Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders

Digby, Gregory J.; Shirey, Jana K.; Conn, P. Jeffrey

doi:10.1039/c002938f

Cited by 58 publications

(63 citation statements)

References 116 publications

(196 reference statements)

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“…The major conceptual and practical shift that has allowed these unprecedented advances in developing subtype-selective ligands has been the move away from ligands that interact with the highly conserved orthosteric ACh site and discovery of compounds that act at allosteric sites to modulate mAChR function. 12,30 A priority for these studies has been the development of selective allosteric activators for the M 1 mAChR subtype because of their potential for treatment of schizophrenia and other CNS disorders that involved impaired cognitive function.…”

Section: ■ Discussionmentioning

confidence: 99%

Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Digby

Utley

Lamsal

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:We previously reported the discovery of VU0364572 and VU0357017 as M 1 -selective agonists that appear to activate M 1 through actions at an allosteric site. Previous studies have revealed that chemical scaffolds for many allosteric modulators contain molecular switches that allow discovery of allosteric antagonists and allosteric agonists or positive allosteric modulators (PAMs) based on a single chemical scaffold. Based on this, we initiated a series of studies to develop selective M 1 allosteric antagonists based on the VU0364572 scaffold. Interestingly, two lead antagonists identified in this series, VU0409774 and VU0409775, inhibited ACh-induced Ca 2+ responses at rat M 1−5 receptor subtypes, suggesting they are nonselective muscarinic antagonists. VU0409774 and VU0409775 also completely displaced binding of the nonselective radioligand [3 H]-NMS at M 1 and M 3 mAChRs with affinities similar to their functional IC 50 values. Finally, Schild analysis revealed that these compounds inhibit M 1 responses through a fully competitive interaction at the orthosteric binding site. This surprising finding prompted further studies to determine whether agonist activity of VU0364572 and VU0357017 may also engage in previously unappreciated actions at the orthosteric site on M 1 . Surprisingly, both VU0364572 and VU0357017 completely displaced [ 3 H]-NMS binding to the orthosteric site of M 1 −M 5 receptors at high concentrations. Furthermore, evaluation of agonist activity in systems with varying levels of receptor reserve and Furchgott analysis using a cell line expressing M 1 under control of an inducible promotor was consistent with an action of these compounds as weak orthosteric partial agonists of M 1 . However, consistent with previous studies suggesting actions at a site that is distinct from the orthosteric binding site, VU0364572 or VU0357017 slowed the rate of [ 3 H]-NMS dissociation from CHOrM 1 membranes. Together, these results suggest that VU0364572 and VU0357017 act as bitopic ligands and that novel antagonists in this series act as competitive orthosteric site antagonists.

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Section: ■ Discussionmentioning

confidence: 99%

Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Digby

Utley

Lamsal

et al. 2012

ACS Chem. Neurosci.

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“…These agents provide new opportunities to determine the physiological roles of individual mAChRs in the basal ganglia circuitry and to assess the antiparkinsonian efficacy of highly selective mAChR antagonists (Conn et al, 2009a, b), but to do so the full specificity profile of these compounds must be characterized in vivo. In this regard, recent in vivo studies indicate that the allosteric modulators display favorable pharmacokinetic properties and bloodbrain barrier permeability, and have confirmed their potential therapeutic benefits in rodent models of Alzheimer's disease and schizophrenia (Caccamo et al, 2006;May et al, 2007;Brady et al, 2008;Chan et al, 2008;Shekhar et al, 2008;Conn et al, 2009a, b;Bridges et al, 2010;Digby et al, 2010 A 2A receptor antagonists (Schwarzschild et al, 2006;Menon and Stacy, 2008;Morelli et al, 2010;Shah and Hodgson, 2010). Adenosine is a ubiquitous purine with signaling properties that mediate its effects through four subtypes of G-protein-coupled adenosine receptors: A 1 , A 2A , A 2B , and A 3 (Schwarzschild et al, 2006;Menon and Stacy, 2008;Morelli et al, 2007Morelli et al, , 2009Morelli et al, , 2010Shah and Hodgson, 2010).…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

“…Unfortunately, previous efforts to develop selective ligands for individual mAChR subtypes have failed. However, recent studies have led to the discovery and characterization of ligands for individual mAChR subtypes, including M1, M4, and M5 (Conn et al, 2009a;Weaver et al, 2009a;Digby et al, 2010), that display a high specificity profile, at least when tested in vitro. The development of these compounds was achieved by targeting allosteric sites on the mAChRs that are not as highly conserved as the orthosteric acetylcholine binding site.…”

Section: Non-dopaminergic Therapiesmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

194

137

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The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

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“…8,9 In particular, M 1 mAChR activation by subtype-selective allosteric enhancement has shown considerable promise as a means of ameliorating cognitive decline and treating disease state pathophysiology. 10 However, the lack of structural information about the M 1 mAChR allosteric binding sites and the complex behavior of allosteric ligands is such that rational drug design and preclinical pharmacological evaluation are fraught with challenges impeding the development of viable therapeutics. This Review will discuss essential considerations in the classification and pharmacological evaluation of allosteric ligands, summarize the M 1 mAChR allosteric ligands reported to date, and offer a perspective on the pharmacological methods employed in their development.…”

mentioning

confidence: 99%

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

Davie

Christopoulos

Scammells

2013

ACS Chem. Neurosci.

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Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M 1 muscarinic acetylcholine receptor (M 1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M 1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M 1 mAChR, comprehensively summarize and critically evaluate the M 1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. KEYWORDS: M 1 mAChR, allosteric ligands, Alzheimer's disease, schizophrenia, cognitive deficits, memory T he muscarinic acetylcholine receptor (mAChR) family is a group of rhodopsin-like (Family A) G protein-coupled receptors (GPCRs) consisting of five distinct subtypes M 1 −M 5 . Activation of the M 1 , M 3 , and M 5 receptor subtypes primarily results in coupling to the G q/11 family of G proteins, activation of phospholipase C (PLC), release of inositol-1,4,5-trisphosphate (IP 3 ), and subsequent mobilization of intracellular calcium Ca 2+ . Activation of the M 2 and M 4 receptor subtypes primarily results in coupling to the G i/o family of G proteins, inhibition of adenylate cyclase (AC), reduction in cyclic AMP (cAMP), and a decrease in neurotransmitter release via the blockage of voltage-gated calcium channels (Figure 1). These pathways represent a generalized view of each receptor's coupling capacity, as all five subtypes couple to a broader range of G protein-and non-G protein-mediated signaling and regulatory pathways, 1 ultimately leading to the regulation of enzymes and neurotransmitters critical for intercellular chemical communication and biological function. In a ...

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Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders

Cited by 58 publications

References 116 publications

Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

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Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders

Cited by 58 publications

References 116 publications

Chemical Modification of the M1 Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Chemical Modification of the M1 Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

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Resources

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Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Chemical Modification of the M₁ Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode

Development of M₁ mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits