Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain
The racemic mixture dimiracetam negatively modulates NMDA-induced glutamate release in rat spinal cord synaptosomal preparations and is orally effective in models of neuropathic pain. In this study, we compared the effects of dimiracetam, its R- or S-enantiomers, and the R:S 3:1 non-racemic mixture...
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2022-12-01
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author | Tiziana Bonifacino Laura Micheli Carola Torazza Carla Ghelardini Carlo Farina Giambattista Bonanno Marco Milanese Lorenzo Di Cesare Mannelli Michael W. Scherz |
author_facet | Tiziana Bonifacino Laura Micheli Carola Torazza Carla Ghelardini Carlo Farina Giambattista Bonanno Marco Milanese Lorenzo Di Cesare Mannelli Michael W. Scherz |
author_sort | Tiziana Bonifacino |
collection | DOAJ |
description | The racemic mixture dimiracetam negatively modulates NMDA-induced glutamate release in rat spinal cord synaptosomal preparations and is orally effective in models of neuropathic pain. In this study, we compared the effects of dimiracetam, its R- or S-enantiomers, and the R:S 3:1 non-racemic mixture (MP-101). In vitro, dimiracetam was more potent than its R- or S-enantiomers in reducing the NMDA-induced [<sup>3</sup>H]D-aspartate release in rat spinal cord synaptosomes. Similarly, acute oral administration of dimiracetam was more effective than a single enantiomer in the sodium monoiodoacetate (MIA) paradigm of painful osteoarthritis. Then, we compared the in vitro effects of a broad range of non-racemic enantiomeric mixtures on the NMDA-induced [<sup>3</sup>H]D-aspartate release. Dimiracetam was a more potent blocker than each isolated enantiomer but the R:S 3:1 non-racemic mixture (MP-101) was even more potent than dimiracetam, with an IC<sub>50</sub> in the picomolar range. In the chronic oxaliplatin-induced neuropathic pain model, MP-101 showed a significantly improved anti-neuropathic profile, and its effect continued one week after treatment suspension. MP-101 also performed better than dimiracetam in animal models of cognition and depression. Based on the benign safety and tolerability profile previously observed with racemic dimiracetam, MP-101 appears to be a novel, promising clinical candidate for the prevention and treatment of several neuropathic and neurological disorders. |
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spelling | doaj.art-0de4dabf2e514ac0b215c48ef46c7c052023-11-24T13:54:34ZengMDPI AGCells2073-44092022-12-011124402710.3390/cells11244027Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic PainTiziana Bonifacino0Laura Micheli1Carola Torazza2Carla Ghelardini3Carlo Farina4Giambattista Bonanno5Marco Milanese6Lorenzo Di Cesare Mannelli7Michael W. Scherz8Department of Pharmacy (DIFAR), Pharmacology and Toxicology Unit, University of Genoa, 16148 Genoa, ItalyDepartment of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, 50139 Florence, ItalyDepartment of Pharmacy (DIFAR), Pharmacology and Toxicology Unit, University of Genoa, 16148 Genoa, ItalyDepartment of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, 50139 Florence, ItalyMetys Pharmaceuticals c/o Novaremed AG, 4051 Basel, SwitzerlandDepartment of Pharmacy (DIFAR), Pharmacology and Toxicology Unit, University of Genoa, 16148 Genoa, ItalyDepartment of Pharmacy (DIFAR), Pharmacology and Toxicology Unit, University of Genoa, 16148 Genoa, ItalyDepartment of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, 50139 Florence, ItalyMetys Pharmaceuticals c/o Novaremed AG, 4051 Basel, SwitzerlandThe racemic mixture dimiracetam negatively modulates NMDA-induced glutamate release in rat spinal cord synaptosomal preparations and is orally effective in models of neuropathic pain. In this study, we compared the effects of dimiracetam, its R- or S-enantiomers, and the R:S 3:1 non-racemic mixture (MP-101). In vitro, dimiracetam was more potent than its R- or S-enantiomers in reducing the NMDA-induced [<sup>3</sup>H]D-aspartate release in rat spinal cord synaptosomes. Similarly, acute oral administration of dimiracetam was more effective than a single enantiomer in the sodium monoiodoacetate (MIA) paradigm of painful osteoarthritis. Then, we compared the in vitro effects of a broad range of non-racemic enantiomeric mixtures on the NMDA-induced [<sup>3</sup>H]D-aspartate release. Dimiracetam was a more potent blocker than each isolated enantiomer but the R:S 3:1 non-racemic mixture (MP-101) was even more potent than dimiracetam, with an IC<sub>50</sub> in the picomolar range. In the chronic oxaliplatin-induced neuropathic pain model, MP-101 showed a significantly improved anti-neuropathic profile, and its effect continued one week after treatment suspension. MP-101 also performed better than dimiracetam in animal models of cognition and depression. Based on the benign safety and tolerability profile previously observed with racemic dimiracetam, MP-101 appears to be a novel, promising clinical candidate for the prevention and treatment of several neuropathic and neurological disorders.https://www.mdpi.com/2073-4409/11/24/4027oxaliplatin-induced neuropathic painsynaptosomesallodyniahyperalgesiaNMDA-induced glutamate releaseallosteric modulation |
spellingShingle | Tiziana Bonifacino Laura Micheli Carola Torazza Carla Ghelardini Carlo Farina Giambattista Bonanno Marco Milanese Lorenzo Di Cesare Mannelli Michael W. Scherz Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain Cells oxaliplatin-induced neuropathic pain synaptosomes allodynia hyperalgesia NMDA-induced glutamate release allosteric modulation |
title | Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain |
title_full | Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain |
title_fullStr | Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain |
title_full_unstemmed | Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain |
title_short | Pharmacological Profile of MP-101, a Novel Non-racemic Mixture of R- and S-dimiracetam with Increased Potency in Rat Models of Cognition, Depression and Neuropathic Pain |
title_sort | pharmacological profile of mp 101 a novel non racemic mixture of r and s dimiracetam with increased potency in rat models of cognition depression and neuropathic pain |
topic | oxaliplatin-induced neuropathic pain synaptosomes allodynia hyperalgesia NMDA-induced glutamate release allosteric modulation |
url | https://www.mdpi.com/2073-4409/11/24/4027 |
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