Screening and Structure–Activity Relationship of D2AAK1 Derivatives for Potential Application in the Treatment of Neurodegenerative Diseases

Abstract

Neurodegenerative and mental diseases are serious medical, economic and social problems. Neurodegeneration is referred to as a pathological condition associated with damage to nerve cells leading to their death. Treatment of neurodegenerative diseases is at present symptomatic only, and novel drugs are urgently needed which would be able to stop disease progression. We performed screening of reactive oxygen species, reactive nitrogen species, glutathione and level intracellular Ca2+. The studies were assessed using one-way ANOVA of variance with Dunnett’s post hoc test. Previously, we reported D2AAK1 as a promising compound for the treatment of neurodegenerative and mental disorders. Here, we show a screening of D2AAK1 derivatives aimed at the selection of the compound with the most favorable pharmacological profile. Selected compounds cause an increase in the proliferation of a hippocampal neuron-like cell line, changes in the levels of reactive oxygen and nitrogen forms, reduced glutathione and a reduced intracellular calcium pool. Upon analyzing the structure–activity relationship, we selected the compound with the most favorable profile for a neuroprotective activity for potential application in the treatment of neurodegenerative diseases.

Effects of small molecules on neurogenesis: Neuronal proliferation and differentiation

“…Notably, structure- and ligand-based virtual screening (VS) techniques, as well as molecular docking supported by advanced molecular dynamics (MD) techniques and QSAR models, enable the determination of the most likely models of the dynamic processes occurring in active receptors 110 . Using these techniques, the multi-target molecule D2AAK1 [3-((4-(5-methoxy-1 H -indol-3-yl)-3,6-dihydropyridin-1(2 H )-yl)methyl)quinolin-2(1 H )-one] was discovered 111 , 112 , 113 . Studies have demonstrated its antipsychotic, anti-anxiety, and pro-cognitive potential, explained by its multi-target nature of action, with affinity for D 1 , D 2 , D 3 , 5-HT 1A , and 5-HT 2A receptors 113 , 114 .…”

AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications

“…Both structures are never reported in research articles or patents, as far as our knowledge. The 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole scaffold, linked to a heterocycle through methylene bridge (the substructure contained in 3 ) was investigated in compounds antagonists of D2 and 5-HT2A receptors (the lead compound is D2AAK1, reported in refs , ) but was never associated with AKR1C3 inhibition. Compound 4 contains the 7-hydroxycoumarin core, substituted at position 4.…”