An antidepressant-related pharmacological signature for positive allosteric modulators of alpha 2/3-containing GABA(A) receptors

作者：Methuku K R; Li X; Cerne R; Gleason S D; Schkeryantz J M; Tiruveedhula V V N P B; Golani L K; Li G; Poe M M; Rahman Md T; Cook J M; Fisher J L; Witkin J M^*

来源：Pharmacology Biochemistry and Behavior, 2018, 170: 9-13.

DOI：10.1016/j.pbb.2018.04.009

Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of alpha 2/3-containing GABA(A) receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of alpha 2/3-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 alpha 2/3-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 alpha 2 and alpha 3 constructs over alpha 1(except KRM-II-82), alpha 4, alpha 5, and alpha 6 proteins in electro-physiological 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 alpha 2/3-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 alpha 1preferring antagonist, beta-CCT, that attenuated the motor-impairing effects of diazepam. We conclude that these alpha 2/3-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.

• 出版日期2018-7