Medicinal Chemistry of Indolylglyoxylamide GABAA/BzR High Affinity Ligands: Identification of Novel Anxiolytic/Non Sedative Agents

Author(s): Silvia Salerno, Federico Da Settimo, Sabrina Taliani, Francesca Simorini, Concettina La Motta, Giacomo Fornaciari, Anna Maria Marini

Journal Name: Current Topics in Medicinal Chemistry

Volume 12 , Issue 4 , 2012

Become EABM
Become Reviewer


The classical benzodiazepines (Bz) constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects acting upon a specific binding site (BzR) belonging to the GABAA receptor complex. Their usefulness, however, is limited by a broad range of side effects; consequently the fact that the action of GABA with the receptor complex could be allosterically modulated by a wide variety of chemical entities, made the Bz binding site, from late eighties to nowdays, the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes. The principal aim has been to discover ideal sedative-hypnotic agents (selective 1 agonists), anxiolytic agents (selective 2/ 3 agonists), or cognitive enhancers (selective 5 inverse agonists). In this connection, an important contribution in the field of GABAA/BzR ligands was made by the research group directed by Professor Antonio Da Settimo at the University of Pisa. The purpose of this review is therefore to describe the studies, performed from early 80s, on the several classes of BzR ligands developed featuring the indol-3-ylglyoxyl scaffold. All the compounds reported have been summarized on the basis of their main chemical structural features, focusing attention on their SARs, which determined the affinity profiles or efficacy-selectivity. Moreover, the biological studies performed within each class of compounds allowed the identification of new derivatives exhibiting an anxiolytic/nonsedative profile, either in vitro (full 2 agonism and 1 partial agonism/ antagonism) and in vivo (anxiolytic/nonsedative activity in mice).

Keywords: Anxiolytic agents, BzR ligands, GABAA/BzR, complex, indolylglyoxylamide, pharmacophore model, structureactivity relationships, benzodiazepines (Bz), hypnotic, anxiolytic and anticonvulsant effects, affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes, indol-3-ylglyoxyl scaffold, anxiolytic/nonsedative profile

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2012
Page: [286 - 311]
Pages: 26
DOI: 10.2174/156802612799078847
Price: $65

Article Metrics

PDF: 13