Abstract
Highly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for improving cognitive function in patients suffering from Alzheimer’s disease and schizophrenia. However, excessive activation of M1 is known to induce seizure activity and have actions in the prefrontal cortex (PFC) that could impair cognitive function. We now report a series of pharmacological, electrophysiological, and behavioral studies in which we find that recently reported M1 PAMs, PF-06764427 and MK-7622, have robust agonist activity in cell lines and agonist effects in the mouse PFC, and have the potential to overactivate the M1 receptor and disrupt PFC function. In contrast, structurally distinct M1 PAMs (VU0453595 and VU0550164) are devoid of agonist activity in cell lines and maintain activity dependence of M1 activation in the PFC. Consistent with the previously reported effect of PF-06764427, the ago-PAM MK-7622 induces severe behavioral convulsions in mice. In contrast, VU0453595 does not induce behavioral convulsions at doses well above those required for maximal efficacy in enhancing cognitive function. Furthermore, in contrast to the robust efficacy of VU0453595, the ago-PAM MK-7622 failed to improve novel object recognition, a rodent assay of cognitive function. These findings suggest that in vivo cognition-enhancing efficacy of M1 PAMs can be observed with PAMs lacking intrinsic agonist activity and that intrinsic agonist activity of M1 PAMs may contribute to adverse effects and reduced efficacy in improving cognitive function.
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Acknowledgements
We would like to thank the Dan Marino foundation for their generous support of the Clinical Neuroscience Scholars program at Vanderbilt University and to thank Weimin Peng for excellent assistance in maintaining colonies and genotyping of transgenic mice. Behavioral experiments were performed in part through the use of the Murine Neurobehavior Core lab at the Vanderbilt University Medical Center. We would also like to thank J Wess for generously sharing the M1 KO mice. This work was supported by NIH F31MH114368 (Moran), NIH T32 MH 64913-14 (Moran), U01 MH087965 (Conn), R01 MH062646 (Conn), R01 MH073676 (Conn) and R01 MH082867 (Lindsley), and CIHR DFS146189 (Maksymetz). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work of JMR has been funded by the NIH, Alzheimer’s Drug Discovery Foundation, Harrington Discovery Institute, Thome Alzheimer’s Disease Drug Discovery Foundation, and Brain & Behavior Research Foundation. The work of CWL has been funded by the NIH, Johnson and Johnson, Bristol-Myers Squibb, AstraZeneca, Michael J. Fox Foundation, as well as Seaside Therapeutics. PJC has been funded by NIH, Michael J. Fox Foundation, Dystonia Medical Research Foundation, CHDI Foundation and others. The work of CMN has been funded by the NIH, rettsyndrome.org, Autism Speaks, Johnson and Johnson, Bristol-Myers Squibb, AstraZeneca, Michael J. Fox Foundation, as well as Seaside Therapeutics.
Author contributions
SPM, JMR, ZX, CWL, CMN, and PJC designed experiments; SPM, HPC, DHR, JM, XL, JWD, CAD, and DWE performed experiments; SPM, JM, JWD, JMR, and PJC wrote the manuscript with input from all the authors.
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JMR is an inventor on patents that protect different classes of muscarinic receptor allosteric modulators. CWL has consulted for AbbVie and received compensation. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. Over the past three years, PJC has served on the Scientific Advisory Boards for Michael J. Fox Foundation, Stanley Center for Psychiatric Research Broad Institute (MIT/Harvard), Karuna Pharmaceuticals, Lieber Institute for Brain Development, Clinical Mechanism (POCM) and Proof of Concept (POC) Consortium, and Neurobiology Foundation for Schizophrenia and Bipolar Disorder. He is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. CMN is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic receptor allosteric modulators. DWE is an inventor on patents that protect different classes of metabotropic glutamate and muscarinic allosteric modulators. The remaining authors declare no competing interests.
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Moran, S.P., Dickerson, J.W., Cho, H.P. et al. M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition. Neuropsychopharmacol 43, 1763–1771 (2018). https://doi.org/10.1038/s41386-018-0033-9
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DOI: https://doi.org/10.1038/s41386-018-0033-9
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