Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders

Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt Medical Center, Nashville, TN 37232, USA.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 03/2009; 30(3):148-55. DOI: 10.1016/
Source: PubMed


Muscarinic acetylcholine receptors (mAChRs) have long been viewed as viable targets for novel therapeutic agents for the treatment of Alzheimer's disease (AD) and other disorders involving impaired cognitive function. More recent evidence indicates that mAChR activators might also have utility in treating psychosis and other symptoms associated with schizophrenia and other central nervous system (CNS) disorders. Efforts to develop mAChR subtype-selective agonists have been hampered by difficulty in achieving high selectivity for individual mAChR subtypes important for CNS function (M(1) and M(4)) and adverse effects due to activation of peripheral mAChRs (especially M(2) and M(3)). Major advances have now been achieved in the discovery of allosteric agonists and positive allosteric modulators of M(1) and M(4) that show greater selectivity for individual mAChR subtypes than do previous mAChR agonists. Early studies indicate that these allosteric mAChR activators have properties needed for optimization as potential clinical candidates and have robust effects in animal models that predict efficacy in the treatment of AD, schizophrenia and related disorders.

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Available from: P. Jeffrey Conn, Oct 04, 2015
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    • "According to the glutamatergic theory of schizophrenia, proposed by Javitt (1987, 2010) and developed later on by Conn et al. (2009) it seems that the ligands of the metabotropic glutamate receptors may constitute a good alternative for presently used neuroleptic therapy. The antipsychotic-like effects were observed for a variety of ligands in preclinical studies. "
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    ABSTRACT: Diverse preclinical studies exploiting the modulation of the GABAergic and/or glutamatergic system in brain via metabotropic receptors suggest their potential therapeutic utility. GS39783 and CDPPB, a positive allosteric modulators of GABAB and mGlu5 receptors, were previously shown to reverse behavioral phenotypes in animal models thought to mimic selected (predominantly positive) symptoms of schizophrenia. In the present study we investigated the activity of selected GABAB (GS39783 and CGP7930) and mGlu5 (CDPPB) positive allosteric modulators. We focused mainly on the aspects of their efficacy in the models of negative and cognitive symptoms of schizophrenia. We used modified swim test, social interactions (models of negative symptoms) and novel object recognition (model of cognitive disturbances). The activity of the compounds was also tested in haloperidol-induced catalepsy test. The mutual interaction between GABAB/mGlu5 ligands was investigated as well. In the second part of the study, DHPG-induced PI hydrolysis in the presence of GABAB receptor antagonist (SKF97541), and SKF97541-induced inhibition of cAMP formationin the presence of DHPG, were performed. Both mGlu5 and GABAB receptor modulators effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783, induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches. The concomitant administration of group I mGlu and GABAB agonists did not displayed any synergistic effects in vitro. Summing up, an activation of both types of receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious towards positive, negative and cognitive symptoms. Copyright © 2015. Published by Elsevier Ltd.
    Neurochemistry International 04/2015; 88. DOI:10.1016/j.neuint.2015.03.010 · 3.09 Impact Factor
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    • "The efficacy of AChEIs in treating AD patients, in conjunction with the efficacy of xanomeline in improving both the cognitive and the behavioral disturbances observed in patients with either AD or SZ, highlight the potential of cholinergic modulation in treating these diseases. However, the poorly tolerated gastrointestinal side effects of AChEIs and xanomeline limit the clinical utility of these compounds.40,41 The adverse side effects observed with nonselective modulation of the cholinergic system are thought to be primarily mediated by peripherally located M2 and M3 receptors.42 "
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    ABSTRACT: Alzheimer's disease (AD) and schizophrenia (SZ) are neurological disorders with overlapping symptomatology, including both cognitive deficits and behavioral disturbances. Current clinical treatments for both disorders have limited efficacy accompanied by dose-limiting side effects, and ultimately fail to adequately address the broad range of symptoms observed. Novel therapeutic options for AD and SZ are needed to better manage the spectrum of symptoms with reduced adverse-effect liability. Substantial evidence suggests that activation of muscarinic acetylcholine receptors (mAChRs) has the potential to treat both cognitive and psychosis-related symptoms associated with numerous central nervous system (CNS) disorders. However, use of nonselective modulators of mAChRs is hampered by dose-limiting peripheral side effects that limit their clinical utility. In order to maintain the clinical efficacy without the adverse-effect liability, efforts have been focused on the discovery of compounds that selectively modulate the centrally located M1 and M4 mAChR subtypes. Previous drug discovery attempts have been thwarted by the highly conserved nature of the acetylcholine site across mAChR subtypes. However, current efforts by our laboratory and others have now focused on modulators that bind to allosteric sites on mAChRs, allowing these compounds to display unprecedented subtype selectivity. Over the past couple of decades, the discovery of small molecules capable of selectively targeting the M1 or M4 mAChR subtypes has allowed researchers to elucidate the roles of these receptors in regulating cognitive and behavioral disturbances in preclinical animal models. Here, we provide an overview of these promising preclinical and clinical studies, which suggest that M1- and M4-selective modulators represent viable novel targets with the potential to successfully address a broad range of symptoms observed in patients with AD and SZ.
    Neuropsychiatric Disease and Treatment 01/2014; 10:183-191. DOI:10.2147/NDT.S55104 · 1.74 Impact Factor
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    • "Allosteric modulators of muscarinic receptors show promise as po - tential therapies for a number of CNS disorders , including Alzheimer ' s disease and schizophrenia . Other target areas of benefit may include neuropathic and chronic pain , epilepsy , sleep disorders , Parkinson ' s disease , and movement disorders ( Conn et al . , 2009b ) . Acetylcholine signals through both muscarinic and nicotinic receptors ."
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    ABSTRACT: The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than do orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction.
    Neurobiology of Disease 09/2013; 61. DOI:10.1016/j.nbd.2013.09.013 · 5.08 Impact Factor
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