Abstract
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants 1 and 8 were further examined to evaluate their neuroprotective properties in vitro. In this study, compound 1 showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC50 = 278 ± 29 nM) for 1 was determined. No toxic effects up to 100 µM of 1 and 8 against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound 1 demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound 1 seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity.
Highlights
One of the effective ways to prevent glutamate-induced neurotoxicity observed in many neurodegenerative conditions such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and parkinsonism (PD) [1,2,3,4] is to target overactivation of ionotropic glutamate receptors that mediate most excitatory synaptic transmission in the central nervous system (CNS)
The family of ionotropic glutamate receptors (iGluRs), especially the so-called non-N-methylD-aspartate receptors: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) receptors, have been implicated in the pathogenesis of many other diseases such as neuropathic pain [3,5,6,7], depression [8,9], and the spread of seizure and neuronal damage associated with epilepsy [1,2,10,11,12,13,14]
Development of a structure-activity relationship for this series allowed us to discover that substitution with a hydroxy group at the distal aromatic moiety had a large impact on both affinity and selectivity of binding at AMPA receptors over KA and NMDA receptors
Summary
One of the effective ways to prevent glutamate-induced neurotoxicity observed in many neurodegenerative conditions such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and parkinsonism (PD) [1,2,3,4] is to target overactivation of ionotropic glutamate receptors (iGluRs) that mediate most excitatory synaptic transmission in the central nervous system (CNS). The family of iGluRs, especially the so-called non-N-methylD-aspartate (non-NMDA) receptors: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) receptors, have been implicated in the pathogenesis of many other diseases such as neuropathic pain [3,5,6,7], depression [8,9], and the spread of seizure and neuronal damage associated with epilepsy [1,2,10,11,12,13,14]. MAO inhibition is an important drug target in the treatment of PD and depression [19]
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