Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor

Samuel Hintermann; Konstanze Hurth; Joachim Nozulak; Marina Tintelnot-Blomley; Reiner Aichholz; Joachim Blanz; Klemens Kaupmann; Johannes Mosbacher

doi:10.1016/j.bmcl.2010.12.107

Exploring subtype selectivity and metabolic stability of a novel series of ligands for the benzodiazepine binding site of the GABAA receptor

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1523-6. doi: 10.1016/j.bmcl.2010.12.107. Epub 2010 Dec 28.

Authors

Samuel Hintermann¹, Konstanze Hurth, Joachim Nozulak, Marina Tintelnot-Blomley, Reiner Aichholz, Joachim Blanz, Klemens Kaupmann, Johannes Mosbacher

Affiliation

¹ Novartis Institutes for BioMedical Research, Neuroscience Research, Basel, Switzerland. samuel.hintermann@novartis.com

PMID: 21277199
DOI: 10.1016/j.bmcl.2010.12.107

Abstract

A novel series of agonists at the benzodiazepine binding site of the GABA(A) receptor was prepared by functionalizing a known template. Adding substituents to the pyrazolone-oxygen of CGS-9896 led to a number of compounds with selectivities for either α2- or α1-containing GABA(A) receptor subtypes offering an entry into indications such as anxiety and insomnia. In this communication, structure-activity relationship and efforts to increase in vitro stabilities are discussed.

MeSH terms

Benzodiazepines / chemistry*
Benzodiazepines / metabolism
Binding Sites
Drug Stability
GABA-A Receptor Agonists / chemical synthesis*
GABA-A Receptor Agonists / chemistry
GABA-A Receptor Agonists / pharmacology
Inhibitory Concentration 50
Ligands
Molecular Structure
Pyrazoles / chemistry*
Pyrazoles / metabolism
Receptors, GABA-A* / metabolism
Structure-Activity Relationship

Substances

GABA-A Receptor Agonists
Ligands
Pyrazoles
Receptors, GABA-A
Benzodiazepines
2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one