Description:

 

Background

This technology encompasses novel activators of neuronal GIRK channels that have activity against anxiety, chronic pain and epilepsy. In particular, they were found effective against post-traumatic stress disorder (PTSD) in animal models. 

 

Technology Overview

This compound, GAT1508, selectively activates brain GIRK1/GIRK2 over cardiac GIRK1/GIRK4 potassium channels with a potency of 76 nM and an efficacy of 165% greater than the non-specific parent compound ML297.

The molecular mechanism of action and specificity of GAT1508 has been determined in the binding of two amino acid residues in the GIRK4 subunit that decrease interactions of the drug binding channel subunit with PIP2 (by disrupting the N-terminus of this subunit from coordinating PIP2).

 

Benefits

- The brain specificity of the GAT1508 compound, along with its improved efficacy and potency make it a lead compound for neuronal indications avoiding cardiac arrhythmias

- Novel pharmacophores within the urea scaffold have been identified that impart high selectivity and efficacy for GIRK1/GIRK2 activation over GIRK2/GIRK4 activation. 

- Urea-containing compounds can be synthesized in a matter of minutes using a microwave method developed in the Thakur lab

- Screening method of 80 compounds revealed substitutions producing specificity for brain over cardiac isoforms. Oocyte two-electrode voltage clamp electrophysiology proved a more reliable method for distinguishing specificity of GAT compounds than the routinely used Thallium fluorescence assay

- Among anxiety disorders that the parent compound ML297 proved effective, the novel indication PTSD was tested in rodent models and shown to be most effectively treated by GAT1508.

 

Applications

- Treatment of post-traumatic stress disorder (PTSD)

- Treatment of chronic and neuropathic pain

 

Opportunity

- License

- Partnering

- Research Collaboration

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Mark Saulich
Associate Director of Commercialization
Northeastern University
m.saulich@northeastern.edu
Inventors:
Ganeshsingh Thakur
Diomedes Logothetis
Anantha Shekhar
Yu Xu
Lucas Cantwell
Keywords: