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Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia


Year of Publication:
Contact PI Name:
Gregory R.J. Thatcher
Contact PI Affiliation:
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois, USA
Jia Luo, Sue H. Lee, Lawren VandeVrede, Zhihui Qin, Sujeewa Piyankarage, Ehsan Tavassoli, Rezene T. Asghodom, Manel Ben Aissa, Mauro Fà, Ottavio Arancio, Lan Yue, David R. Pepperberg
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Drug Discovery Foundation (ADDF)
UIC Center for Clinical and Translational Science
National Eye Institute (NEI)
Research to Prevent Blindness Inc.
Institute for the Study of Aging (ISOA)
Study Goal and Principal Findings:

Background: Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-β, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and antiinflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. Results: The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. Conclusion: Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
4-methyl-5-(2-(nitrooxy) ethyl) thiazol-3-ium chloride (NMZ)
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Step-Through Passive Avoidance Test
Loss of Righting Reflex (LORR)
Motor Function
Rotarod Test
GABA Levels
Long Term Potentiation (LTP)
field Excitatory Postsynaptic Potential (fEPSP)
Oral Bioavailability (F%)
PK/PD Modeling
Area Under the Curve (AUC)
Drug Concentration-Plasma
Drug Concentration-Brain
Binding Affinity