Anxiolytic-like effects of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis.
Novel N,N-disubstituted indol-3-ylglyoxylamides (1-56), bearing different combinations of substituents R 1-R 5, were synthesized and evaluated as ligands of the translocator protein (TSPO), the 18 kDa protein representing the minimal functional unit of the "peripheral-type benzodiazepine receptor" (PBR). Most of the new compounds showed a nanomolar/subnanomolar affinity for TSPO and stimulated steroid biosynthesis in rat C6 glioma cells with a potency similar to or higher than that of classic TSPO ligands such as PK 11195. Moreover, when evaluated in vivo by means of the elevated-plus-maze (EPM) paradigm in the rat, compound 32, the best-performing derivative in terms of TSPO affinity and pregnenolone production, showed clear anxiolytic effects. The results of this study suggested that the novel N,N-disubstituted indol-3-ylglyoxylamides may represent a promising class of compounds potentially suited for the treatment of anxiety disorders.
Da Settimo
Federico
F
Dipartimento di Scienze Farmaceutiche and Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa,Via Bonanno 6, 56126 Pisa, Italy.
Simorini
Francesca
F
Taliani
Sabrina
S
La Motta
Concettina
C
Marini
Anna Maria
AM
Salerno
Silvia
S
Bellandi
Marusca
M
Novellino
Ettore
E
Greco
Giovanni
G
Cosimelli
Barbara
B
Da Pozzo
Eleonora
E
Costa
Barbara
B
Simola
Nicola
N
Morelli
Micaela
M
Martini
Claudia
C
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D018782:Maze Learning; D011284:Pregnenolone / Q000096:biosynthesis*; D011869:Radioligand Assay; D051381:Rats
D000577:Amides; D014151:Anti-Anxiety Agents; D007546:Isoquinolines; D011284:Pregnenolone; C037850:PK 11195