Positive allosteric modulation of M 1 and M 4 muscarinic receptors as potential therapeutic treatments for schizophrenia

Abstract

Current antipsychotic drugs provide symptomatic relief for positive symptoms of schizophrenia, but do not offer symptom management for negative and cognitive symptoms. In addition, many patients discontinue treatment due to adverse side effects. Therefore, there is a critical need to develop more effective and safe treatment options. Although the etiology of schizophrenia is unclear, considerable data from post-mortem, neuroimaging and neuropharmacology studies support a role of the muscarinic acetylcholine (mAChRs) in the pathophysiology of schizophrenia. Substantial evidence suggests that activation of mAChRs has the potential to treat all symptom domains of schizophrenia. Despite encouraging results in demonstrating efficacy, clinical trials of nonselective mAChR agonists were limited in their clinical utility due to dose-limiting peripheral side effects. Accordingly, efforts have been made to specifically target centrally located M and M mAChR subtypes devoid of adverse-effect liability. To circumvent this limitation, there have been tremendous advances in the discovery of ligands that bind at allosteric sites, binding sites distinct from the orthosteric site, which are structurally less conserved and thereby afford high levels of receptor subtype selectivity. The discovery of subtype-specific allosteric modulators has greatly advanced our understanding of the physiological role of various muscarinic receptor subtypes in schizophrenia and the potential utility of M and M mAChR subtypes as targets for the development of novel treatments for schizophrenia and related disorders. This article is part of the Special Issue entitled 'Neuropharmacology on Muscarinic Receptors'.

Cell Type- and Layer-Specific Muscarinic Potentiation of Excitatory Synaptic Drive onto Parvalbumin Neurons in Mouse Prefrontal Cortex

“…Consistent with a crucial role of ACh-mediated neuromodulation, a deficit in cholinergic signaling is thought to contribute to the pathophysiology of various psychiatric illnesses that impair cognition, in particular schizophrenia (Higley and Picciotto, 2014). Moreover, mAChRs, specifically of the M1 subtype shown here to mediate many of the cholinergic effects in PFC, have been suggested as a potential target for schizophrenia treatment (Jones et al, 2012; Yohn and Conn, 2018). Alterations in γ oscillations and PV + neurons in the PFC are a central feature in schizophrenia pathophysiology (Lewis, 2014).…”

Biased M1positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

“…To increase selectivity for M1 and therefore minimize nonselective adverse effects, multiple research efforts shifted to developing compounds that act via allosteric sites on mAChRs, which are structurally distinct from the orthosteric binding site and may be less highly conserved among receptor subtypes. To date, we and others have identified highly subtype-selective positive allosteric modulators (PAMs) of the M1 receptor that avoid activation of other mAChR subtypes (see reviews (10)(11)(12)). Importantly, M1 PAMs have shown robust efficacy in enhancing cognition and rescuing cognitive deficits in preclinical animal models relevant for AD and schizophrenia (13)(14)(15)(16)(17)(18).…”

A Novel Genotyping Method for Detection of Muscarinic Receptor M1 Gene rs2067477 Polymorphism and Its Genotype/Allele Frequencies in a Turkish Population

“…M1 receptors could be important for neuronal disorder and cognitive function in the pathophysiology of schizophrenia due to the location in the medial prefrontal cortex and hippocampus. 18,19 Lower levels of muscarinic receptors in the CNS of people with schizophrenia have been found in some studies. 18,20 Scarr et al, showed that decreased M1 levels in cortical region of brain could contribute to the pathophysiology of schizophrenia.…”