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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Main Authors: Tiziana Bonifacino, Laura Micheli, Carola Torazza, Carla Ghelardini, Carlo Farina, Giambattista Bonanno, Marco Milanese, Lorenzo Di Cesare Mannelli, Michael W. Scherz
Format: Article
Language:English
Published: MDPI AG 2022-12-01
Series:Cells
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Online Access:https://www.mdpi.com/2073-4409/11/24/4027
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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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