2-[N-Acylamino(C1-C3)alkyl]indoles as MT1 melatonin receptor partial agonists, antagonists, and putative inverse agonists.
The synthesis of several novel indole melatonin analogues substituted at the 2-position with acylaminomethyl (8-11), acylaminoethyl (5a-k), or acylaminopropyl (13) side chains is reported. On the basis of a novel in vitro functional assay (specific binding of [35S]GTPgammaS), which can discriminate agonist from partial agonist, antagonist, and inverse agonist ligands, 5a,g, h,j and 13 were shown to be partial agonists, 5d,e and 8-11 competitive antagonists, and 5b,c,k putative inverse agonists. Binding and functional assays were performed on cloned human MT1 receptor. Structure-activity relationship considerations indicate that N-[1-aryl-2-(4-methoxy-1H-indol-2-yl)(C1-C2)alkyl]alkanamides represent a lead structure for this type of ligands.
Spadoni
G
G
Cattedra di Chemioterapia, Dipartimento di Farmacologia, Università degli Studi di Milano, Via Vanvitelli, 32, I-20129 Milano, Italy.
Balsamini
C
C
Bedini
A
A
Diamantini
G
G
Di Giacomo
B
B
Tontini
A
A
Tarzia
G
G
Mor
M
M
Plazzi
P V
PV
Rivara
S
S
Nonno
R
R
Pannacci
M
M
Lucini
V
V
Fraschini
F
F
Stankov
B M
BM
D016475:3T3 Cells; D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008550:Melatonin / Q000378:metabolism*; D051379:Mice; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D044094:Receptors, Melatonin; D012965:Sodium Chloride / Q000378:metabolism; D013329:Structure-Activity Relationship
D007211:Indoles; D008024:Ligands; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D012965:Sodium Chloride; D019204:GTP-Binding Proteins; D008550:Melatonin