Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

Abstract

Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA A receptors containing a 1 , a 2 , a 3 or a 5 subunits. Genetic studies suggest that modulation at the a 1 subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA A receptors containing the a 1 subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA A receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for a 2 -, a 3 -, and a 5 -containing subtypes of GABA A receptors (SH-053-S-CH3 and SH-053-S-CH3-2 0 F) or essentially selective for a 5 subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of a 1 subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2 0 F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by a 5 -containing GABA A receptors. Hence, it could be of importance to avoid substantial agonist activity at a 5 receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

“…PWZ-029 exerted negligible activity in 42 other receptor and enzyme assays (B. Roth et al, NIMH Psychoactive Drug Screening Program, UNC, unpublished results, available at https://kidbdev.med.unc.edu/pdsp). The in vitro concentration-effects curves for SH-053-R-CH3-2'F, the ligand used for interaction study in the locomotor activity test, showed it is a high-efficacy agonist at the α5-containing GABA A receptors, with very low efficacies at α1, α2 and α3-containing subtypes (Rowlett, Furtmüller, Cook, unpublished data); the profile was comparable with that published for its close congener SH-053-R-CH3 (Savić et al, 2008), except for greater potencies and α5-efficacy of SH-053-R-CH3-2'F.…”

“…Based on the results with three novel BZ site agonists functionally silent at the α1 subunit, we recently set out the hypothesis that positive modulation at the GABA A receptors containing α5 subunits may contribute to sedative properties of BZ site agonists (Savić et al, 2008). The finding that SH-053-R-CH3-2'F at the lower (10 mg/kg), but not higher dose (20 mg/kg), antagonized the hypolocomotor effect of PWZ-029 adds to the notion that there may exist certain discontinuous 'effective windows' of the modulation of locomotion exerted by neurons expressing the α5-subunit containing GABA A receptors.…”

Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling

“…GABA A receptor ligands active in the central nervous system (CNS) can have many effects including anxiolytic, sedative, hypnotic, amnesic, anticonvulsant, and muscle relaxant effects. This motivated a search for benzodiazepine (BDZ) ligands that discriminate among the ␣-subunits of GABA A receptors (41,42).A novel approach to achieve this goal was developed by Cook and coworkers in the 1980s (1, 25) that employed a pharmacophore/receptor model based on the binding affinity of rigid ligands to BDZ/GABA A receptor sites (8). From this series of receptor models for ␣ 1-6 ␤3␥2 subtypes a robust pharmacophore for ␣5-subtype selective ligands emerged resulting in the synthesis of a novel ␣5␤3␥2 partial agonist modulator:…”

Effects of the 5-HT_1A Receptor Agonist Tandospirone on ACTH-Induced Sleep Disturbance in Rats

“…Conversely, alpha5-GABA A receptors were insensitive and developed tolerance to the sedative actions of benzodiazepines. [21][22][23] Verkuyl et al 24) reported that expression of alpha5, not alpha1-GABA A receptors was increased in patients with hyperfunctional HPA axes. Therefore the absence of a flunitrazepam-induced hypnotic effect may be the result of tolerance developed by upregulation of alpha5-GABA A receptors in ACTH-treated rats.…”