Clinically available antipsychotics are not effective in the remediation of the negative symptoms and cognitive impairments observed in individuals with schizophrenia and are associated with a number of dose-limiting adverse effects. Thus, there is a critical need to develop novel therapeutic approaches for schizophrenia with broader efficacy and fewer adverse effects. Clinical and preclinical studies indicate that selective modulation of the M1 muscarinic acetylcholine receptor may provide a novel approach for the treatment of the different symptoms in schizophrenia. Mechanistically, selective M1 activation fits well with the glutamate hypothesis, or N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, as both M1 and the NR1a NMDAR subunits are co-localized at specific postsynaptic sites, and activation of M1 by orthosteric mAChR agonists, and more recently, highly selective M1 allosteric agonists and M1 positive allosteric modulators (PAMs), developed during the previous funding period, potentiate NMDAR currents in hippocampal and medial prefrontal cortical neurons, and enhance cognitive performance in multiple hippocampal- and/or prefrontal cortical-driven models. Importantly, we and others have shown that M1 allosteric agonists display brain region- dependent (M1-expression dependent) pharmacology and suffer many of the problems associated with previous orthosteric M1 agonist programs. Thus, M1 PAMs represent the mechanism by which to address the therapeutic potential of selective M1 activation in man to target the negative and cognitive symptom clusters in schizophrenia, alone or in combination with standard antipsychotics and/or cholinesterase inhibitors. In Project 1 of this application, we will conduct a series of studies to establish the efficacy for our lead M1 PAM VU0467319 relative to potential adverse effects that have limited the development of previous M1 ligands and to establish a functional biomarker strategy to support future clinical dose-finding studies in Project 4 of this application.

Public Health Relevance

To date, there has been limited success in the development of novel antipsychotic therapies that provide efficacy for negative and cognitive symptoms observed in schizophrenia patients. The studies outlined in project 1 of this NCDDG will provide critical preclinical information for the development of a novel therapeutic strategy through potentiation of M1 mAChRs for the cognitive deficits and negative symptoms in schizophrenia. In particular, these preclinical studies will help in the translation from animal models to clinical studies outlined in project 4.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZMH1-ERB-C (01))
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Vanderbilt University Medical Center
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Moran, Sean P; Dickerson, Jonathan W; Cho, Hyekyung P et al. (2018) M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition. Neuropsychopharmacology 43:1763-1771
Berizzi, Alice E; Bender, Aaron M; Lindsley, Craig W et al. (2018) Structure-Activity Relationships of Pan-G?q/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators. ACS Chem Neurosci 9:1818-1828
Bender, Aaron M; Cho, Hyekyung P; Nance, Kellie D et al. (2018) Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold. ACS Chem Neurosci 9:1572-1581
Rook, Jerri M; Bertron, Jeanette L; Cho, Hyekyung P et al. (2018) A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity. ACS Chem Neurosci 9:2274-2285
Rook, Jerri M; Abe, Masahito; Cho, Hyekyung P et al. (2017) Diverse Effects on M1 Signaling and Adverse Effect Liability within a Series of M1 Ago-PAMs. ACS Chem Neurosci 8:866-883
Lindsley, Craig W; Emmitte, Kyle A; Hopkins, Corey R et al. (2016) Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors. Chem Rev 116:6707-41
Panarese, Joseph D; Cho, Hykeyung P; Adams, Jeffrey J et al. (2016) Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration. Bioorg Med Chem Lett 26:3822-5