Studies with new ergoline derivatives on the effects of central and peripheral 5-hydroxytryptamine receptors.
The antiserotonin properties of a series of new ergoline derivatives were investigated in several pharmacological test systems which have been proposed for the characterization of putative antagonists at central and peripheral 5-HT2 receptors. In radioligand binding studies with [3H]ketanserin among the new ergolines only 1-methyl-2-brom-9,10-dihydrolysergic acid-bis(beta-acetoxyethyl)-amide (AWD 52-336) showed high affinity at cortical 5-HT2 receptors (Ki-5.4 nmol/l). In 5-HT-amplified ADP-induced aggregation of human platelets 6-nor-6-propyl-9,10-dihydro ergometrine (AWD 52-227) and 9,10-dihydrolysergic acid-di-ethanol-amide (AWD 52-302) were potent inhibitors of 5-HT response. Comparison of this two in vitro tests demonstrated a significant correlation (r = 0.636; p < 0.05) between the ability of the ergolines to block the 5-HT aggregation mediated by platelet 5-HT2 receptors and their affinity to [3H]ketanserin-labelled binding sites in rat cortical membranes. In the used in vivo tests (tryptamine tremor, 5-HTP-induced head twitches) 1-methyl-9,10-dihydrolysergic acid-bis(beta-acetoxyethyl)-amide (AWD 52-83) and AWD 52-336 were found to antagonize the behavioural responses with comparatively moderate potency. The results suggest, therefore, that AWD 52-83 and AWD 52-336 may be both central and peripheral acting 5-HT2 antagonists, whereas AWD 52-227 and AWD 52-302 seem to be potent blockers at peripheral 5-HT2 receptors. Furthermore, the obtained results allow to reveal structure-activity relationships of ergolines. Substitution in position 1 in the tetracyclic ergoline ring system may be important with respect to the efficacy at central 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Harhammer
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Institute of Pharmacology and Toxicology, Humboldt University of Berlin Fed. Rep. of Germany.
Schäfer
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Ott
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D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004873:Ergolines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D014202:Tremor / Q000139:chemically induced / Q000523:psychology; D014363:Tryptamines / Q000378:metabolism
D004873:Ergolines; D010975:Platelet Aggregation Inhibitors; D011985:Receptors, Serotonin; D014363:Tryptamines; D012701:Serotonin; D007650:Ketanserin; D006916:5-Hydroxytryptophan