1-(2-Alkanamidoethyl)-6-methoxyindole derivatives: a new class of potent indole melatonin analogues.
A new series of indole melatonin analogues, bearing the amido ethyl side chain attached at the N-1 position of the indole nucleus, were synthesized and tested for their affinity for the melatonin receptor isolated from quail optic tecta in a series of in vitro ligand-binding experiments using 2-[125I]iodomelatonin as the labeled ligand. The biological activity was evaluated using two models: effects on the forskolin-stimulated cAMP accumulation in explants from quail optic tecta and evaluation of the GTP gamma S index derived from competition experiments performed in the absence or presence of GTP gamma S. Compounds 2a and 2k-n, obtained by shifting the methoxy group and the ethylamido side chain from the C-5 and C-3 positions of melatonin to the C-6 and N-1 positions of the indole nucleus, exhibited an affinity similar to that of melatonin itself, as well as full agonist activity. Optimization of the C-2 substituent by introducing Br, phenyl, or COOCH3 (2b-d) resulted in a significantly enhanced affinity (in the picomolar range) and improved agonist biological activity. Compounds lacking the methoxy group and bearing an N-alicyclic group (2h-j) behaved as partial agonists or antagonists.
Tarzia
G
G
Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Urbino, Italy.
Diamantini
G
G
Di Giacomo
B
B
Spadoni
G
G
Esposti
D
D
Nonno
R
R
Lucini
V
V
Pannacci
M
M
Fraschini
F
F
Stankov
B M
BM
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002645:Chickens; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008956:Models, Chemical; D011784:Quail; D013477:Superior Colliculi / Q000187:drug effects / Q000378:metabolism
D007211:Indoles; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D008550:Melatonin