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First Compound for Receptors in Schizophrenia, Alzheimer's Holds Promise
But because the compounds are "dirty" scientific lingo for a lack of selectivity they activate not only the essential M1 and M 4 muscarinic receptors but also the other three members of the family, designated M2, M3 and M5, resulting in unacceptable gastrointestinal and other side effects.
That may soon change, thanks to the discovery of a truly selective agonist that targets only the M1 receptor, known to be central to cognition and thus implicated in diseases like AD and schizophrenia.
On April 20, speaking at the Experimental Biology 2009 meeting in New Orleans, Vanderbilt graduate student Evan Lebois in the laboratories of Dr. David Weaver and Dr. Craig Lindsley describes the complex, labor-intensive screening and discovery process that allowed Vanderbilt scientists to pinpoint what big pharma's computers and robots could not, and the process now underway to move the compound toward becoming an effective drug to treat AD and schizophrenia. The presentation is part of the scientific program of the American Society for Pharmacology and Experimental Therapeutics.
In stage one, the search for the appropriate molecule, Dr. David Weaver, director of the Vanderbilt Chemical Biology's High-Throughput Screening facility and co-director of the Molecular Library Screening Center, painstakingly ran high-throughput screens of every compound in the molecular library to see which ones activated the M1 receptor. Most such studies are done on computers with robots and automatic scoring mechanisms. By looking with his own eyes at the waveform reactions of every compound in the library, including those already rejected by the robotic systems, Dr. Weaver identified the molecule the scientists dubbed VU019467.
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