NMDAR & Neurodegenerative Disorders

Small Molecules to Improve Treatments for Neurodegenerative Disorders

Over 12 million Americans suffer from neurodegenerative disorders, such as Parkinson’s, Epilepsy, Alzheimer’s, and treatment resistant depression. Such disorders often have debilitating symptoms including extreme memory loss, hallucinations, and volatile changes in mood and behavior. Unfortunately, the diagnosis and treatment of many of these disorders have long challenged medical professionals. The existing drug options for most neurodegenerative disorders are largely inadequate for both addressing the underlying diseases or managing their symptoms. Additionally, these medications have many adverse side effects including dissociative feelings and hallucinations and they are often not effective for many patients suffering from the diseases they are trying to treat.

A new treatment approach created by Emory researchers Stephen Traynelis, PhD, Dennis Liotta, PhD, and their research team may solve this medical gap for neurodegenerative disorders as well as a range of other neuron related ailments.

The researchers suspected that by studying the ion channel proteins, N-methyl-D-aspartate receptors (NMDAR), which are located in the membranes of nerve cells they could develop a novel way to treat neurodegenerative ailments. NMDARs are influential in several pathophysiological and neurodegenerative conditions because they act as the gatekeepers to nerve cells that allow ions, particularly the calcium ions, to pass from outside the cell to inside the cell, thereby triggering the nerve cell to send out electrical and chemical signals. These gatekeepers allow ions in when two molecules, glutamate and glycine, act as keys by binding to specific NDMAR sites on the protein’s GluN1 and GluN2 subunits. However, when glutamate and glycine begin to over-actively or under-actively bind to the NMDARs, they can cause nerve cells to begin to either send too many or not enough signals, thereby causing diseases such as Parkinson’s, Stokes, Alzheimer’s disease etc.

Emory researchers hypothesized that by finding a way to regulate and normalize the binding of glutamate and glycine to the NDMARs they could potentially create a new, more effective treatment for nerve related disorders. Consequently, they created molecules that would bind to the NMDAR at a site known as the allosteric binding site, a place different from those where glutamate and glycine bind. These molecules, known as allosteric modulators act to change the frequency at which glutamate and glycine bind to the NMDARs. There are two types of allosteric modulators: positive and negative (also known as positive potentiators and negative potentiators). Positive allosteric modulators serve to activate glutamate and glycine and increase the frequency with which they bind to NDMARs. Conversely, negative allosteric modulators reduce the activity and frequency at which glutamate and glycine and increase bind to NDMARs. Currently, the Emory researchers are focusing on positive allosteric modulators.

Raj Guddneppanavar, the licensing associate in the Office of Technology Transfer working with these researchers says, “Modulating the NMDA receptors in specific brain structures is very challenging but it’s essential to develop effective therapeutics with minimal side effects for several neurological disorders. We are very excited about the novel subtype-selective modulators and look forward to their progress into clinical development.”

The researchers’ goal is to see these compounds developed into drug candidates for clinical trials. “There are neurological diseases that constitute a huge burden on humanity, families, and (create) a huge cost on society. Very few (people with these diseases) are adequately treated with existing medications,” says Traynelis, “With these molecules, we hope to target specific subunits known to be directly involved in these neurological diseases and hopefully alleviate some the burden they cause.”

The full research team also includes Subhrajit Bhattacharya, Matt Epplin, Pavan Kumar Reddy Gangireddy, Yao Jing, Hiro Kusumoto, Phuong Le, Lanny Liebeskind, Miranda McDaniel, David Menaldino, Rhonda Moore, Riley Perszyk, Samantha Summer, Sharon Swanger, Hongjie Yuan, and Jing Zhang.

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