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

Tiziana Bonifacino; Laura Micheli; Carola Torazza; Carla Ghelardini; Carlo Farina; Giambattista Bonanno; Marco Milanese; Lorenzo Di Cesare Mannelli; Michael W Scherz

doi:10.3390/cells11244027

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. 2022 Dec 13;11(24):4027. doi: 10.3390/cells11244027.

Authors

Affiliations

¹ Department of Pharmacy (DIFAR), Pharmacology and Toxicology Unit, University of Genoa, 16148 Genoa, Italy.
² Inter-University Center for the Promotion of the 3Rs Principles in Teaching & Research (Centro 3R), 56122 Pisa, Italy.
³ Department of Neuroscience, Psychology, Drug Research and Child Health, NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy.
⁴ Metys Pharmaceuticals c/o Novaremed AG, 4051 Basel, Switzerland.
⁵ IRCCS, Ospedale Policlinico San Martino, 16132 Genoa, Italy.

Abstract

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 [³H]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 [³H]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 IC₅₀ 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.

Keywords: NMDA-induced glutamate release; allodynia; allosteric modulation; hyperalgesia; oxaliplatin-induced neuropathic pain; synaptosomes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cognition
D-Aspartic Acid
Depression
Glutamic Acid
N-Methylaspartate* / pharmacology
Neuralgia* / chemically induced
Neuralgia* / drug therapy
Rats

Substances

dimiracetam
N-Methylaspartate
D-Aspartic Acid
Glutamic Acid

Grants and funding

This work was supported by research funding from Metys Pharmaceuticals AG to G.B., M.M., T.B. and by the Italian Ministry of Instruction, University and Research (MIUR) and the University of Florence.