Currently available antipsychotics for schizophrenia are not effective for the treatment of all major symptoms associated with the disease and are associated with a number of dose-limiting adverse effects. Thus, there is a critical need to develop novel therapeutic agents for treatment of schizophrenia that have broader efficacy and fewer adverse effects than currently available medications. We propose studies aimed at discovery and optimization of novel drug candidates for treatment of schizophrenia that are mechanistically unrelated to currently available antipsychotic agents and have the potential to provide efficacy in treatment of all major symptom clusters of this disease. The most advanced of these programs is focused on discovery of novel compounds that inhibit the glycine transporter 1, GlyT1. Glycine is a co-agonist with glutamate at the A/-methyl-D-aspartate (NMDA) subtype of glutamate receptors and provides an excellent approach to increasing NMDA receptor function while maintaining activity dependence of NMDA receptor activation. A number of clinical and animals studies suggest that GlyTI inhibitors have exciting potential for treatment of schizophrenia. To date, we have optimized novel scaffolds of GlyTI inhibitors with excellent pharmacokinetic and brain penetration profiles, robust efficacy in animal models, and lack significant toxicity. A second program is focused on discovery and optimization of highly selective allosteric agonists of the M1 muscarinic acetylcholine receptor. We have established a novel approach to development of highly selective agonists of the M1 muscarinic acetylcholine receptor by targeting allosteric sites and have shown that these compounds have robust efficacy in animal models that predict efficacy in treatment of schizophrenia. Both the Ml and GlyTI programs are based on strong validation from animal models and exciting clinical data that provide support for pursuing these novel targets. Our overall objective is to optimize drug candidates that interact with each of these targets. Ultimately, we will work with industry partners to develop these drug candidates in clinical studies. We will begin with lead optimization of GlyTI inhibitors, followed by hit-tc-lead and lead optimization of Ml allosteric agonists with a goal of advancing molecules that interact with each of these to a stage where they are ready for preclinical and clinical development. Finally, we have a pipeline of additional targets for which we have chemically diverse verified hits and early drug leads that are poised for full lead optimization efforts. While not specifically included in this application, this provides a robust discovery pipeline that will be important for the future directions of this program.

Public Health Relevance

The overarching goal of this proposal is to understand the cellular and molecular features of TLR2/NLR mediated responses, how these signaling events contribute to the host's ability to restrain bacterial growth, protective immunity, and how mAb bound to Ft and AAO Ft influences these immunological processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH087965-03
Application #
8377752
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$462,688
Indirect Cost
$166,093
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Gould, Robert W; Nedelcovych, Michael T; Gong, Xuewen et al. (2016) State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 - Relation to antipsychotic-like drug effects. Neuropharmacology 102:244-53
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Pancani, Tristano; Foster, Daniel J; Moehle, Mark S et al. (2015) Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice. Proc Natl Acad Sci U S A 112:14078-83
Gould, R W; Dencker, D; Grannan, M et al. (2015) Role for the M1 Muscarinic Acetylcholine Receptor in Top-Down Cognitive Processing Using a Touchscreen Visual Discrimination Task in Mice. ACS Chem Neurosci 6:1683-95
Maltese, Marta; Martella, Giuseppina; Madeo, Graziella et al. (2014) Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors. Mov Disord 29:1655-65
Jones, Carrie K; Sheffler, Douglas J; Williams, Richard et al. (2014) Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: development of a potent and CNS penetrant [3.1.0]-based lead. Bioorg Med Chem Lett 24:1067-70

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