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

Abstract

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.

• Authors: Ermitas Alcalde, Neus Mesquida, Jordi Frigola, Sara López-Pérez, Ramon Mercè
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 6 Issue 20 Pg. 3795-810 (Oct 21 2008) ISSN: 1477-0539 [Electronic] England
• PMID: 18843410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indenes
• Ligands
• Receptors, Serotonin
• serotonin 6 receptor
• indene

Topics

• Cell Line
• Drug Design
• Humans
• Indenes (chemical synthesis, chemistry, metabolism)
• Ligands
• Protein Binding
• Receptors, Serotonin (metabolism)