AC-260584, an orally bioavailable M1 muscarinic receptor allosteric agonist, improves cognitive performance in an animal model

Bradley, Stefania Risso; Lameh, Jelveh; Ohrmund, Linda; Son, Thomas; Bajpai, Abhishek; Nguyen, Derek; Friberg, Mikael; Burstein, Ethan S.; Spalding, Tracy A.; Ott, Thomas; Schiffer, Hans H.; Tabatabaei, Ali; McFarland, Krista; Davis, Robert E.; Bonhaus, Douglas W.

doi:10.1016/j.neuropharm.2009.10.003

Cited by 64 publications

(61 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are now a number of M1 activators (agonists or modulators) in production. As predicted, these drugs have been shown to improve cognitive performance, in paradigms such as spatial memory tasks [58], novel object recognition [59], and improving reversal learning in a mouse proposed to model some of the pathophysiology of Alzheimer's disease [60]. In addition, M1 allosteric activators have been shown to be effective in animal models that are used to predict antipsychotic activity; including amphetamine-induced hyperlocomotion [61], MK-801-induced hyperlocomotion, and apomorphine-induced climbing [58].…”

Section: E Scarrmentioning

confidence: 63%

Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets

Scarr

2011

CNS Neuroscience & Therapeutics

View full text Add to dashboard Cite

SUMMARYPhylogenetically, acetylcholine is an ancient neurochemical. Therefore, it is not surprising that cholinergic neurons project extensively throughout the central nervous system, innervating a wide range of structures within the brain. In fact, acetylcholine is involved in processes that underpin some of our most basic central functions. Both muscarinic and nicotinic receptor families, which mediate cholinergic transmission, have been implicated in the pathophysiology of psychiatric and neurological disorders. The question that remains to be definitively answered is whether or not these receptors are viable targets for the development of future therapeutic agents.

show abstract

Section: E Scarrmentioning

confidence: 63%

Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets

Scarr

2011

CNS Neuroscience & Therapeutics

View full text Add to dashboard Cite

show abstract

“…122,123 While these results show great therapeutic promise, the ligand's classification as a purely allosteric agonist is likely premature. AC-260584 exhibited the same potential for binding orthosteric site residues as did AC-42.…”

Section: ■ M 1 Machr-selective Ligandsmentioning

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.

View full text Add to dashboard Cite

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 ...

show abstract

“…A structural analog of AC-42, AC-260584, has also been shown to produce effects in animal models of antipsychoticlike activity after systemic dosing (Vanover et al, 2008;Bradley et al, 2010). AC-260584 has been shown to be a potent M 1 mAChR allosteric agonist devoid of agonist activity at the M 3 mAChR subtype; however, some M 2 mAChR agonism has been reported (Bradley et al, 2010).…”

Section: Allosteric Modulation Of Muscarinic Receptorsmentioning

confidence: 99%

“…AC-260584 has been shown to be a potent M 1 mAChR allosteric agonist devoid of agonist activity at the M 3 mAChR subtype; however, some M 2 mAChR agonism has been reported (Bradley et al, 2010). In microdialysis studies, AC-260584, like xanomeline, increased ACh and DA levels in both the PFC and hippocampus, effects that are thought to be beneficial in schizophrenia Li et al, 2007).…”

Section: Allosteric Modulation Of Muscarinic Receptorsmentioning

confidence: 99%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

View full text Add to dashboard Cite

Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

show abstract

AC-260584, an orally bioavailable M1 muscarinic receptor allosteric agonist, improves cognitive performance in an animal model

Cited by 64 publications

References 38 publications

Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets

Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets

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

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Contact Info

Product

Resources

About

AC-260584, an orally bioavailable M1 muscarinic receptor allosteric agonist, improves cognitive performance in an animal model

Cited by 64 publications

References 38 publications

Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets

Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets

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

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Contact Info

Product

Resources

About

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