Abstract
N-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile and low affinity to off-targets. It interacts with aminergic GPCRs, forming an electrostatic interaction between its protonatable nitrogen atom and the conserved Asp 3.32 of the receptors. At the dose of 100 mg/kg D2AAK4 decreases amphetamine-induced hyperactivity predictive of antipsychotic activity, improves memory consolidation in passive avoidance test and has anxiogenic properties in elevated plus maze test (EPM). Further optimization of the virtual hit D2AAK4 will be aimed to balance its multitarget profile and to obtain analogs with anxiolytic activity.
Highlights
Schizophrenia is a severe and chronic mental illness with high prevalence [1], and it remains among the 20 leading causes of health loss in terms of years lived with disability (YLDs) from 161 causes analyzed worldwide [2]
We carried out a structure-based virtual screening that resulted in the identification of the compound D2AAK4, among other novel dopamine D2 receptor ligands
The pharmacological profiling of D2AAK4 on a selected panel of dopamine D1-like (D1) and D2-like (D2, D3), as well as serotonin (5-HT1A and 5-HT2A), receptors led to its characterization as a low-affinity D2 receptor antagonist with moderate (3.67 times higher) affinity for 5-HT2A receptors [9] (Table 1), being a 5-HT2A/D2 affinity ratio (Ki D2/Ki 5-HT2A) higher or equal to 1.12 (Meltzer’s ratio), considered relevant for antipsychotic clinical efficacy and safety [31]
Summary
Schizophrenia is a severe and chronic mental illness with high prevalence (appearing in about 0.5%–1% of the population) [1], and it remains among the 20 leading causes of health loss in terms of years lived with disability (YLDs) from 161 causes analyzed worldwide [2]. Symptoms of schizophrenia generally emerge during adolescence or early adulthood and are grouped into positive, negative and cognitive symptoms. Psychotic or positive symptoms include severe thought disorganization like hallucinations (often auditory hallucinations) and delusions (which often involve persecution or megalomania). Deficit or negative symptoms include affect flattening, poverty of speech, social withdrawal and anhedonia. The pathomechanism of schizophrenia remains unclear, but it is generally agreed that it involves many neurotransmitter systems. In particular serotonin and γ-aminobutyric acid (GABA), as well as cholinergic, cannabinoid and opioid systems, are important in the pathogenesis of schizophrenia
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