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A focused library of psychotropic analogs with neuroprotective and neuroregenerative potential

AuthorsUliassi, Elisa; Peña-Altamira, Luis Emiliano; Morales, Aixa V. ; Massenzio, Francesca; Petralla, Sabrina; Rossi, Michele; Roberti, Marinella; Martínez-González, Loreto ; Martínez, Ana ; Monti, B.; Bolognesi, Maria Laura
KeywordsNeurodegenerative diseases
Neural regeneration
Phenotypic screening
Psychotropic agents
Issue Date9-Oct-2018
PublisherAmerican Chemical Society
CitationACS Chem Neurosci 10:279−294 (2018)
AbstractOvercoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol, which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression.
Description50 p.-5 fig.
Publisher version (URL)https://doi.org/10.1021/acschemneuro.8b00242
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