Selective Influence on Contextual Memory: Physiochemical Properties Associated with Selectivity of Benzodiazepine Ligands at GABA_AReceptors Containing the α5 Subunit

Abstract

Ligands that bind to the benzodiazepine binding site on the GABA A receptor can attenuate or potentiate cognition. To investigate this property, the chemical determinants favoring selective binding or selective activation of the alpha5beta2gamma2 and alpha1beta2gamma2 GABA A receptor isoforms were examined. A 3D-pharmacophore, developed from a diverse set of BDZR ligands, was used as an initial basis for multivariate discriminant, fragment, and 3D-quantitative structure-activity relationship analyses, which formed the criteria for selection of additional compounds for study. We found that the electrostatic potential near the ligands' terminal substituent correlated with its binding selectivity toward the alpha5beta2gamma2 versus alpha1beta2gamma2 isoform; while the fragment length and frontier molecular orbital energetics correlated with a compounds influence on electrophysiological activity. Compounds with promising alpha5 profiles were further assessed for their ability to attenuate scopolamine-induced contextual memory impairment in mice. Surprisingly, both weak inverse agonist and antagonists that display binding selectivity toward the alpha5beta2gamma2 isoform were able to attenuate contextual memory impairment.

Essential oils found in the smoke of "tira-capeta", a cigarette used by some quilombolas living in pantanal wetlands of Brazil

“…Ligands that bind to the benzodiazepine binding site on the gamma-aminobutyric acid receptor type A (GABAA) receptor can attenuate cognition. Anxiolytics act together with the gabaergic receptors facilitating coupling to GABAA, which is the main neurotransmissor inhibitor to the central nervous system (Harris et al, 2008). Aoshima & Hamamoto (1999) verified that pinene potentiate the response in the presence of GABA at low concentrations, possibly because they bound to the potentiation-site in GABA(A) receptors and increase the affinity of GABA to the receptors.…”

Chemical composition of hydroethanolic extracts from Siparuna guianensis, medicinal plant used as anxiolytics in Amazon region

“…Anxiolytics facilitate the coupling of GABAergic receptors to GABAA and produce their pharmacological effect by binding to a benzodiazepine recognition site on the GABAA receptor complex (Harris et al, 2008;Ennaceur et al, 2008). The fi rst drugs used to treat anxiety were barbiturates, toxic compounds that produce a variety of adverse effects.…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…In terms of memory-enhancing properties, orally administered PWZ-029 successfully improved the task learning of rats in a hippocampal-dependent passive avoidance test without producing anxiety or convulsions, although hypo-locomotion was observed at higher doses [55]. In a Pavlovian fear conditioning study, PWZ-029 notably reversed the scopolamine-induced impairment of contextual memory [54], in addition to improving the performance in novel object recognition test [56]. However, in contrast to most tested α 5 GABA A R negative modulators, PWZ-029 failed to improve cognitive performance in the Morris water maze model, either alone or in countering scopolamine-induced cognitive impairment in rats, prompting the need for further investigations to validate the cognition-enhancing properties of PWZ-029 [56].…”

“…PWZ-029 is unusual in that it inhibits α 5 GABA A Rs at nanomolar concentrations but potentiates other GABA A R isoforms at much lower potencies [54,55]. In terms of memory-enhancing properties, orally administered PWZ-029 successfully improved the task learning of rats in a hippocampal-dependent passive avoidance test without producing anxiety or convulsions, although hypo-locomotion was observed at higher doses [55].…”