The development of dopaminergic supersensitivity was evaluated, after single oral administration of the long-acting neuroleptic drug isofloxythepin, in nigrostriatal and tuberoinfundibular system in the rat. Isofloxythepin (5 mg/kg orally) increased concentration homovanillic acid (HVA) in the striatum for up to 24 h after administration, whereas a significant decrease below control values was found after 4-5 days. A similar biphasic effect appeared in behavior, since there was an enhancement of apomorphine stereotypy 4-5 days after administration of isofloxythepin (5 and 10 mg/kg orally). Both findings agree with the hypothesis of development of nigrostriatal dopaminergic supersensitivity at long intervals after isofloxythepin. On the other hand, the increase in prolactin (PRL) secretion induced by isofloxythepin indicated only the blocking action of this drug on dopamine receptors in the tuberoinfundibular system, and provided no evidence for tuberoinfundibular dopaminergic supersensitivity after neuroleptic treatment. It is concluded that a single dose of isofloxythepin is capable of inducing dopaminergic supersensitivity in the nigrostriatal system, but not in the tuberoinfundibular system.

6-Substituted 1-[(5R,8S,10R)-8-ergolinyl]-3,3-diethylureas II-VII were prepared from hydrazides of (5R,8S,10R)-6-alkyl-8-ergolinecarboxylic acids (VIIIa, VIIIb) via the corresponding azides IXa and IXb and isocyanates Xa and Xb, and/or from 1-[(5R,8S,10R)-6-methyl-8-ergolinyl]-3,3-diethylurea (I) via XI and XII. Two of the by-products arising in the latter route have been identified (XIII, XIV). Some of the ureas prepared, especially II and III, had strong inhibitory effects in vivo on the secretion of prolactin in rats.

No abstract

Die Titelverbindungen (Ib)‐(Ie) werden synthetisiert und mit dem Methylderivat (Ia) (Tergurid) vergleichend hinsichtlich der pharmakologischen Eigenschaften untersucht.