Imidazo[1,2-b][1,2,4]triazines as α2/α3 subtype selective GABAA agonists for the treatment of anxiety

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

“…On the other hand, it is noticeable that standard studies of motor activity, which form the very basis of knowledge of drug effects on behavior (Kelley, 1993), were not employed for characterization of recently reported putative anxioselective compounds (Atack et al, 2006c;Jennings et al, 2006;Griebel et al, 2001;Russell et al, 2006). Jennings et al (2006) reported on an a2/a3-BZ site-selective ligand from the class of imidazo[1,2-b][1,2,4]triazines with anxiolytic activity in the rat EPM test at the dose of 1 mg/kg, which showed no motor incapacitation in the mouse rotarod test at doses up to 30 mg/kg.…”

“…Jennings et al (2006) reported on an a2/a3-BZ site-selective ligand from the class of imidazo[1,2-b][1,2,4]triazines with anxiolytic activity in the rat EPM test at the dose of 1 mg/kg, which showed no motor incapacitation in the mouse rotarod test at doses up to 30 mg/kg. A close congener of that compound was anxiolytic in the rat EPM test at 3 mg/kg, whereas it showed no significant activity in a surrogate assay of sedation (chain-pulling test in rats) and in the mouse rotarod test when tested in doses up to 10 mg/kg; reportedly, this compound was chosen as a clinical candidate .…”

International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans

“…In an effort to compare the actions of compounds at various receptor subtypes with those of chlordiazepoxide (Blackaby et al, 2006;Carling et al, 2006;Jennings et al, 2006), diazepam (Griebel et al, 2001;Alhambra et al, 2011;de Lucas et al, 2015), or zolpidem (Griebel et al, 2001), their efficacy was often also given relative to the maximal efficacy of these reference drugs measured in the same oocyte or cell culture system. Although such presentation allows for an immediate estimation of whether the compound exhibits a stronger or weaker effect at a receptor subtype than the reference compound, it also distorts the actual efficacy of the compound.…”

Regulation of GABAAReceptor Subunit Expression by Pharmacological Agents

“…It is noteworthy that work with ␣3 knockout mice suggests a role for reduced function of ␣3 subunit-containing GABA A receptors in schizophrenia-like sensorimotor deficits and excessive dopamine function (Yee at al., 2005); also, in this mouse model, diazepam had little anxiolytic effect. Experimental compounds having ␣2 and/or ␣3 agonist selectivity already exist (e.g., Jennings et al, 2006;Van Laere et al, 2008;Taliani et al, 2009), but they have not been well tested in patients with anxiety (Atack, 2008). Furthermore, neurobiological findings suggest that these same receptor subtypes at the spinal level should be tested as targets for alleviating neuropathic pain (Knabl et al, 2008).…”