Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6 receptor ligands

• Published in: Organic & biomolecular chemistry 2008-10, Vol.6 (20), p.3795-3810
• Main Authors: Alcalde, Ermitas, Mesquida, Neus, Frigola, Jordi, López-Pérez, Sara, Mercè, Ramon
• Format: Article
• Language: English
• Subjects: Cell Line; Drug Design; Humans; Indenes - chemical synthesis; Indenes - chemistry; Indenes - metabolism; Ligands; Protein Binding; Receptors, Serotonin - metabolism
• ISSN: 1477-0539
• DOI: 10.1039/b808641a

A series of novel indene derivatives designed by a scaffold selection gave access to several examples of (Z)-arylmethylideneindenes and indenylsulfonamides that acted as serotonin 5-HT(6) receptor ligands. Different synthetic multistep routes could be applied to these target compounds, each with their own complexity and limitations. A reasonable route involved the (3-indenyl)acetic acids as the key intermediates, and two alternatives were also examined. The first protocol used was a two-step sequence employing a modified Horner-Wadsworth-Emmons reaction, but better results were obtained with a procedure based on the condensation of indanones with the lithium salt of ethyl acetate, followed immediately by dehydration with acid and hydrolysis/isomerization under basic catalysis. (3-Indenyl)acetic acids were transformed to the corresponding acetamides, which were effectively reduced to indenylsulfonamides using an optimized procedure with AlH(3)-NMe(2)Et. The binding at the 5-HT(6) receptor was with moderate affinity (K(i) = 216.5 nM) for the (Z)-benzylideneindenylsulfonamide and enhanced affinity for the simple indenylsulfonamide counterpart (K(i) = 50.6 nM). Selected indenylsulfonamides were then tested, showing K(i) values as low as 20.2 nM.