Faculty Collaboration Database

Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABA_AR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability. J Med Chem 2018 Mar 22;61(6):2422-2446

Date

02/27/2018

Pubmed ID

29481759

Pubmed Central ID

PMC6941172

DOI

10.1021/acs.jmedchem.7b01664

Scopus ID

2-s2.0-85044203204 (requires institutional sign-in at Scopus site)   33 Citations

Abstract

Recent reports indicate that α6β2/3γ2 GABA_AR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABA_AR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABA_AR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABA_ARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABA_ARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABA_AR α6β2/3γ2 subtypes.

Author List

Knutson DE, Kodali R, Divović B, Treven M, Stephen MR, Zahn NM, Dobričić V, Huber AT, Meirelles MA, Verma RS, Wimmer L, Witzigmann C, Arnold LA, Chiou LC, Ernst M, Mihovilovic MD, Savić MM, Sieghart W, Cook JM

Authors

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee
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

Animals
Anti-Anxiety Agents
Behavior, Animal
Biological Availability
Deuterium
Drug Design
Female
GABA Antagonists
HEK293 Cells
Humans
Hypnotics and Sedatives
Male
Maze Learning
Mice
Mice, Inbred C57BL
Microsomes, Liver
Motor Activity
Muscle Strength
Rats
Rats, Wistar
Receptors, GABA-A
Substrate Specificity