Preclinical characterization of ACH-000029, a novel anxiolytic compound acting on serotonergic and alpha-adrenergic receptors

In this study, the anxiolytic-like effects of a novel compound, ACH-000029, 3-(2-(4-(2-methoxyphenyl) piperazine-1-yl) ethyl) quinazoline-4(3H)-one, which modulates the activities of both serotonergic and α-adrenergic receptors, is reported. This compound acts at selected serotonergic (5-HT1A and 5-HT1D partial agonism and 5-HT2A antagonism) and α-adrenergic (α-1A, 1B and 1D antagonism) receptors, with good selectivity over other G-protein-coupled receptors. ACH-000029 exhibited high blood-brain barrier permeation and acute anxiolytic effects in the marble burying (MB) and light-dark box (LDB) models of anxiety over the dose ranges 8–32 mg/kg i.p. and 16–30 mg/kg p.o. The anxiolytic activity was comparable to that observed for serotonin reuptake inhibitors (paroxetine and fluoxetine) and benzodiazepines (alprazolam, diazepam and clobazam). The analysis of the whole-brain c-fos expression following oral dosing showed that ACH-000029 regulated regions highly associated with the processing of environmental stimuli and anxiety behavior, such as the amygdala, paraventricular nucleus of the thalamus, retrosplenial dorsal, pallidum, bed nuclei of the stria terminalis, and locus ceruleus. No safety concerns were identified for ACH-000029 in the functional observational battery up to 50 mg/kg i.p. and in the nonprecipitated withdrawal test up to 30 mg/kg p.o. twice daily for 20 days. This work supports the further development of ACH-000029 as a drug candidate ...
Source: Progress in Neuro Psychopharmacology and Biological Psychiatry - Category: Psychiatry Source Type: research