2. Academic Validation
  3. From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease

  • Cell. 2021 Nov 24;184(24):5886-5901.e22. doi: 10.1016/j.cell.2021.11.001.
Alastair J H Brown 1,  Sophie J Bradley 2,  Fiona H Marshall 1,  Giles A Brown 1,  Kirstie A Bennett 1,  Jason Brown 1,  Julie E Cansfield 1,  David M Cross 3,  Chris de Graaf 1,  Brian D Hudson 1,  Louis Dwomoh 4,  João M Dias 1,  James C Errey 1,  Edward Hurrell 1,  Jan Liptrot 1,  Giulio Mattedi 1,  Colin Molloy 4,  Pradeep J Nathan 5,  Krzysztof Okrasa 1,  Greg Osborne 1,  Jayesh C Patel 1,  Mark Pickworth 1,  Nathan Robertson 1,  Shahram Shahabi 6,  Christoffer Bundgaard 7,  Keith Phillips 6,  Lisa M Broad 6,  Anushka V Goonawardena 8,  Stephen R Morairty 8,  Michael Browning 9,  Francesca Perini 10,  Gerard R Dawson 11,  John F W Deakin 12,  Robert T Smith 1,  Patrick M Sexton 13,  Julie Warneck 14,  Mary Vinson 1,  Tim Tasker 1,  Benjamin G Tehan 1,  Barry Teobald 1,  Arthur Christopoulos 15,  Christopher J Langmead 16,  Ali Jazayeri 1,  Robert M Cooke 1,  Prakash Rucktooa 1,  Miles S Congreve 1,  Malcolm Weir 17,  Andrew B Tobin 18
Affiliations

Affiliations

  • 1 Sosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK.
  • 2 Sosei-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.
  • 3 Sosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK; Cross Pharma Consulting Ltd, 20-22 Wenlock Road, London, N17GU, UK.
  • 4 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.
  • 5 Sosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK; Brain Mapping Unit, University of Cambridge, Department of Psychiatry, Herchel Smith Building, Cambridge, CB20SZ, UK.
  • 6 Eli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
  • 7 Eli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK; H. Lundbeck A/S, Neuroscience Research, Ottiliavej 9, 2500 Valby, Copenhagen, Denmark.
  • 8 Center for Neuroscience, Biosciences Division, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
  • 9 University Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX12JD, UK; P1vital, Manor house, Howbery Buisness Park, Wallingford, OX108BA, UK.
  • 10 Centre for Cognitive Neuroscience - Duke-NUS Medical School, 8 College Road, 169857, Singapore.
  • 11 University Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX12JD, UK.
  • 12 Neuroscience and Psychiatry Unit, University of Manchester, Manchester, M139PT UK.
  • 13 Drug 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.
  • 14 Protogenia Consulting Ltd, PO-Box 289, Ely, CB79DR, UK.
  • 15 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville 3052, Victoria, Australia.
  • 16 Sosei-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.
  • 17 Sosei-Heptares, Steinmetz Building, Granta Park, Cambridge, CB21 6DG, UK. Electronic address: malcolm.weir@soseiheptares.com.
  • 18 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. Electronic address: andrew.tobin@glasgow.ac.uk.
PMID: 34822784 DOI: 10.1016/j.cell.2021.11.001
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.

Keywords

Alzheimer's disease; G protein coupled receptors; M1 muscarinic acetylcholine receptor; muscarinic receptor; neurodegeneration; prion disease; structural based drug design.

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