The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists

Johnson, Dale J.; Forbes, Ian J.; Watson, Steve P.; Garzya, Vincenzo; Stevenson, Graeme I.; Walker, Graham; Mudhar, Harminder; Flynn, Sean T.; Wyman, Paul; Smith, Paul W.; Murkitt, G.S.; Lucas, A.; Mookherjee, Claudette; Watson, Jeannette M.; Gartlon, Jane; Bradford, Andrea M.; Brown, Fiona

doi:10.1016/j.bmcl.2010.07.097

Cited by 22 publications

(16 citation statements)

References 19 publications

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“…An M1 preferring agonist improved SOR performance with a 2-or 24-h delay (Bradley et al 2010;Johnson et al 2010). Conversely, pre-sample administration of the muscarinic receptor antagonist scopolamine reliably impaired SOR with delays ranging across studies from 1 min to 24 h (1 min, Woolley et al 2003;15 min, De Bruin and Pouzet 2006;60 min, Hirst et al 2008 andBoultadakis et al 2010;180 min, Ballaz et al 2007; 90 min and 24 h, Botton et al 2010).…”

Section: Muscarinic Achrs (Chrms)mentioning

confidence: 91%

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

2011

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Section: Muscarinic Achrs (Chrms)mentioning

confidence: 91%

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

2011

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“…In other studies, 142,143 optimization of a novel N-substituted benzimidazolone hit structure gave the CNS-penetrant, orally active, and subtypeselective compounds 44 and 45 ( Figure 29). Recently, the M 1 mAChR allosteric agonist GSK1034702, an isomer of compound 44, has shown efficacy in improving episodic memory in humans in a nicotine abstinence model of cognitive dysfunction.…”

Section: ■ M 1 Machr-selective Ligandsmentioning

confidence: 94%

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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“…6,17–20 Recently, numerous additional M 1 full and partial agonists have been reported with improved properties and efficacy in cognition models. 21–23 Positive allosteric modulators (PAMs) from three structural classes, 5 – 7 , have also been reported, with exquisite selectivity for M 1 versus M 2 –M 5 and BARs, allowing limited in vivo proof of concept studies to be conducted. 24–26,28,29,31,32 For all of these PAMs, both DMPK properties and CNS penetration are barely adequate for in vivo studies; 24–26,28,29,31,32 however, two scaffolds variants of the BQCA PAM scaffold have overcome the DMPK issues and afforded PAMs with good properties and CNS exposure.…”

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confidence: 99%

Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071

Lebois

Digby

Sheffler

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists

Cited by 22 publications

References 19 publications

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

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

Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071

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The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists

Cited by 22 publications

References 19 publications

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

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

Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071

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Product

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