1-(aminoalkyl)-2-phenylindoles as novel pure estrogen antagonists.
A number of 1-(omega-aminoalkyl)-5-hydroxy-2-(4-hydroxyphenyl)indoles were synthesized and studied for their binding affinities for the calf uterine estrogen receptor and estrogen antagonistic activities. Highest binding affinities were found with derivatives bearing a methyl group in position 3 and a hexamethylene chain between the indole and amino nitrogen atoms. Values for relative binding affinity (RBA) are between 20 and 30 for derivatives 5b, 5c, 5f, and 5h (17 beta-estradiol = 100). In the mouse uterine weight test, no significant agonistic (estrogenic) activity was observed up to a daily dose of 125 micrograms/animal, except for derivatives 5c, 5j, and 5l. 2-Phenylindoles with amino (5b), pyrrolidino (5f), piperidino (5h), and morpholino (5k) groups as the amino function completely suppressed estrone-stimulated uterine growth as a dose of 125 micrograms/animal (100% antagonism). Therefore, these derivatives can be considered as first examples of nonsteroidal pure antiestrogens.
von Angerer
E
E
Institut für Pharmazie, Universität Regensburg, Federal Republic of Germany.
Knebel
N
N
Kager
M
M
Ganss
B
B
D000588:Amines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects
D000588:Amines; D004965:Estrogen Antagonists; D007211:Indoles; D009025:Morpholines; D010880:Piperidines; D011759:Pyrrolidines; D011960:Receptors, Estrogen