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Synthesis, pharmacology and molecular modeling of N-substituted 2-phenyl-indoles and benzimidazoles as potent GABAA agonists

2006; Elsevier BV; Volume: 41; Issue: 8 Linguagem: Inglês

10.1016/j.ejmech.2006.03.031

1768-3254

José Luis Falcó, Maria Piqué, Miguel A. González, Irma Buira, Eva Méndez, J. Terencio, Cristina Pérez, Marta Príncep, Albert Palomer, Antonio Guglietta,

Receptor Mechanisms and Signaling

Among the known non-benzodiazepine hypnotic drugs, Zolpidem (1a), Indiplon (2a) and Zaleplon (2b) have shown high affinity and selectivity for the alpha(1) subunit of the GABA-A receptor. Our group has performed pharmacophoric and ADMET-prediction studies to evaluate a virtual library of new molecules based on privileged structures. Among these, we have synthesized a library of N-substituted indoles and a library of N-substituted benzimidazoles. Afterwards, in vitro screening and in vivo spontaneous motor activity in mice has revealed molecules with good in vitro affinities for the alpha(1) receptor and potent in vivo induction of sedation.