The Antipsychotic D2AAK1 as a Memory Enhancer for Treatment of Mental and Neurodegenerative Diseases

Abstract

The treatment of memory impairments associated with the central nervous system diseases remains an unmet medical need with social and economic implications. Here we show, that a multi-target ligand of aminergic G protein-coupled receptors with antipsychotic activity in vivo (D2AAK1) stimulates neuron growth and survival and promotes neuron integrity. We focused on the multilevel evaluation of the D2AAK1-related effects on neurons in terms of behavioral, cellular, molecular, and biochemical features in vivo and in vitro, such as memory-related responses, locomotor activity, tissue sections analysis, metabolic activity, proliferation level, neurons morphology, and proteins level involved in intracellular signaling pathways. In silico studies indicate that activation of calcium/calmodulin-dependent protein kinase I (CaMKI) may underline some of the observed activities of the compound. Furthermore, the compound increases hippocampal neuron proliferation via the activation of neurotrophic factors and cooperating signals responsible for cell growth and proliferation. D2AAK1 improves memory and learning processes in mice after both acute and chronic administration. D2AAK1 also causes an increase in the number of hippocampal pyramidal neurons after chronic administration. Because of its neuroprotective properties and pro-cognitive activity in behavioral studies D2AAK1 has the potential for the treatment of memory disturbances in neurodegenerative and mental diseases.

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

“…Previously, we provided evidence of the unique properties of the lead structure D2AAK1 in terms of neuronal growth stimulation and cell survival promotion. The events observed were related to the up-regulation of neurotrophic factors, CAMKI kinase and mechanisms related to cell proliferation confirmed by BrdU incorporation into newly synthesized DNA [ 8 ]. Moreover, D2AAK1 showed antioxidant properties, decreased the levels of ROS and RNS and prevented excitotoxicity by decreasing intracellular calcium and NMDA levels.…”

“…Increasing the proliferation of neurons and creating new neural connections is a key point in the treatment of neurodegenerative and mental diseases [ 2 ]. Upon analyzing the structure–proliferation relationship of the tested compounds, it can be clearly stated that the lead structure of D2AAK1 causes the highest increase in proliferation [ 8 ] compared to its derivatives. The increase in proliferation can be induced as a result of the activation of mechanisms related to the hormesis effect.…”

“…The assay was performed in accordance with our previous research [ 8 ]. Cells were seeded on 96-well plates at standard density.…”

“…This compound has been identified in structure-based virtual screening as a multi-target ligand of aminergic G protein-coupled receptors (GPCRs) [ 7 ]. Moreover, the compound is characterized by neuroprotective properties as well as stimulation of neuron growth and survival [ 8 , 9 ]. This important finding suggests its potential application in the treatment of neurodegenerative and mental disorders.…”

Current computer-aided drug design methodologies in discovery of novel drug candidates for neuropsychiatric and inflammatory diseases

“…Compound 2 (D2AAK1) was selected as the most promising compound from this VS study (Figure 3). Additional in silico, in vitro and in vivo studies confirmed that D2AAK1 is a multi-target ligand of aminergic GPCRs, with neuroprotective properties and pro-cognitive activity, therefore providing a new therapeutic option for the treatment of multifactorial brain disorders (92)(93)(94). Since in vitro studies showed the affinity of D2AAK1 for dopamine D1 and D3 receptors, as well as for serotonin 5-HT1A and 5-HT2A receptors, molecular dynamics (using Desmond) and molecular docking (using GLIDE) studies were used to reveal its interactions and binding poses with these targets at the molecular level.…”