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

被引：64

作者：

Brown, Alastair J. H. ^{[1
]}

Bradley, Sophie J. ^{[1
]}

Marshall, Fiona H. ^{[1
]}

Bown, Giles A. ^{[1
,17
]}

Bennett, Kirstie A. ^{[1
]}

Brown, Jason ^{[1
]}

Cansfield, Julie E. ^{[1
]}

Cross, David M. ^{[1
,3
]}

de Graaf, Chris ^{[1
]}

Hudson, Brian D. ^{[1
]}

Dwomoh, Louis ^{[2
]}

Dias, Joao M. ^{[1
,18
]}

Errey, James C. ^{[1
,19
]}

Hurrell, Edward ^{[1
]}

Liptrot, Jan ^{[1
]}

Mattedi, Giulio ^{[1
]}

Molloy, Colin ^{[2
]}

Nathan, Pradeep J. ^{[1
,4
,15
]}

Okrasa, Krzysztof ^{[1
]}

Osborne, Greg ^{[1
]}

Patel, Jayesh C. ^{[1
]}

Pickworth, Mark ^{[1
]}

Robertson, Nathan ^{[1
,20
]}

Shahabi, Shahram ^{[5
]}

Bundgaard, Christoffer ^{[5
,6
]}

Phillips, Keith ^{[5
]}

Broad, Lisa M. ^{[5
]}

Goonawardena, Anushka V. ^{[7
]}

Morairty, Stephen R. ^{[7
]}

Browning, Michael ^{[8
,9
]}

Perini, Francesca ^{[10
]}

Dawson, Gerard R. ^{[8
]}

Deakin, John F. W. ^{[11
]}

Smith, Robert T.

Sexton, Patrick M. ^{[12
,13
,14
]}

Warneck, Julie ^{[15
]}

Vinson, Mary ^{[21
]}

Tasker, Tim

Tehan, Benjamin G.

Teobald, Barry ^{[16
]}

Christopoulos, Arthur ^{[22
]}

Langmead, Christopher J. ^{[12
,13
]}

Jazayeri, Ali ^{[12
,13
]}

Cooke, Robert M. ^{[17
]}

Rucktooa, Prakash

Congreve, Miles S.

Weir, Malcolm

Tobin, Andrew B. ^{[2
,22
]}

机构：

[1] Sosei Heptares, Steinmetz Bldg,Granta Pk, Cambridge CB21 6DG, England

[2] Univ Glasgow, Coll Med Vet & Life Sci, Inst Mol Cell & Syst Biol, Ctr Translat Pharmacol, Glasgow G12 8QQ, Lanark, Scotland

[3] Cross Pharma Consulting Ltd, 20-22 Wenlock Rd, London N17GU, England

[4] Univ Cambridge, Dept Psychiat, Brain Mapping Unit, Herchel Smith Bldg, Cambridge CB2 0SZ, England

[5] Eli Lilly & Co, Neurosci Discovery, Erl Wood Manor, Surrey GU20 6PH, England

[6] H Lundbeck & Co AS, Neurosci Res, Ottiliavej 9, DK-2500 Copenhagen, Denmark

[7] SRI Int, Ctr Neurosci, Biosci Div, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA

[8] Univ Oxford, Warneford Hosp, Univ Dept Psychiat, Oxford OX1 2JD, England

[9] P1vital, Manor House,Howbery Buisness Pk, Wallingford OX1 08BA, Oxon, England

[10] Duke NUS Med Sch, Ctr Cognit Neurosci, 8 Coll Rd, Singapore 169857, Singapore

[11] Univ Manchester, Neurosci & Psychiat Unit, Manchester M13 9PT, Lancs, England

[12] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia

[13] Monash Univ, Dept Pharmacol, 12222, Parkville, Vic 3052, Australia

[14] Monash Univ, Monash Inst Pharmaceut Sci, ARC Ctr Cryoelect Microscopy Membrane Proteins, Parkville, Vic 3052, Australia

[15] Protogenia Consulting Ltd, POB 289, Ely CB7 9DR, England

[16] Merck Res Labs, Rahway, NJ 07065 USA

[17] OMass Therapeut, Schrodinger Bldg,Heatley Rd,,Oxford Sci Pk, Oxford OX4 4GE, England

[18] Pfizer, Struct Biol & Biophys, East 42nd St, New York, NY 10017 USA

[19] Evotec UK Ltd, 114 Innovat Dr,Pk, Milton OX14 4RZ, Abingdon, England

[20] OXGENE Biotechnol, Medawar Ctr, Robert Robinson Ave, Oxford OX4 4HG, England

[21] Autolus Therapeut PLC, Mediaworks 5, 191 Wood Lane, London W12 7FP, England

[22] Sitryx Therapeut Ltd, Oxford Sci Pk, Oxford OX4 4GA, England

来源：

CELL | 2021年 / 184卷 / 24期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

ALLOSTERIC MODULATORS; CHOLINESTERASE-INHIBITORS; CHOLINERGIC HYPOTHESIS; BEHAVIORAL SYMPTOMS; SELECTIVE AGONISTS; CRYSTAL-STRUCTURE; BINDING MODE; MEMORY; XANOMELINE; PAM;

D O I：

10.1016/j.cell.2021.11.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5886 / +

页数：39

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