A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential

Abstract

Overcoming 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 purposely developed phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bcshowed 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.

Turning Donepezil into a Multi‐Target‐Directed Ligand through a Merging Strategy

“…Lack of hepatotoxicity would be a critical determinant for the drug‐likeness of new donepezil derivatives, as aging, comorbidity and subsequent polytherapy significantly increase the risk of liver injury in AD patients [35] . As shown in Figure 3, up to 5 μM, there was no toxic effect from any of the molecules toward Hep‐G2 cells, an established model for early ADME/Tox predictions.…”

“…Considering the well‐known cytotoxicity mediated by quinones and to get further proof of the drug‐likeness of 9 , we tested its neurotoxicity against a primary cell line of cerebellar granule neurons (CGNs), widely used as a model for studying neuronal death in AD [35] . Notwithstanding the notion that primary neurons are overall more sensitive to drug treatment than immortalized cell lines (e. g., SH‐SY5Y), 9 showed a safe profile also in this cell model (Figure 9).…”

“…Cytotoxicity assays in primary neurons . Primary cultures of cerebellar granule neurons (CGNs) were prepared from 7‐day‐old pups of Wistar rat strain, as previously described [35] . All animal experiments were authorized by the University of Bologna bioethical committee (protocol no.…”

Phenothiazine‐based chalcones as potential dual‐target inhibitors toward cholinesterases (AChE, BuChE) and monoamine oxidases (MAO‐A, MAO‐B)

“…The improvement in learning molecular mechanisms of Alzheimer's disease (AD) which is the most prevalent disorder in older persons with mental deterioration has been fascinating. [ 1,2 ]…”

“…The improvement in learning molecular mechanisms of Alzheimer's disease (AD) which is the most prevalent disorder in older persons with mental deterioration has been fascinating. [1,2] The current pharmaceuticals used in the treatment of AD are cholinesterase inhibitors (ChEIs) (Donepezil, Rivastigmine, and Galantamine) and N-methyl-Daspartate (NMDA) receptor antagonists (Memantine). [3] ChEIs have been used to prevent the degradation of the neurotransmitter acetylcholine (ACh) by inhibiting acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BuChE, EC 3.1.1.8) enzymes that influence breakdown of acetylcholine in synapses.…”