The Department of Pharmacology at the University of Maryland School of Medicine invites you to join us as P. Jeffrey Conn, PhD, the Lee E. Limbird Professor of Pharmacology and director of the Vanderbilt Center for Neuroscience Drug Discovery at Vanderbilt University, presents the 5th Hugh Arthur Pritchard Memorial Lecture for Graduate Students.
The lecture is titled “Positive Allosteric Modulators of GPCRs as a Novel Treatment for Schizophrenia” and will be held Thursday, Jan. 10, at 3 p.m. in the Health Science Research Facility II Auditorium, with a reception to follow.
Previous clinical studies as well as a large number of cellular and animal behavioral studies suggest that selective activators of M1 and/or M4 subtypes of muscarinic acetylcholine receptors (mAChRs) could provide a novel approach to treatment of schizophrenia. Especially exciting is the possibility that such agents could have efficacy in treatment of positive, negative, and cognitive symptoms in schizophrenia patients. Unfortunately, previous efforts to develop selective agonists of individual mAChR subtypes have not been successful and previous compounds have failed in development because of adverse effects due to activation of multiple mAChR subtypes.
Furthermore, the relative roles of M1 and M4 in mediating the overall therapeutic effects of less-selective mACh agonists are not understood. We have developed highly selective positive allosteric modulators (PAMs) of both M1 and M4 that have excellent properties for in vivo studies and as drug candidates. Electrophysiology and genetic studies are providing important new insights into the mechanisms by which M1 and M4 PAMs act in specific cortical and midbrain circuits that are relevant for treatment of different symptom domains in schizophrenia patients. Interestingly, selective M1 PAMs have specific effects in forebrain circuits that are relevant for cognitive deficits and negative symptoms and have robust efficacy in animal models of these symptom domains. In contrast, selective M4 PAMs have novel cellular actions in the basal ganglia relevant for positive symptoms and have robust antipsychotic-like effects in animal models. Also we have now advanced highly optimized M1 and M4 PAMs into preclinical and clinical development to evaluate their potential utility in treatment of schizophrenia.
More recently, we have built on recent human genetic studies that implicate two specific subtypes of metabotropic glutamate (mGlu) receptors, mGlu1 and mGlu3, in schizophrenia. Optimized mGlu1 and mGlu3 PAMs were used along with mouse genetic studies to evaluate the roles of these receptors in specific basal ganglia and forebrain circuits that have been implicated in schizophrenia. These studies are providing exciting new evidence that highly selective activators of these two glutamate receptors have potential utility in treatment of positive (mGlu1), negative (mGlu1), and cognitive (mGlu3) symptoms of schizophrenia patients. Furthermore, the novel mGlu1 and mGlu3 PAMs discovered in these studies provide excellent drug leads for further optimization and ultimate clinical testing. Collectively, these studies are providing insights that could lead to exciting new approaches for treatment of multiple symptom clusters in schizophrenia patients.