Trial reportCell2021
From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.
Open access · greenAbstract readRandomized Controlled Trial
In one paragraph
Trial report in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
0numbers the graph read from it
0cells of the map it votes in
54citing papers in PubMed
4.9field-weighted citation impact, top 3% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
54 citing papers in PubMed, 89 citations in OpenAlex.
- Traditional Chinese medicine ginseng regulates neurotrophic factors to improve neurodegenerative diseases: A potential strategy for Alzheimer's disease treatment.Journal of ginseng research · 2026Review
- Mapping Trofinetide Polypharmacology in Rett Syndrome: A Multi-Stage Computational Analysis.Journal of computational chemistry · 2026Article
- Correspondence of Basal Forebrain Resting-State Functional Connectivity and Cerebral Glucose Metabolism Alterations With Neurotransmitter Maps in Alzheimer's Disease.CNS neuroscience & therapeutics · 2026Article
- Functional Evaluation of Tetrahydroisoquinoline-Derived Ligands Reveals Distinct Modulatory Profiles at the Muscarinic M1 Receptor.ACS medicinal chemistry letters · 2026Article
- Exploring the Evolving Role of Scopolamine in Pharmacotherapy: From Cognitive Impairment to Neuroplasticity?-A Narrative Review.Molecules (Basel, Switzerland) · 2026Review
- The GPCR Connection: Linking Alzheimer's Disease and Glioblastoma.Journal of cellular and molecular medicine · 2026Review
- Targeting muscarinic receptors for treating schizophrenia.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Extracellular nanobody screening using conformationally stable GPCR variants.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cholinergic neurotransmission in the brain of streptozotocin-induced rat model of sporadic Alzheimer's disease: long-term follow up.Journal of neural transmission (Vienna, Austria : 1996) · 2025Article
- Cryo-EM reveals an extrahelical allosteric binding site at the MNature communications · 2025Article
- Structures and functions of the MICOS: Pathogenesis and therapeutic implications in Alzheimer's disease.Acta pharmaceutica Sinica. B · 2025Review
- Downstream Signaling of Muscarinic MPharmacology research & perspectives · 2025Article
- Gnb5 is a negative regulator of the BACE1-mediated Aβ generation and ameliorates cognitive deficits in a mouse model of Alzheimer's disease.PLoS biology · 2025Article
- A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.Pharmaceuticals (Basel, Switzerland) · 2025Review
- AiGPro: a multi-tasks model for profiling of GPCRs for agonist and antagonist.Journal of cheminformatics · 2025Article
- Combining Photochemical Oxyfunctionalization and Enzymatic Catalysis for the Synthesis of Chiral Pyrrolidines and Azepanes.The Journal of organic chemistry · 2025Article
- Comprehensive medicinal chemistry survey highlights a portfolio of lead molecules for Alzheimer's disease therapy.Frontiers in chemistry · 2025Review
- Cholinergic System Structure and Function Changes in Individuals with Down Syndrome During the Development of Alzheimer's Disease.Current topics in behavioral neurosciences · 2025Review
- The novel orthosteric agonist M1 muscarinic acetylcholine receptor reveals anti-Alzheimer's disease activity.Scientific reports · 2024Article
- A golden age of muscarinic acetylcholine receptor modulation in neurological diseases.Nature reviews. Drug discovery · 2024Review
Corrections and comments
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Authors and funding
48 authors at 11 institutions in 5 countries.
Alastair J H BrownSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Sophie J BradleySosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK; The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
Fiona H MarshallSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Giles A BrownSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Kirstie A BennettSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Jason BrownSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Julie E CansfieldSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
David M CrossSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK; Cross Pharma Consulting Ltd, 20-22 Wenlock Road, London, N17GU, UK.
Chris de GraafSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Brian D HudsonSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Louis DwomohThe Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
João M DiasSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
James C ErreySosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Edward HurrellSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Jan LiptrotSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Giulio MattediSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Colin MolloyThe Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
Pradeep J NathanSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK; Brain Mapping Unit, University of Cambridge, Department of Psychiatry, Herchel Smith Building, Cambridge, CB20SZ, UK.
Krzysztof OkrasaSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Greg OsborneSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Jayesh C PatelSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Mark PickworthSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Nathan RobertsonSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Shahram ShahabiEli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
Christoffer BundgaardEli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK; H. Lundbeck A/S, Neuroscience Research, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark.
Keith PhillipsEli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
Lisa M BroadEli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
Anushka V GoonawardenaCenter for Neuroscience, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
Stephen R MorairtyCenter for Neuroscience, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
Michael BrowningUniversity Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX12JD, UK; P1vital, Manor house, Howbery Buisness Park, Wallingford, OX108BA, UK.
Francesca PeriniCentre for Cognitive Neuroscience - Duke-NUS Medical School, 8 College Road, 169857, Singapore.
Gerard R DawsonUniversity Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX12JD, UK.
John F W DeakinNeuroscience and Psychiatry Unit, University of Manchester, Manchester, M139PT UK.
Robert T SmithSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Patrick M SextonDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville 3052, Victoria, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
Julie WarneckProtogenia Consulting Ltd, PO-Box 289, Ely, CB79DR, UK.
Mary VinsonSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Tim TaskerSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Benjamin G TehanSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Barry TeobaldSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Arthur ChristopoulosDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville 3052, Victoria, Australia.
Christopher J LangmeadSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville 3052, Victoria, Australia.
Ali JazayeriSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Robert M CookeSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Prakash RucktooaSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Miles S CongreveSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
Malcolm WeirSosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK. Electronic address: malcolm.weir@soseiheptares.com.
Andrew B TobinThe Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK. Electronic address: andrew.tobin@glasgow.ac.uk.
Heptares Therapeutics (United Kingdom) · GBUniversity of Glasgow · GBEli Lilly (United Kingdom) · GBMonash University · AUSRI International · USWarneford Hospital · GBDuke-NUS Medical School · SGGranta Design (United Kingdom) · GBLundbeck (Denmark) · DKUniversity of Cambridge · GBUniversity of Manchester · GB
Funding
Cancer Research UK C596/A17196Medical Research Council MR/P019366/1Wellcome Trust 201529Wellcome Trust 201529/Z/16/Z
Abstract
Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
Indexed as
Drug DesignAgedAged, 80 and overAgingAlzheimer DiseaseAmino Acid SequenceAnimalsBlood PressureCHO CellsCholinesterase InhibitorsCricetulusCrystallizationDisease Models, AnimalDogsDonepezilElectroencephalographyCholinesterase InhibitorsDonepezilReceptor, Muscarinic M1Alzheimer's diseaseG protein coupled receptorsM1 muscarinic acetylcholine receptormuscarinic receptorneurodegenerationprion diseasestructural based drug design
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.