Comparison of the effects of recently developed alpha 2-adrenergic antagonists with yohimbine and rauwolscine on monoamine synthesis in rat brain.

The effects of two recently developed alpha 2-adrenergic antagonists, RX 781094 and WY 26703, on the synthesis of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in rat brain were compared to those of yohimbine, its diastereoisomer rauwolscine, and mianserin. Intraperitoneal administration of these compounds increased cortical NE synthesis with the potency order: yohimbine, RX 781094, WY 26703 greater than rauwolscine greater than mianserin. Within a similar dose range, yohimbine, rauwolscine and WY 26703 also stimulated striatal DA synthesis and decreased hypothalamic 5-HT synthesis, while RX 781094 and mianserin were very weak or inactive. Yohimbine and the structurally-related WY 26703 were also active as DA antagonists in the gamma-butyrolactone model for DA autoreceptor function. Based on the drug-induced changes in monoamine synthesis as indication of receptor-mediated events, RX 781094 has greater selectivity as an alpha 2-antagonist than compounds structurally related to yohimbine.