Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure

Abstract

SUMMARYConflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA A receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA A receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH 3 and SH-053-2'F-R-CH 3 at GABA A receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA A receptors containing α1 subunits and varying degrees of efficacy and affinity at GABA A receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (nonsuppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABA A receptors containing α1 and α5 subunits. In contrast, SH-053-2'F-S-CH 3 and SH-053-2'F-R-CH 3 produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABA A receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABA A receptor positive modulators are dependent on their relative efficacy and affinity at different GABA A receptor subtypes.

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

“…This led to the synthesis of a series of chiral R-and S-isomers of earlier imidazobenzodiazepines that exhibited subtype selectivity at ␣2 and ␣3 subtypes. However, as reported in Fischer et al (14), the in vitro binding affinity of SH-053-2=F-R-CH 3 was clearly higher at ␣5␤3␥2 subtypes with very little affinity at ␣1, ␣2, or ␣3 subtypes [K i values: ␣1␤3␥2 (759.1), ␣2 (948.2), ␣3 (768.8), and ␣5 (95.2) nM]. The C-6 pendent phenyl ring of SH-053-2=F-R-CH 3 is incompatible with binding at ␣4 and ␣6 diazepam-insensitive benzodiazepine GABA receptors.…”

“…The C-6 pendent phenyl ring of SH-053-2=F-R-CH 3 is incompatible with binding at ␣4 and ␣6 diazepam-insensitive benzodiazepine GABA receptors. Moreover, the efficacy in oocytes (% control currents) at ␣5-subtypes was higher than at the other three subtypes (14). In addition, the in vivo data for SH-053-2=F-R-CH 3 compared with diazepam in primates clearly show that SH-053-2=F-R-CH 3 is not sedating (␣1 activity is low) and that the anxiolytic activity of this R-CH 3 isomer is either very weak or nonexistent.…”

Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

“…Another possibility is that a1-sparing compounds possess effects that suppress, or impair, lever pressing; and these effects are attenuated in midazolam-but not cocaineexperienced monkeys. However, a1-sparing compounds generally lack sedative-motor effects in monkeys and do not impair performance in tasks requiring lever pressing (Rowlett et al, 2005;Fischer et al, 2010Fischer et al, , 2011.…”

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

“…Briefly, the R stereoisomer of a5GABA A R treatment and schizophrenia KM Gill et al (Fischer et al, 2010). For electrophysiological recordings, SH-053-2 0 F-R-CH3 was initially dissolved in 50% propylene glycol and 50% deinonized water with 10 ml EtOH.…”

“…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.…”