Optimization of Selective M4 Muscarinic Receptor Antagonists for Treatment of Dystonia
Abstract
Dystonia is a brain disorder that leads to debilitating and painful motor symptoms. Dystonia is characterized by persistent or intermittent severe muscle contractions causing painful and disabling abnormal movements and/or postures. Dystonia often results from traumatic brain injury, but can also result from trauma to other body regions. These may include a neck injury, from whiplash or other neck trauma, or injury of other body parts. These types of trauma often occur in combat situations and can lead to severe chronic disability with a dystonic condition for which there are no highly effective treatments. Among the few pharmacological treatments for dystonia are antagonists that inhibit the function of a family of receptors for a neurotransmitter in the brain called acetylcholine (ACh). These neurotransmitter receptors are called muscarinic acetylcholine receptors (mAChRs) and are critical for communication between brain cells in areas of the brain that control motor function. Unfortunately, in addition to inhibiting mAChRs in brain regions involved in dystonia, currently available mAChR antagonists block mAChRs in virtually all areas of the brain and in other body systems. This leads to serious adverse side effects that are unrelated to their efficacy in treatment of dystonia but limit their clinical use. Over the past several years, we have made a major breakthrough in developing novel drug-like compounds that are capable of selectively inhibiting the specific subtype of mAChR, called the M4 receptor, in brain regions that are involved in dystonia. Importantly, these agents work without blocking mAChRs that are responsible for the severe side effects of these medicines. Furthermore, we found that these highly selective antagonists of M4 may have robust efficacy in reversing motor impairment in animal models of dystonia without inducing observable side effects. This major breakthrough opens an exciting opportunity to develop a new medicine that could be very effective in treatment of dystonia without inducing the severe dose-limiting adverse effects of previous nonselective mAChR antagonists. However, the compounds that we have discovered have not yet been chemically optimized to have the balance of properties that are required for use as an orally administered medicine that could be approved by the U.S. Food and Drug Administration (FDA) and used in dystonia patients. We are now poised to fully optimize selective M4 antagonists that can advance to clinical development for treatment of this devastating disorder. We propose a series of studies aimed at optimizing highly selective M4 antagonists that have a balance of properties required to apply to the FDA for permission to initiate clinical testing of an Investigational New Drug (IND) and test these compounds in dystonia patients. Specifically, we will optimize a lead drug candidate and at least one backup compound that can be advanced to further development required to gain FDA approval.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910355
Entities
People
- Peter Conn
Organizations
- United States Army
- Vanderbilt University