Ergot alkaloids. New ergolines as selective dopaminergic stimulants

A new two-step sequence for the epimerization of methyl dihydrolysergate (5) at C-8 leading to methyl dihydroisolysergate (7) is presented. The latter compound was used as a starting material for the synthesis of various ergolines, of which (5R,8R,10R)-8-(cyanomethyl)-6-methylergoline (4) is a very strong and long-lasting central dopaminergic agent. Furthermore, it was found that some 8-(arylthiomethyl)-6-methyler-golenes are not able to induce apomorphine-like stereotyped behavior in normal rats but exhibit a remarkable activity in rats unilaterally lesioned by 6-OH-DA in the nigrostriatal region. Compound 4 and (5R,8R)-8-[(2-pyridyl)thiomethyl]-6-methylergolene (9) were further tested for their ability to inhibit ovum implantation and to depress serum prolactin levels in rats. Their potency was evaluated in comparison with (5R,8S,10R)-8-(cyanomethyl)-6-methylergolines (2a and 2b) and 2-bromo-alpha-ergocryptine (1) as standards.