlorpromazine and yohimbine, mezilamine reversed the inhibitory effect of clonidine on the electrically stimulated tachycardia. All these results suggested opposite effects of mezilamine on presynaptic and postsynaptic α-adrenoceptors. Mezilamine acts as a presynaptic α-antagonist and a postsynaptic α-agonist.