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Project: 1
Development and Pharmacological Characterization of Mechanistically Distinct Glutamate-Concentration–Biased Allosteric Modulators (BAMs) of the NMDA Receptor
Most pharmacological agents that bind within the NMDA receptor agonist-binding domain (ABD) cleft exhibit limited subtype selectivity for specific GluN2 subunits. To address this limitation, we target the less conserved GluN1/GluN2 ABD interface to design subtype-selective positive and negative allosteric modulators. Two-electrode voltage clamp and patch-clamp electrophysiology techniques are employed to characterize NMDA receptor function and modulation. Computational modeling, molecular docking, and molecular dynamics simulations are used to identify novel allosteric binding sites and guide rational ligand design.
CNS4 is a mechanistically distinct NMDA receptor allosteric modulator that exhibits glutamate-concentration–dependent bias, enabling context-dependent modulation of receptor activity. Its pharmacological profile has been evaluated in preclinical studies across both rodent and non-rodent species, supporting its translational potential. Collectively, these findings position CNS4 as a promising lead compound for therapeutic development with an improved balance of efficacy and safety.
Project: 2
Improving Brain Metabolic Waste Clearance in an Animal Model of Alzheimer’s Disease by Cranial Osteopathic Manipulation
A novel "Mechanoceutics TM" Treatment Strategy for Alzheimer’s Disease
Studying the potential use of mild mechanical pressure for the treatment of Alzheimer’s disease. This idea was conceived based on knowledge of the existence of brain lymphatic vessels and the ability of cranial osteopathic manipulation (COM) to improve fluid circulation in the brain. COM-treated eighteen-month-old rats exhibit improvements in spatial learning and memory, reductions in Aβ plaque burden, and changes in substrates associated with CNS fluid clearance. Currently, this work is being extended using a transgenic rat (TgF344-AD) model of Alzheimer’s disease.
There are numerous animal models available for Alzheimer’s disease. The most commonly used models are transgenic animals that overexpress amyloid precursor protein (APP), the precursor of Aβ, which accumulates in the brain and initiates Alzheimer’s disease pathology. At toxic levels, amyloid accumulation produces hallmark features of Alzheimer’s disease, including deficits in learning and memory. We use a transgenic rat (TgF344-AD) model of Alzheimer’s disease that mimics age-dependent cognitive decline and offers greater translational relevance to humans compared with other models. These animals express the human amyloid precursor protein (APP) gene with two Swedish mutations (K595N and M596L) and a presenilin-1 gene with an exon-9 deletion.
Following are the techniques used for this study:
Spatial learning and memory assays.
Positron emission tomography (PET) imaging for Aβ plaques using the FDA-approved radiotracer, Florbetapir F18 injection (Amyvid).
Biochemical analysis of brain tissue samples.
Above projects received funding from the following agencies:
Project 1 & 2
Project 1
Project 2
Project 2
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