1. M 1 -positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition.
- Author
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Moran SP, Dickerson JW, Cho HP, Xiang Z, Maksymetz J, Remke DH, Lv X, Doyle CA, Rajan DH, Niswender CM, Engers DW, Lindsley CW, Rook JM, and Conn PJ
- Subjects
- Allosteric Regulation, Animals, CHO Cells, Cricetulus, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Male, Mice, Inbred C57BL, Prefrontal Cortex drug effects, Prefrontal Cortex physiology, Pyramidal Cells drug effects, Pyramidal Cells physiology, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M1 agonists, Receptor, Muscarinic M1 genetics, Recognition, Psychology drug effects, Tissue Culture Techniques, Cholinergic Agents pharmacology, Nootropic Agents pharmacology, Receptor, Muscarinic M1 metabolism
- Abstract
Highly selective positive allosteric modulators (PAMs) of the M
1 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.- Published
- 2018
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