NMDA Receptor-based Therapeutics
BACKGROUND
|
The NMDA receptor plays critical roles in:
- Development of the CNS - Generation of central rhythms - Synaptic plasticity - Learning and memory - Cognitive processes |
NMDA receptor dysfunction may result in acute and chronic
neurological disorders |
|
NMDAR
hypo-function
contributes to: |
NMDAR hyper-activation contributes to: - Stroke - Vascular dementia |
| Although the NMDA receptor is an important therapeutic target, clinical results using antagonists, and partial agonists have been relatively disappointing thus far, due to a combination of unacceptable side effects and lack of efficacy. | |
HYPOTHESIS
| Allosteric modulators alter receptor function without interacting with
the ligand binding sites. Therefore they don't display agonism and they
don't compete with the endogenous ligands (glutamate and glycine for
the NMDA receptor). Because allosteric modulators do not activate the NMDA receptor in the absence of endogenous agonist, they should not display excito-toxicity, unlike previously tested drugs that are (partial) agonists. Negative allosteric modulators are intrinsically dose-limiting, unlike competitive antagonists, which should limit the side effects associated with excessive inhibition of the NMDA receptor. Positive allosteric modulators enhance endogenous NMDA receptor function (without directly stimulating the receptor). This property is unique to this class of drugs. It is therefore hypothesized that allosteric modulators of the NMDA receptor constitute a novel class of safe and effective therapeutics for treatment of a range of neurological disorders. |
APPROACH
Mutagenesis experiments in our laboratory have
identified the binding site for allosteric modulators in the NMDA
receptor as the dimer interface formed by two neighboring ligand binding
domains (LBDs). Altering the stability of the dimer interface changes
the extent to which the receptor can be activated b y
agonists. This figure shows a surface representation of the NR1-NR2A ligand binding domain interface, based on the published crystallographic structure. The dimer interface displays several complex cavities, which could act as binding sites for small molecules. A virtual 3D library of 8,000,000 small molecules is being docked into this allosteric binding site and ranked by their predicted binding affinity. The figure below shows an example of a compound docked into the dimer interface. Only the NR2A half of the dimer is shown for clarity.  Top ranking compounds are tested for NMDA receptor efficacy, affinity, selectivity and allosteric mechanism of action. Efficacy of lead compounds is studied in vitro using cultured hippocampal neurons, and selected compounds are further evaluated in vivo using rodent behavioral models. This analysis is expected to yield a range of lead compounds, which allosterically attenuate or enhance NMDA receptor function to a well-defined extent. Because these compounds do not display agonism and are intrinsically dose-limiting, they should be much safer than previously tested drugs. |