Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases

Felder, Christian C.; Goldsmith, Paul; Jackson, Kimberley; Sanger, Helen; Evans, David A.; Mogg, Adrian J.; Broad, Lisa M.

doi:10.1016/j.neuropharm.2018.01.028

Cited by 73 publications

(71 citation statements)

References 58 publications

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“…Of note, three orthosteric reference agonists which have advanced to the clinic, xanomeline, AZD‐6088 and HTL‐9936, similar to SPP1, displayed partial agonist profiles at native rat and human receptors in cortical membranes. The potency and partial efficacy profile of xanomeline and AZD‐6088 was comparable to those of SPP1 (EC 50 9–37 nM, E max 14–29%), while HTL‐9936 was significantly less potent but with higher efficacy (EC 50 2–2.7 μM, E max 45–77%) (Figure ; Felder et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…In rat atrial (M 2 receptor ) and rat ileum (M 3 receptor) functional assays, SPP1 was devoid of agonistic effects up to the highest concentration tested (Figure ) but did block a subsequent challenge to a non‐selective M receptor agonist, carbachol, with IC 50 (K i ) values of 5.37 μM (1.74 μM) and 26.3 μM (9.89 μM) respectively (Supporting Information Figure S3). Potency and efficacy of three clinically advanced mAChR agonists, xanomeline, HTL‐9936 and AZD‐6088, were also assessed in these atrial and ileum tissue assays and have been reported (Felder et al ., ). SPP1 also possessed high selectivity versus a panel of 29 other general cross‐reactivity targets when assessed at 10 μM (Supporting Information Table S1).…”

Section: Resultsmentioning

confidence: 97%

“…M 2 and M 3 receptors are the major subtypes expressed in peripheral tissues and are proposed to underlie the undesirable gastrointestinal and cardiovascular side effects of non-selective agonists such xanomeline. However, M 1 receptors are involved along with M 3 receptors in mediating sweating and salivation (Felder et al, 2018). Thus, there is a clear need for M 1 receptor agonists that are highly brain penetrant with a partial agonist efficacy profile to minimize peripheral load and M 1 receptormediated adverse effects.…”

Section: Introductionmentioning

confidence: 99%

“…Recent efforts to develop selective M 1 receptor ligands have focused on developing PAMs, allosteric agonists or orthosteric M 1 receptor agonists (Felder et al, 2018). Allosteric and orthosteric agonists have in common the ability to directly activate M 1 receptors , albeit through interaction at distinct sites.…”

Section: Introductionmentioning

confidence: 99%

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Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M₁ receptors

Broad

Sanger

Mogg

et al. 2018

British J Pharmacology

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Background and Purpose We aimed to identify and develop novel, selective muscarinic M1 receptor agonists as potential therapeutic agents for the symptomatic treatment of Alzheimer's disease. Experimental Approach We developed and utilized a novel M1 receptor occupancy assay to drive a structure activity relationship in a relevant brain region while simultaneously tracking drug levels in plasma and brain to optimize for central penetration. Functional activity was tracked in relevant native in vitro assays allowing translational (rat–human) benchmarking of structure–activity relationship molecules to clinical comparators. Key Results Using this paradigm, we identified a series of M1 receptor selective molecules displaying desirable in vitro and in vivo properties and optimized key features, such as central penetration while maintaining selectivity and a partial agonist profile. From these compounds, we selected spiropiperidine 1 (SPP1). In vitro, SPP1 is a potent, partial agonist of cortical and hippocampal M1 receptors with activity conserved across species. SPP1 displays high functional selectivity for M1 receptors over native M2 and M3 receptor anti‐targets and over a panel of other targets. Assessment of central target engagement by receptor occupancy reveals SPP1 significantly and dose‐dependently occupies rodent cortical M1 receptors. Conclusions and Implications We report the discovery of SPP1, a novel, functionally selective, brain penetrant partial orthosteric agonist at M1 receptors, identified by a novel receptor occupancy assay. SPP1 is amenable to in vitro and in vivo study and provides a valuable research tool to further probe the role of M1 receptors in physiology and disease.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M₁ receptors

Broad

Sanger

Mogg

et al. 2018

British J Pharmacology

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“…However, the cholinergic system is also involved in many other, notably autonomic, functions, which is the reason these drugs have a range of adverse effects (e.g., nausea, diarrhoea, and vomiting). The clinical dose of these drugs has been empirically selected to balance their tolerability against therapeutic benefit (Gauthier, ; Thompson, Lanctôt, & Herrmann, ), although it is likely that greater efficacy could be achieved if tolerability could be improved (Felder et al, ). The only other approved symptomatic treatment for AD is memantine, which is a non‐competitive NMDA glutamate receptor blocker, although its mechanism of action was only discovered during its clinical development, which was driven by empirical observation of symptomatic benefit (Lipton, ; McShane, Areosa Sastre, & Minakaran, ).…”

Section: Existing Treatments For Admentioning

confidence: 99%

A short perspective on the long road to effective treatments for Alzheimer's disease

Reynolds

2019

British J Pharmacology

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Globally, there are approximately 47 million people living with dementia, and about two thirds of those have Alzheimer's disease (AD). Age is the single biggest risk factor for the vast majority of sporadic AD cases, and because the world's population is aging, the number of people living with AD is set to rise dramatically over the coming decades. There are currently no disease‐modifying treatments for AD, and the few symptomatic agents available have limited impact on the disease. Perhaps surprisingly, there is relatively little activity in the AD research and development field compared with other diseases with a high mortality burden, such as cancer. There is enormous economic incentive to discover and develop the first disease‐modifying treatment, but previous failure has significantly reduced further industrial investment in this field. The short review looks at the historical path trodden to develop treatments and reflects on the journey down the road to truly effective treatments for people living with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Cholinergics/Anticholinergics

Griffith¹,

Dukat²

2021

Burger's Medicinal Chemistry and Drug Discovery

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This article covers classes of drugs and chemicals that act directly on muscarinic and nicotinic cholinergic receptors as agonists, antagonist, or allosteric modulators, together with an overview of the structures of muscarinic and nicotinic receptors. A brief history of the use of the small molecules muscarine, nicotine, and atropine to differentiate nicotinic and muscarinic receptors both of which respond to the neurotransmitter acetylcholine. This followed by discussion of the physical nature of the muscarinic G‐protein‐coupled‐receptor and the ligand‐gated‐ion‐channel nicotinic receptor. The structure–activity relationships of muscarinic agonists and antagonists are discussed with reference to attempts to develop of drugs selective for one of the five muscarinic receptors. Muscarinic antagonists are employed to treat disease states such as asthma, COPD, and overactive bladder. Muscarinic agonists have potential in the treatment of Alzheimer's disease. The structure–activity relationships of agonists and antagonists of nicotinic receptors are presented. Nicotinic agonists have been employed to assist in smoking cessation and have potential in treating Alzheimer's disease. Nicotinic antagonists have primarily been employed as neuromuscular blockers in surgery. The use of both positive and negative allosteric modulators of both muscarinic and nicotinic are discussed.

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Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases

Cited by 73 publications

References 58 publications

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M₁ receptors

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M₁ receptors

A short perspective on the long road to effective treatments for Alzheimer's disease

Cholinergics/Anticholinergics

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Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases

Cited by 73 publications

References 58 publications

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M1 receptors

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M1 receptors

A short perspective on the long road to effective treatments for Alzheimer's disease

Cholinergics/Anticholinergics

Contact Info

Product

Resources

About

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M₁ receptors

Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M₁ receptors