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Preclinical Characterization of ACH-000029, a Novel Anxiolytic Compound Acting on Serotonergic and Alpha-Adrenergic Receptors

Preclinical Characterization of ACH-000029, a Novel Anxiolytic Compound Acting on Serotonergic and Alpha-Adrenergic Receptors

Hatylas Azevedo, Marcos Ferreira, Renata Watanabe Costa, Valter Russo, Elisa Russo, Alessandra Mascarello, Cristiano Ruch Werneck Guimarães

Prog Neuropsychopharmacol Biol Psychiatry. 2019 Dec 20;95:109707.

PMID: 31330215

Abstract:

Anxiety disorders are serious and common mental diseases, yet there is still a need for the development of more effective anxiolytics with better safety profiles than benzodiazepines and serotonin reuptake inhibitors. The serotonergic and noradrenergic systems have reciprocal interactions and are intricately related to the pathogenesis of anxiety. In this study, the anxiolytic-like effect of the novel compound ACH-000029, 3-(2-(4-(2-methoxyphenyl) piperazine-1-yl) ethyl) quinazoline-4(3H)-one, 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 of 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 for the treatment of anxiety disorders. The analysis of the in vitro pharmacology and brain regions regulated by this compound may also lead to the exploration of other indications within the psychiatry field.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP28910896	Alprazolam Related Compound A		28910-89-6	Price
CS31042719	Paroxetine Related Compound G			Price

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