M₁-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition

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.