Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT6 receptor ligands.
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.
Alcalde
Ermitas
E
Laboratori de Química Orgànica, Departament de Farmacologia i Química Terapèutica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, E-08028, Barcelona, Spain. ealcalde@ub.edu
Mesquida
Neus
N
Frigola
Jordi
J
López-Pérez
Sara
S
Mercè
Ramon
R
D002460:Cell Line; D015195:Drug Design; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D011485:Protein Binding; D011985:Receptors, Serotonin / Q000378:metabolism*
D007192:Indenes; D008024:Ligands; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; C093581:indene