Faculty Collaboration Database

Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABA_A receptors containing the α5 subunit. Eur J Pharmacol 2016 Nov 15;791:433-443

Date

10/30/2016

Pubmed ID

27639297

Pubmed Central ID

PMC5107132

DOI

10.1016/j.ejphar.2016.09.016

Scopus ID

2-s2.0-84988476311 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

We have synthesized and characterized MP-III-022 ((R)-8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy-selective positive allosteric modulator of GABA_A receptors containing the α5 subunit (α5GABA_ARs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 1-10mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of α5βγ2 GABA_A receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200mg/kg), but at the price of activating non-α5 GABA_ARs as well as the desired α5GABA_ARs at the highest dose. At the dose of 10mg/kg, which elicits a strong positive modulation of α5GABA_ARs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of α5GABA_ARs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism.

Author List

Stamenić TT, Poe MM, Rehman S, Santrač A, Divović B, Scholze P, Ernst M, Cook JM, Savić MM

Author

James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Amphetamine
Animals
Diazepam
Drug Stability
Electrophysiological Phenomena
GABA-A Receptor Agonists
HEK293 Cells
Hand Strength
Humans
Imidazoles
Kinetics
Locomotion
Male
Maze Learning
Rats
Rats, Wistar
Receptors, GABA-A
Xenopus laevis