NTRX-07, A potent and selective CB2 agonist:
Immune cells, including microglia within the central nervous system, express CB2 receptors. When activated these receptors can modulate immune cell migration and cytokine release decreasing pro-inflammatory responses. For this reason, CB2 receptors have become the subject of considerable research as a potential therapeutic target to treat a host of neuro-inflammatory disorders. The ideal therapeutic candidate will have high affinity for the CB2 receptor while avoiding the adverse psychotropic effects that accompany CB1 receptor-based therapies. Furthermore, it will be able to penetrate the blood-brain barrier providing for high expression levels in the CNS.
Through a multidisciplinary medicinal approach we have developed NTRX-07 as a potent and selective CB2 receptor agonist that can be orally administered, yielding high-level CNS expression. Multiple pre-clinical studies have demonstrated that NTRX-07 promotes neuronal survival through decreasing pro-inflammatory microglial activity. Pre-clinical efficacy has been established in multiple neuropathic pain models, including chemotherapy-induced peripheral neuropathy (CIPN), nerve ligation, and complex regional pain syndrome (CRPS) induced by ischemic injury. Furthermore, NTRX-07 has been shown to improve memory loss observed in Alzheimer disease rodent models. NTRX-07 has passed all basic ADMET testing as well as genotoxicity and in-vitro cardiac safety; no in vivo toxicology or psychomimetic effects have been observed.
Key Publications – Alzheimer’s Disease Model
NTRX-07 is identified as MDA7 in previous publications, they are the same compound.
- Bie, B, Wu, J, B, Yang, H, Xu, J, Brown, DL. Naguib, M. Suppression of Neuroligin 1 Underlies Amyloid-induced Memory Deficiency. Nature Neuroscience, 2014;17:223-31
- Wu, J, Bie, B, Yang, H, Xu, J, Brown, DL. Naguib, M. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiology of Aging 2012. 2013;34:791-804.
- Wu, J, Bie, B, Yang, H, Xu, J, Brown, DL. Naguib, M. Suppression of Central chemokine fractalkine signaling alleviates amyloid-induced memory deficiency. Neurobiology of Aging, 2013;34:2843-2852.
- Naguib M, Bie B, Ting AH. Fundamental concepts of epigenetics for consideration in anesthesiology. Current Opinion in Anesthesiology. 2012; 25:434-443.
Key Publications – Neuropathic Pain Model
- Naguib M, Xu JJ, Diaz P, Brown DL, Bie B, Hu J, Craig S, Hittelman WN. Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system. Anesthesia & Analgesia 2012;114:1104-1120.
- Naguib M, Diaz F, Xu JJ, Astruc-Diaz F, Craig S, Vivas-Mejia PE, Brown DL. MDA7: a novel selective cannabinoid receptor 2 agonist that prevents allodynia in rodent neuropathic pain models. British Journal of Pharmacology 2008; 155: 1104-1116
- Xu JJ, Diaz P, Bie, B, Wu J, Astruc-Diaz F, Brown DL, Naguib M. Spinal gene expression profiling and pathways analyses of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy. Neuroscience 2014;260:185-94.
- Xu JJ, Diaz F, Astruc-Diaz F, Craig S, Munoz E, and Naguib M. Pharmacological characterization of a novel cannabinoid ligand, MDA19, for treatment of neuropathic pain. Anesthesia and Analgesia 2010; 111: 99-109.
Key Publications – Chemistry, development, and formulation
- Diaz P, Phatak SS, Xu J, Fronczek FR, Astruc-Diaz F, Thompson CM, Cavasotto CN and Naguib M. 2,3-Dihydro-1-benzofuran Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Agonists: Design, Synthesis, and Binding Mode Prediction through Ligand-steered Modeling. ChemMedChem 2009; 4: 1615-1629.
- Diaz P, Xu JJ, Astruc-Diaz F, Pan H-M, Brown DL, Naguib M. Design and synthesis of a novel series of N-alkyl isatin acylhydrazone derivatives that act as selective CB2 agonists for the treatment of neuropathic pain Journal of Medicinal Chemistry 2008, 51: 4932-4947.
- Diaz P, Phatak SP, Xu J, Astruc-Diaz F, Cavasoto CN, Naguib M. 6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction. Journal of Medicinal Chemistry 2009; 52: 433-44
- Luo Z, Naguib M. A Synthetic Approach for (S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone, a Selective CB2 Receptor Agonist. Tetrahedron Letters 2012; 53: 3316–3318
- Diaz F, McDaniel S, Xu J, Brown DL, Naguib M, Diaz P. In vivo efficacy of enabling formulations based on hydroxypropyl-β-cyclodextrins, micellar preparation and liposomes for the lipophilic cannabinoid CB2 agonist, MDA7. Journal of Pharmaceutical Sciences 2013;102:352-364.