Azepino- and diazepinoindoles: synthesis and dopamine receptor binding profiles.
Starting from the readily available building blocks 7, 10, 11, and 15, the synthesis of the fused indoles 1, 2, 5, and 6, respectively, is reported. The syntheses involved Pictet-Spengler cyclizations, Michael addition reactions, lactamization, directed metallation, and reductive amination as the key reaction steps. Radioligand displacement studies comprising the dopamine receptor subtypes D1, D2long D2short, D3, and D4.4 were performed when the diazepinoindole 6 revealed D1 and D4 affinities (Ki = 0.11 microM and 1.7 microM, respectively) which are comparable to the partial D1 agonist SKF 38393 (3b). In contrast to the benzazepine 3b, the indole based test compounds turned out less selective over the D2 and D3 receptor subtype.
Kraxner
J
J
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Erlangen, Germany.
Hübner
H
H
Gmeiner
P
P
D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D002417:Cattle; D003342:Corpus Striatum / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050638:Receptors, Dopamine D4; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D001552:Benzazepines; C493599:DRD4 protein, human; D007202:Indicators and Reagents; D007211:Indoles; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D050638:Receptors, Dopamine D4