Activity of two new potent dopaminergic agonists at the striatal and anterior pituitary levels

Abstract

Two N-diphenethylamine derivatives, RU24213 and RU24926, displaced [ 3H]-dihydroergocryptine binding to bovine anterior pituitary membranes at K D values of 150 and 100 nM, respectively, and were potent inhibitors of prolactin release in anterior pituitary cells in primary culture at respective ED 50 values of 5 and 3 nM. After administration by the oral route in the rat, both compounds (5 mg/kg), exerted potent and long-lasting inhibitory effects on plasma prolactin levels which were still reduced to 45% of control 6 hr after the administration of the compound with longer-lasting activity, RU24926. Furthermore, these two drugs were more potent than apomorphine in decreasing striatal dopamine turnover and increasing striatal acetylcholine levels in either intact rats or animals having a unilateral 6-hydroxy dopamine-induced lesion of the nigrostriatal dopaminergic pathway. The stimulatory effect of both RU24213 and RU24926 on striatal acetylcholine levels in intact rats was much longer-lasting than that of apomorphine, a significant effect of RU24926 being still observed 4 hr after intraperitoneal administration of the compound (5 mg/kg). At concentrations up to 10 −4 M, RU24213 and RU24926 were inactive on either basal or dopamine-stimulated striatal adenylyl cyclase activity. The present data indicate that these two new drugs have potent dopaminergic activity at the striatal and anterior pituitary levels and therefore have a potential therapeutic activity for the treatment of Parkinson's disease and prolactin-secreting adenomas.