Novel positive allosteric modulators of GABAA receptors: Do subtle differences in activity at α1 plus α5 versus α2 plus α3 subunits account for dissimilarities in behavioral effects in rats?

Abstract

Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA A receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA A receptors containing the α 1 subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently-synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA A receptors containing the α 1 subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably α 1 receptor-mediated sedative effects of GABA A modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at α 2 -and α 3 -GABA A receptors, may have been partly connected with its preferential affinity at α 5 -GABA A receptors © 2010 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. coupled with weak agonist activity at α 1 -containing subtypes. The memory impairment in watermaze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at α 1 GABA A receptors is needed for effecting spatial learning and memory impairments, while much weaker activity at α 1 -and α 5 -GABA A receptors is sufficient for eliciting sedation. NIH Public Access

A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia

“…The drug was then brought to a final concentration of 0.1 mg/kg in 50% propylene glycol and 50% deionized water for systemic administration (i.v.). The 1 mM concentration of SH-053-2 0 F-R-CH3, used for local infusion into the ventral HPC, has been demonstrated in competition binding assays to provide optimal binding to the a5 subunit of the GABA A receptor with little nonspecific binding at the other alpha (1-3) subunits (Savic et al, 2010). Local infusions were performed in anesthetized animals before electrophysiological recordings.…”

“…In the present study, we use the MAM model to demonstrate the effectiveness of a novel compound, SH-053-2 0 F-R-CH3, in restoring normal HPC activity and secondary spontaneous DA activity. SH-053-2 0 F-R-CH3 is unique as a benzodiazepine-positive allosteric modulator (PAM) selective for the a5 subunit of the GABA A R (Cook et al, 2009;Fischer et al, 2010;Savic et al, 2010). Furthermore, the efficacy of a5GABA A R PAM treatment in reducing the hyperlocomotor response of MAM animals to amphetamine is explored.…”

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

“…Taken together, this research of the S-CH 3 enantiomers has provided several novel ligands that possess good safety and metabolic profiles for further in vivo behavioral testing in animal models in both schizophrenia and depression. [23][24][25][31][32] The in vivo activity of 8c and 9a in models of schizophrenia and depression is ongoing and preliminary studies look very promising.…”

“…Since 1 and 2 both target the α5-subunit, they have been assayed in several behavioral models. Examination of the results revealed that 2 exerted anxiolytic effects in both rhesus monkeys 31 and rats, 32 while 1 had only a minimal anxiolytic effect when much higher doses were applied. Interestingly, 2 also successfully mitigated the amphetamine-induced hyperactivity in a poly (I:C) animal model of schizophrenia.…”

“…For instance, lead compound 2 exhibited a fairly low LD 50 value, however it was not toxic in a number of pharmacological assays in the mice, rats and primates. [23][24][25][30][31][32] The cytotoxicity assays indicated which analogs were least cytotoxic but were not potent enough (nM) to rule out further pharmacological studies in models of schizophrenia or depression.…”