Synthesis, pharmacology and molecular modeling of N-substituted 2-phenyl-indoles and benzimidazoles as potent GABA(A) agonists.
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.
Falcó
José Luis
JL
Medicinal Chemistry Department, R and D Center, Ferrer Internacional S.A., Juan de Sada 32, E-08028 Barcelona, Spain. jlfalco-research@ferrergrupo.com
Piqué
Maria
M
González
Miguel
M
Buira
Irma
I
Méndez
Eva
E
Terencio
Jose
J
Pérez
Cristina
C
Príncep
Marta
M
Palomer
Albert
A
Guglietta
Antonio
A
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D058785:GABA-A Receptor Agonists; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular
D001562:Benzimidazoles; D058785:GABA-A Receptor Agonists; D007211:Indoles