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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- 作者：Giampaolo Primofiore ; Sabrina Taliani ; Federico Da Settimo ; Anna Maria Marini ; Concettina La Motta ; Francesca Simorini ; Maria Paola Patrizi ; Valentina Sergianni ; Ettore Novellino ; Giovanni Greco ; Barb
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：April 5, 2007
- 年：2007
- 卷：50
- 期：7
- 页码：1627 - 1634
- 全文大小：130K
- 年卷期：v.50,no.7(April 5, 2007)
- ISSN：1520-4804
文摘
Novel N-substituted indol-3-ylglyoxylamides (10-37) were synthesized and evaluated as ligands of thebenzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, thesecompounds were designed to probe the LDi and L2 lipophilic regions. Taking the 
1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changesgave no shift of selectivity from the 1 toward the 2 or 5 subtypes, thus confirming that a ligand whichoccupies the LDi region probably exhibits 1 selectivity, despite its interactions with other lipophilic areasin the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), whichselectively binds with a full agonist efficacy at the 1 receptor subtype and displays sedative action, can beregarded as an interesting potential zolpidem-like sedative-hypnotic agent.
1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changesgave no shift of selectivity from the 1 toward the 2 or 5 subtypes, thus confirming that a ligand whichoccupies the LDi region probably exhibits 1 selectivity, despite its interactions with other lipophilic areasin the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), whichselectively binds with a full agonist efficacy at the 1 receptor subtype and displays sedative action, can beregarded as an interesting potential zolpidem-like sedative-hypnotic agent.