Ergolines as selective 5-HT1 agonists.
The synthesis and serotonin receptor subtype affinity of a series of ergolines are described. High selectivity for the 5-HT1 subtype was found with a number of 8-substituted (3 beta, 5 beta)-9,10-didehydro-6-methylergolines. The more potent and selective of these compounds increased the concentration of serotonin and decreased the concentration of 5-HIAA in rat brain and increased corticosterone concentration in rat serum. Oral administration of 13, (3 beta)-2,3-dihydrolysergine, produced long-lasting decreases in serotonin turnover. Compound 13 lacked substantial dopaminergic activity as measured by its effects on dopamine turnover in whole brain or striatum and its affinity for alpha-adrenergic binding sites was significantly less than for 5-HT1 binding sites. The increases in serum corticosterone concentrations produced by 13 were not blocked by the serotonin uptake inhibitor fluoxetine or by the serotonin synthesis inhibitor p-chlorophenylalanine, suggesting that 13 exerts its effects through direct stimulation of serotonin receptors.
Ward
J S
JS
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285.
Fuller
R W
RW
Merritt
L
L
Snoddy
H D
HD
Paschal
J W
JW
Mason
N R
NR
Horng
J S
JS
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003345:Corticosterone / Q000097:blood; D004347:Drug Interactions; D004873:Ergolines / Q000138:chemical synthesis* / Q000494:pharmacology; D010134:Fenclonine / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004873:Ergolines; D011985:Receptors, Serotonin; C056710:2,3-dihydrolysergine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D001058:Apomorphine; D010134:Fenclonine; D003345:Corticosterone