Over 50 years ago, antimuscarinic agents were shown to induce a psychotic state in humans similar to schizophrenia and exacerbate existing symptoms in schizophrenic patients. At about this time, muscarinic agonists were shown to be moderately effective as neuroleptic agents, which gave rise a cholinergic hypothesis of schizophrenia, decades before the now prevalent hyperdopaminergic hypothesis. Recent preclinical and Phase III clinical data further strengthens the cholinergic hypothesis by demonstrating that muscarinic acetylcholine receptor (mAChR) agonists, such as the pan-muscarinic agonist xanomeline, are effective in improving cognition and reducing psychotic symptoms in schizophrenic and Alzheimer's disease (AD) patients. However, the clinical utility of of mAChR agonists has been limited due to intolerable side effects resulting from a lack of mAChR subtype selectivity. The development of subtype selective muscarinic agonists has been difficult to the highly conserved orthosteric binding site for acetylcholine (ACh) among the five muscarinic receptor subtypes (M1-M5). We have identified and plan to develop novel, selective allosteric agonists and potentiators of the M1 mAChR that activate the receptor through an allosteric binding site that is topologically distinct from the orthosteric binding site. Since mounting evidence suggests that the cognitive, antipsychotic and Ab lowering effects of cholinergic agents are mediated by the M1 mAChR subtype, we have performed a high throughput screen to identify M1 potentiators and allosteric agonists. This effort afforded small molecule M1 potentiators and M1 allosteric agonist leads representing multiple new chemotypes. While a significant accomplishment, these screening leads will require several rounds of chemical lead optimization in order to produce M1 allosteric agonists and M1 potentiators suitable as proof of concept tools to study in vivo. In addition, we have made significant progress in the evaluation of TBPB, a highly selective and potent M1 allosteric agonist in vivo, which further supports our strategy of pursuing selective M1 activation as a treatment for schizophrenia. This research has direct relevance to the mission of NIMH and has the potential to impact human health directly. Our goal for this project is to develop, in parallel, selective M1 allosteric agonists and M1 positive allosteric modulators with acceptable profiles for preclinical and ultimately clinical development that may lead to a new drug for the treatment of the positive, negative and cognitive symptoms of schizophrenia.

Public Health Relevance

Recent preclinical and Phase III clinical data has shown that muscarinic acetylcholine receptor (mAChR) agonists, such as the pan-muscarinic agonist xanomeline, are effective in improving cognition and reducing psychotic symptoms in schizophrenic and Alzheimer's disease (AD) patients. We have completed a high throughput screen, identified and plan to develop novel, selective allosteric agonists and potentiators of the M1 mAChR that activate the receptor through a novel binding site which affords complete, unprecedented selectivity for M1 versus M2-M5. Our goal for this project is to develop, in parallel, selective M1 allosteric agonists and M1 positive allosteric modulators with acceptable profiles for preclinical and ultimately clinical development that may lead to a new drug for the treatment of the positive, negative and cognitive symptoms of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH082867-05
Application #
8260205
Study Section
Special Emphasis Panel (ZRG1-MNPS-C (09))
Program Officer
Driscoll, Jamie
Project Start
2008-05-20
Project End
2013-07-31
Budget Start
2012-05-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$341,921
Indirect Cost
$119,171
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Conn, P Jeffrey; Lindsley, Craig W; Meiler, Jens et al. (2014) Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov 13:692-708
Melancon, Bruce J; Tarr, James C; Panarese, Joseph D et al. (2013) Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease. Drug Discov Today 18:1185-99
Poslusney, Michael S; Melancon, Bruce J; Gentry, Patrick R et al. (2013) Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule. Bioorg Med Chem Lett 23:1860-4
Engers, Darren W; Lindsley, Craig W (2013) Allosteric modulation of Class C GPCRs: a novel approach for the treatment of CNS disorders. Drug Discov Today Technol 10:e269-76
Sheffler, Douglas J; Sevel, Christian; Le, Uyen et al. (2013) Further exploration of M? allosteric agonists: subtle structural changes abolish M? allosteric agonism and result in pan-mAChR orthosteric antagonism. Bioorg Med Chem Lett 23:223-7
Melancon, Bruce J; Poslusney, Michael S; Gentry, Patrick R et al. (2013) Isatin replacements applied to the highly selective, muscarinic M1 PAM ML137: continued optimization of an MLPCN probe molecule. Bioorg Med Chem Lett 23:412-6
Gentry, Patrick R; Bridges, Thomas M; Lamsal, Atin et al. (2013) Discovery of ML326: The first sub-micromolar, selective M5 PAM. Bioorg Med Chem Lett 23:2996-3000
Melancon, Bruce J; Hopkins, Corey R; Wood, Michael R et al. (2012) Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem 55:1445-64
Melancon, Bruce J; Gogliotti, Rocco D; Tarr, James C et al. (2012) Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor. Bioorg Med Chem Lett 22:3467-72
Melancon, Bruce J; Lamers, Alexander P; Bridges, Thomas M et al. (2012) Development of a more highly selective M(1) antagonist from the continued optimization of the MLPCN Probe ML012. Bioorg Med Chem Lett 22:1044-8

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