Faculty Collaboration Database

An antidepressant-related pharmacological signature for positive allosteric modulators of α2/3-containing GABA_A receptors. Pharmacol Biochem Behav 2018 Jul;170:9-13

Date

05/02/2018

Pubmed ID

29715490

DOI

10.1016/j.pbb.2018.04.009

Scopus ID

2-s2.0-85046636547 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of α2/3-containing GABA_A receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of α2/3-selective PAMs has been presented along with the clinical potential for a milder motor-impacting profile compared to non-selective GABA_A receptor PAMs. A new series of α2/3-selective PAMs was recently introduced which has anxiolytic and anticonvulsant activity in rodent models. These molecules also produce efficacy against pain in multiple animal models. Additionally, co-morbid states of depression are prevalent among patients with pain and patients with anxiety. Compounds were shown to be selective for α2 and α3 constructs over α1 (except KRM-II-82), α4, α5, and α6 proteins in electrophysiological assays in transfected HEK-293T cells. Utilizing the forced-swim assay in mice that detects conventional and novel antidepressant drugs, we demonstrate for the first time that α2/3-selective PAMs are active in the forced-swim assay at anxiolytic-producing doses. In contrast, activity in a related model, the tail-suspension test, was not observed. Diazepam was not active in the forced-swim assay when given alone but produced an antidepressant-like effect in mice when given in conjunction with the α1-preferring antagonist, β-CCT, that attenuated the motor-impairing effects of diazepam. We conclude that these α2/3-selective PAMs deserve further scrutiny for their potential treatment of major depressive disorder. If effective, such a mechanism could add a beneficial antidepressant component to the anxiolytic, analgesic, and anticonvulsant spectrum of effects of these compounds.

Author List

Methuku KR, Li X, Cerne R, Gleason SD, Schkeryantz JM, Tiruveedhula VVNPB, Golani LK, Li G, Poe MM, Rahman MT, Cook JM, Fisher JL, Witkin JM

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

Allosteric Regulation
Animals
Antidepressive Agents
Depressive Disorder, Major
Diazepam
HEK293 Cells
Hindlimb Suspension
Humans
Male
Mice
Mice, Inbred C57BL
Motor Activity
Receptors, GABA-A
Swimming