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Novel N-Substituted Indol-3-ylglyoxylamides Probing the LDi and L1/L2 Lipophilic Regions of the Benzodiazepine Receptor Site in Search for Subtype-Selective Ligands

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journal contribution
posted on 05.04.2007, 00:00 by Giampaolo Primofiore, Sabrina Taliani, Federico Da Settimo, Anna Maria Marini, Concettina La Motta, Francesca Simorini, Maria Paola Patrizi, Valentina Sergianni, Ettore Novellino, Giovanni Greco, Barbara Cosimelli, Vincenzo Calderone, Marina Montali, François Besnard, Claudia Martini
Novel N-substituted indol-3-ylglyoxylamides (1037) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, these compounds were designed to probe the LDi and L2 lipophilic regions. Taking the α1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds 1023) or replaced the benzyl moiety with alkyl groups (compounds 2437). The above structural changes gave no shift of selectivity from the α1 toward the α2 or α5 subtypes, thus confirming that a ligand which occupies the LDi region probably exhibits α1 selectivity, despite its interactions with other lipophilic areas in the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), which selectively binds with a full agonist efficacy at the α1 receptor subtype and displays sedative action, can be regarded as an interesting potential zolpidem-like sedative−hypnotic agent.