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.
D000818:Animals; D003342:Corpus Striatum / Q000502:physiology; D010064:Embryo Implantation / Q000187:drug effects; D004873:Ergolines / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D006892:Hydroxydopamines / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011388:Prolactin / Q000097:blood; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000502:physiology; D013378:Substantia Nigra / Q000502:physiology
D004873:Ergolines; D006892:Hydroxydopamines; D011954:Receptors, Dopamine; D011388:Prolactin