Identification of anxiolytic/nonsedative agents among indol-3-ylglyoxylamides acting as functionally selective agonists at the gamma-aminobutyric acid-A (GABAA) alpha2 benzodiazepine receptor.
Anxioselective agents may be identified among compounds binding selectively to the alpha(2)beta(x)gamma(2) subtype of the gamma-aminobutyric acid-A (GABA(A))/central benzodiazepine receptor (BzR) complex and behaving as agonists or among compounds binding with comparable potency to various BzR subtypes but eliciting agonism only at the alpha(2)beta(x)gamma(2) receptor. Because of subtle steric differences among BzR subtypes, the latter approach has proved much more successful. A biological screening within the class of indol-3-ylglyoxylamides 1-3 allowed us to identify compounds 1c and 2b as potential anxiolytic/nonsedative agents showing alpha(2) selective efficacy in vitro and anxioselective effects in vivo. According to molecular modeling studies, and consistently with SARs accumulated in the past decade, 5-NO(2)- and 5-H-indole derivatives would preferentially bind to BzR by placing the indole ring in the L(Di) and the L(2) receptor binding sites, respectively.
Taliani
Sabrina
S
Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Via Bonanno 6, 56126 Pisa, Italy. barbara.cosimelli@unina.it
Cosimelli
Barbara
B
Da Settimo
Federico
F
Marini
Anna Maria
AM
La Motta
Concettina
C
Simorini
Francesca
F
Salerno
Silvia
S
Novellino
Ettore
E
Greco
Giovanni
G
Cosconati
Sandro
S
Marinelli
Luciana
L
Salvetti
Francesca
F
L'Abbate
Gianluca
G
Trasciatti
Silvia
S
Montali
Marina
M
Costa
Barbara
B
Martini
Claudia
C
D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D058785:GABA-A Receptor Agonists; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists