Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies (original) (raw)
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Bioorganic & Medicinal Chemistry, 2002
Excessive release of glutamate, a potent excitatory neurotransmitter, is thought to play an important role in a variety of acute and chronic neurological disorders, suggesting that excitatory amino acid antagonists may have broad therapeutic potential in neurology. Here, we describe the synthesis, pharmacological properties and neuroprotective activity of 9-carboxymethyl-imidazo-[1-2a]indeno[1-2e]pyrazin-4-one-2-carboxylic acid (RPR117824), an original selective AMPA antagonist. RPR117824 can be obtained through a six-step synthesis starting from (1-oxo-indan-4-yl) acetic acid, which has been validated on a gram-scale with an overall yield of 25%. Monosodium or disodium salts of the compound exhibit excellent solubility in saline ( !10 g/L), enabling intravenous administration. RPR117824 displays nanomolar affinity (IC 50 =18 nM) for AMPA receptors and competitive inhibition of electrophysiological responses mediated by AMPA receptors heterologously expressed in Xenopus oocytes (K B =5 nM) and native receptors in rat brain slices (IC 50 =0.36 mM). In in vivo testing, RPR117824 behaves as a powerful blocker of convulsions induced in mice or rats by supramaximal electroshock or chemoconvulsive agents such as pentylenetetrazole, bicuculline, isoniazide, strychnine, 4-aminopyridine and harmaline with half maximal effective doses ranging from 1.5 to 10 mg/kg following subcutaneous or intraperitoneal administration. In disease models in rats and gerbils, RPR117824 possesses significant neuroprotective activity in global and focal cerebral ischemia, and brain and spinal cord trauma. #
Journal of Neurochemistry, 2005
Iron-dependent oxidative stress, elevated levels of iron and of monoamine oxidase (MAO)-B activity, and depletion of antioxidants in the brain may be major pathogenic factors in Parkinson's disease, Alzheimer's disease and related neurodegenerative diseases. Accordingly, iron chelators, antioxidants and MAO-B inhibitors have shown efficacy in a variety of cellular and animal models of CNS injury. In searching for novel antioxidant iron chelators with potential MAO-B inhibitory activity, a series of new iron chelators has been designed, synthesized and investigated. In this study, the novel chelators were further examined for their activity as antioxidants, MAO-B inhibitors and neuroprotective agents in vitro. Three of the selected chelators (M30, HLA20 and M32) were the most effective in inhibiting iron-dependent lipid peroxidation in rat brain homogenates with IC 50 values (12-16 lM), which is comparable with that of desferal, a prototype iron chelator that is not has orally active. Their antioxidant activities were further confirmed using electron paramagnetic resonance spectroscopy. In PC12 cell culture, the three novel chelators at 0.1 lM were able to attenuate cell death induced by serum deprivation and by 6-hydroxydopamine. M30 possessing propargyl, the MAO inhibitory moiety of the anti-Parkinson drug rasagiline, displayed greater neuroprotective potency than that of rasagiline. In addition, in vitro, M30 was a highly potent nonselective MAO-A and MAO-B inhibitor (IC 50 < 0.1 lM). However, HLA20 was more selective for MAO-B but had poor MAO inhibition, with an IC 50 value of 64.2 lM. The data suggest that M30 and HLA20 might serve as leads in developing drugs with multifunctional activities for the treatment of various neurodegenerative disorders.
Antioxidant and antihypoxic properties of neuroprotective drugs
Russian Chemical Bulletin, 2016
The screening of the library containing 320 drugs and biologically active compounds was carried out. The library was created for testing potent agents on Rett syndrome models (SMART library) using new generation luciferase reporters to identify stabilizers of transcription factors triggering genetic programs for defense against hypoxia and oxidative stress (HIF1 and Nrf2, respec tively). Nine compounds proved to be activators of HIF1, and 18 compounds were shown to activate Nrf2. A histone deacetylase inhibitor (oxamflatin) and a carbonic anhydrase inhibitor (ethamide) were found to be the most powerful Nrf2 activators, which are equipotent or superior to sulforaphane and quercetin. Oxamflatin was also shown to activate HIF with potency comparable or superior to the commercial HIF activators developed by Fibrogen (USA) and GlaxoSmithKline (UK), but it was a significantly weaker activator than branched tail oxyquinolines, developed in our previous studies. The structural motif identified in oxamflatin can be used in the future design of branched oxyquinolines having higher activity and/or more specific against individual isoforms of HIF prolyl hydroxylase.
Monoamine Oxidase Inhibitory Properties of Some Methoxylated and Alkylthio Amphetamine Derivatives
Biochemical Pharmacology, 1997
The monoamine oxidase (MAO) inhibitory properties of a series of amphetamine derivatives with different substituents at or around the para position of the aromatic ring were evaluated. In in vitro studies in which a crude rat brain mitochondrial suspension was used as the source of MAO, several compounds showed a strong (IC so in the submicromolar range), selective, reversible, time-independent, and concentration-related inhibition of MAO-A. After i.p. injection, the compounds induced an increase of serotonin and a decrease of 5-hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confirming the in vitro results. The analysis of structure-activity relationships indicates that: molecules with amphetamine-like structure and different substitutions on the aromatic ring are potentially MAO-A inhibitors; substituents at different positions of the aromatic ring modify the potency but have little influence on the selectivity; substituents at the para position such as amino, alkoxyl, halogens, or alkylthio produce a significant increase in the activity; the para-substituent must be an electron donor; bulky groups next to the t'ara substituent lead to a decrease in the activity; substituents located at positions more distant on the aromatic ring have less influence and, even when the substituent is a halogen (Cl, Br), an increase in the activity of the compound is obtained. Finally, the MAO-A inhibitory properties of some of the compounds evaluated are discussed in relation to: (a) potential antidepressant activity, and (b) their reported hallucinugenic, neurotoxic, or anxiolytic effects. BIOCHEM
J Neural Transm, 1996
Glutamate receptor-mediated excitotoxicity is linked to the activation of multiple receptors including those activated by ct-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate. In this study, the novel glutamate receptor antagonist, as its active isomer (3S,4aR,6R,8aR)-6-[2-(l(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid ((-)LY293558) and it's + racemate (LY215490), was examined for neuroprotectant effects against excitotoxic injury in vitro and in vivo. This agent selectively protected against AMPA and kainate injury in cultured primary rat hippocampal neurons, an in vivo rat striatal neurotoxicity model, and against agonist-evoked seizures in mice. Thus, (3S,4aR,6R,8aR)-6-[2-(l(2)H-tetrazole-5-yl)ethyl]decahydroisguinoline-3-carboxylic acid represents a novel receptor selective and potent systemically active AMPA/kainate receptor antagonist for exploring neuroprotection via non-NMDA receptor mechanisms.
Journal of Neural Transmission, 1996
Glutamate receptor-mediated excitotoxicity is linked to the activation of multiple receptors including those activated by ct-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate. In this study, the novel glutamate receptor antagonist, as its active isomer (3S,4aR,6R,8aR)-6-[2-(l(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid ((-)LY293558) and it's + racemate (LY215490), was examined for neuroprotectant effects against excitotoxic injury in vitro and in vivo. This agent selectively protected against AMPA and kainate injury in cultured primary rat hippocampal neurons, an in vivo rat striatal neurotoxicity model, and against agonist-evoked seizures in mice. Thus, (3S,4aR,6R,8aR)-6-[2-(l(2)H-tetrazole-5-yl)ethyl]decahydroisguinoline-3-carboxylic acid represents a novel receptor selective and potent systemically active AMPA/kainate receptor antagonist for exploring neuroprotection via non-NMDA receptor mechanisms.
European Journal of Medicinal Chemistry, 2018
The multifactorial pathophysiology of neurodegenerative disorders remains one of the main challenges in the design of a single molecule that may ultimately prevent the progression of these disorders in affected patients. In this article, we report on twelve novel polycyclic amine cage derivatives, synthesized with or without a propargylamine function, designed to possess inherent multifunctional neuroprotective activity. The MTT cytotoxicity assay results showed the SH-SY5Y human neuroblastoma cells to be viable with the twelve compounds, particularly at concentrations less than 10 µM. The compounds also showed significant neuroprotective activity, ranging from 31% to 66% at 1 µM, when assayed on SH-SY5Y human neuroblastoma cells in which neurodegeneration was induced by MPP +. Calcium regulation assays conducted on the same cell line showed the compounds to be significant VGCC blockers with activity ranging from 26.6% to 51.3% at 10 µM; as well as significant NMDAr antagonists, with compound 5 showing the best activity of 88.3% at 10 µM. When assayed on human MAO isoenzymes, most of the compounds showed significant inhibitory activity, with compound 5 showing the best activity (MAO-B: IC 50 = 1.70 µM). Generally, the compounds were about 3-52 times more selective to the MAO-B isoenzyme than the MAO-A isoenzyme. Based on the time-dependency studies conducted, the compounds can be defined as reversible MAO inhibitors. Several structure activity relationships were derived from the various assays conducted, and the compounds' possible putative binding modes within the MAO-B enzyme cavity were assessed in silico.