Vanderbilt University scientists Drs. Jeffrey Conn, Paul Newhouse, and Craig W. Lindsley have led a special effort that could benefit patients with Alzheimer’s disease and schizophrenia. They succeeded in advancing compound VU319 into phase 1 clinical trials - 50 healthy adult volunteers are currently receiving the compound to test its safety and tolerability.

VU319 targets the muscarinic acetylcholine receptor M1, a key component of cognition that is severely downregulated in a large portion of schizophrenic patients. Its downregulation may contribute to the cognitive disturbances and negative symptoms of schizophrenia, such as loss of motivation, inability to feel pleasure, and social withdrawal.

Interest for muscarinic receptors began in the 1980s, when autopsy studies showed loss of cholinergic neurons in Alzheimer’s disease patients. This observation led to the development of cholinesterase inhibitors which prevent breakdown of acetylcholine - a chemical messenger in the brain important for learning and memory. However, patients receiving cholinesterase inhibitors developed severe side effects likely due to activation of other subtypes of muscarinic receptors. These side effects prevented them from fully benefitting from the treatment.

In the 1990s, scientists tried to develop M1 selective agonists, given the importance of the M1 receptor in cognition. However, “no one was successful, likely because the acetylcholine binding site is highly conserved across the muscarinic receptor subtypes,” Conn explains. “It was impossible to develop an agonist that only activated the M1 receptor.”

While at Merck, Conn and his colleagues wanted to try a new approach. Instead of using receptor agonists to directly target the M1 receptor, they set out to develop allosteric modulators - compounds capable of modifying the primary binding site of a molecular target by binding a site other than the primary site. “The Acetylcholine binding site is highly conserved, so we intentionally moved away from it and we tried to develop molecules that could act on allosteric sites to increase the response to Acetylcholine.” Conn then moved to Vanderbilt where he initiated the Vanderbilt Center for Neuroscience and Drug Discovery, an academic center built with the infrastructure normally available only in pharmaceutical companies. “We developed cell lines and assays that allowed us to screen for allosteric modulators, and published key papers showing that our compounds enhanced cognitive function across multiple Alzheimer’s disease and schizophrenia models,” says Conn.

From there, Conn and his colleagues developed drug candidates that had all the properties needed to perform the regulatory studies that the FDA requires before a drug can advance to human trials. These include demonstrating that the drug is orally bioavailable and that there are no toxic liabilities. They demonstrated lack of cholinergic adverse effects in rodents, dogs, and monkeys. Completion of these experiments was possible thanks to the financial support of The William K. Warren Foundation; their help was key in obtaining approval from the FDA to begin clinical testing.

Phase 1 clinical trials for VU319 are currently underway. Conn hopes to have an industry partner lined up by the end of 2018 when the phase 1 studies will be completed. “The main goal of the phase 1 clinical studies is to show that the drug does not have any cholinergic adverse effects,” says Conn. Given the previous history of serious side effects caused by muscarinic compounds, demonstrating that this new compound does not lead to those same adverse effects in humans is key to get industry partners to invest and fund phases 2 and 3 of the clinical study.

“The next 6 months will be crucial to see how things develop,” says Conn.” If everything goes well, we could see this drug in the market within 5-7 years.”