Novel Pharmacotherapy for Treating Cognitive Dysfunction and Chronic Pain in Alzheimers Disease

Presenter: Ganesh Thakur

Research Category: Health Sciences
Student Type: Graduate
Award Winner Category: Health Sciences

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder which leads to dementia and chronic pain; a combination difficult to treat and worsens over time. Current therapies modestly manage only one of these medical conditions and a pharmacotherapy that addresses the above issues without side effects is an unmet medical need. α7 nicotinic acetylcholine receptor (nAChR) has emerged as a target that holds such a promise.

The orthosteric activation of α7 nAChRs has met with limited clinical success due to lack of efficacy and off-target activity. An alternative strategy is to target the α7 nAChR allosteric site(s). 4BP-TQS, an allosteric agonist-positive allosteric modulator (ago-PAM) is one such ligand that activates the receptor and enhances the activity of the endogenous ligands.

In-house microwave-accelerated synthesis of 4BP-TQS and its enantioseparation yielded GAT107 [(+) enantiomer], which was found to be the active enantiomer in electrophysiology studies in Xenopus oocytes. GAT107 was furthered into in vivo studies with various animal models of memory and cognition [Morris water maze, novel object recognition test and Barnes Test] and chronic pain models [formalin test and chronic constructive injury model (CCI)] to evaluate its efficacy. GAT107 was found to be very effective without any addictive, locomotor or hypothermic side effects.

Our preliminary data strongly supports that this novel class of compounds acting through a unique mechanism (ago-PAM) provides a better approach for improving cognitive deficiencies and associated chronic pain. GAT107 will help develop novel, potent and safe α7 nAChR ago-PAMs as an effective and unique pharmacotherapy for Alzheimer’s disease.