This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent research has focused on understanding the GABA-A receptor mechanisms underlying the behavioral effects of benzodiazepines (BZs). Two newly developed compounds, ANX3 and ANX4, are 8-acetylenyl analogs of the sedative-hypnotic BZ triazolam. In human GABA-A receptors, the overall efficacy and potency profiles of ANX3 and ANX4 resemble that of triazolam; however, at low concentrations ANX4 has reduced potency at the alpha-1 subunit-containing GABA-A receptor compared to both ANX3 and triazolam. We evaluated the extent to which ANX4's functional selectivity resulted in anxiolytic and sedative-motor effects that differed from triazolam and ANX3. Anxiolytic-like activity was assessed in rhesus monkeys. Observable behavioral effects were evaluated in squirrel monkeys and included measurement of muscle relaxation, ataxia, and procumbent posture. ANX3, ANX4 and triazolam induced anxiolytic-like effects and had reliable effects in all behavioral measures. Examination of the minimally effective doses to engender all behaviors indicated a rank order of relative potency of triazolam greater than ANX3 greater than ANX4. While ANX3 was approximately 3-fold less potent than triazolam at all behavioral measures, ANX4 was less potent at engendering ataxia and procumbent posture (30-fold) than muscle relaxation, which may reflect this compound's reduced potency at alpha-1 GABA-A receptors.
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