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

Brown AJH, Bradley SJ, Marshall FH, Brown GA, Bennett KA, Brown J, Cansfield JE, Cross DM, de Graaf C, Hudson BD, Dwomoh L, Dias JM, Errey JC, Hurrell E, Liptrot J, Mattedi G, Molloy C, Nathan PJ, Okrasa K, Osborne G, Patel JC, Pickworth M, Robertson N, Shahabi S, Bundgaard C, Phillips K, Broad LM, Goonawardena AV, Morairty SR, Browning M, Perini F, Dawson GR, Deakin JFW, Smith RT, Sexton PM, Warneck J, Vinson M, Tasker T, Tehan BG, Teobald B, Christopoulos A, Langmead CJ, Jazayeri A, Cooke RM, Rucktooa P, Congreve MS, Weir M, Tobin AB
Cell 184 5886-5901.e22 (2021)
Related entries: 6zg4, 6zg9

Cited: 28 times
EuropePMC logo PMID: 34822784

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.

Reviews - 6zfz mentioned but not cited (1)

  1. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)

Articles - 6zfz mentioned but not cited (3)

  1. α-Linolenic Acid Screened by Molecular Docking Attenuates Inflammation by Regulating Th1/Th2 Imbalance in Ovalbumin-Induced Mice of Allergic Rhinitis. Ren M, Wang Y, Lin L, Li S, Ma Q. Molecules 27 5893 (2022)
  2. Evaluating GPCR modeling and docking strategies in the era of deep learning-based protein structure prediction. Lee S, Kim S, Lee GR, Kwon S, Woo H, Seok C, Park H. Comput Struct Biotechnol J 21 158-167 (2023)
  3. Cymbopogon citratus Essential Oil: Extraction, GC-MS, Phytochemical Analysis, Antioxidant Activity, and In Silico Molecular Docking for Protein Targets Related to CNS. Cortes-Torres AG, López-Castillo GN, Marín-Torres JL, Portillo-Reyes R, Luna F, Baca BE, Sandoval-Ramírez J, Carrasco-Carballo A. Curr Issues Mol Biol 45 5164-5179 (2023)


Reviews citing this publication (7)

  1. Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders. Johnson CR, Kangas BD, Jutkiewicz EM, Bergman J, Coop A. Biomedicines 10 398 (2022)
  2. Beyond antipsychotics: a twenty-first century update for preclinical development of schizophrenia therapeutics. Spark DL, Fornito A, Langmead CJ, Stewart GD. Transl Psychiatry 12 147 (2022)
  3. Targeting the M1 muscarinic acetylcholine receptor in Alzheimer's disease. Dwomoh L, Tejeda GS, Tobin AB. Neuronal Signal 6 NS20210004 (2022)
  4. Function and structure of bradykinin receptor 2 for drug discovery. Shen JK, Zhang HT. Acta Pharmacol Sin 44 489-498 (2023)
  5. Understanding How Physical Exercise Improves Alzheimer's Disease: Cholinergic and Monoaminergic Systems. Zong B, Yu F, Zhang X, Zhao W, Sun P, Li S, Li L. Front Aging Neurosci 14 869507 (2022)
  6. A Comprehensive Review of Essential Oils and Their Pharmacological Activities in Neurological Disorders: Exploring Neuroprotective Potential. Qneibi M, Bdir S, Maayeh C, Bdair M, Sandouka D, Basit D, Hallak M. Neurochem Res (2023)
  7. G protein-coupled receptors as targets for transformative neuropsychiatric therapeutics. Schmitz GP, Roth BL. Am J Physiol Cell Physiol 325 C17-C28 (2023)

Articles citing this publication (17)

  1. G protein-biased GPR3 signaling ameliorates amyloid pathology in a preclinical Alzheimer's disease mouse model. Huang Y, Rafael Guimarães T, Todd N, Ferguson C, Weiss KM, Stauffer FR, McDermott B, Hurtle BT, Saito T, Saido TC, MacDonald ML, Homanics GE, Thathiah A. Proc Natl Acad Sci U S A 119 e2204828119 (2022)
  2. Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics. Vuckovic Z, Wang J, Pham V, Mobbs JI, Belousoff MJ, Bhattarai A, Burger WAC, Thompson G, Yeasmin M, Nawaratne V, Leach K, van der Westhuizen ET, Khajehali E, Liang YL, Glukhova A, Wootten D, Lindsley CW, Tobin A, Sexton P, Danev R, Valant C, Miao Y, Christopoulos A, Thal DM. Elife 12 e83477 (2023)
  3. Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-β-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning. Yamahashi Y, Lin YH, Mouri A, Iwanaga S, Kawashima K, Tokumoto Y, Watanabe Y, Faruk MO, Zhang X, Tsuboi D, Nakano T, Saito N, Nagai T, Yamada K, Kaibuchi K. Mol Psychiatry 27 3479-3492 (2022)
  4. A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease. Nathan PJ, Millais SB, Godwood A, Dewit O, Cross DM, Liptrot J, Ruparelia B, Jones SP, Bakker G, Maruff PT, Light GA, Brown AJH, Weir MP, Congreve M, Tasker T. Alzheimers Dement (N Y) 8 e12273 (2022)
  5. The M1 muscarinic receptor is present in situ as a ligand-regulated mixture of monomers and oligomeric complexes. Marsango S, Jenkins L, Pediani JD, Bradley SJ, Ward RJ, Hesse S, Biener G, Stoneman MR, Tobin AB, Raicu V, Milligan G. Proc Natl Acad Sci U S A 119 e2201103119 (2022)
  6. Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR. Burger WAC, Pham V, Vuckovic Z, Powers AS, Mobbs JI, Laloudakis Y, Glukhova A, Wootten D, Tobin AB, Sexton PM, Paul SM, Felder CC, Danev R, Dror RO, Christopoulos A, Valant C, Thal DM. Nat Commun 14 5440 (2023)
  7. Xanomeline restores endogenous nicotinic acetylcholine receptor signaling in mouse prefrontal cortex. Power SK, Venkatesan S, Lambe EK. Neuropsychopharmacology 48 671-682 (2023)
  8. A Novel Resveratrol-Induced Pathway Increases Neuron-Derived Cell Resilience against Oxidative Stress. Cracco P, Montalesi E, Parente M, Cipolletti M, Iucci G, Battocchio C, Venditti I, Fiocchetti M, Marino M. Int J Mol Sci 24 5903 (2023)
  9. Back to the Future of Neuropsychopharmacology. Bespalov A, van Gaalen M, Steckler T. Adv Neurobiol 30 207-224 (2023)
  10. Cryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase. Yang X, Ding Z, Peng L, Song Q, Zhang D, Cui F, Cui F, Xia C, Li K, Yin H, Li S, Li Z, Huang H. Nat Commun 13 6955 (2022)
  11. Docking for EP4R antagonists active against inflammatory pain. Gahbauer S, DeLeon C, Braz JM, Craik V, Kang HJ, Wan X, Huang XP, Billesbølle CB, Liu Y, Che T, Deshpande I, Jewell M, Fink EA, Kondratov IS, Moroz YS, Irwin JJ, Basbaum AI, Roth BL, Shoichet BK. Nat Commun 14 8067 (2023)
  12. Efficacy of Donepezil Hydrochloride plus Olanzapine for Senile Dementia and Its Effect on the Recovery of Cognitive Function. Zheng W, Sun X, Liu J. Evid Based Complement Alternat Med 2022 4156312 (2022)
  13. Functional screening and rational design of compounds targeting GPR132 to treat diabetes. Wang JL, Dou XD, Cheng J, Gao MX, Xu GF, Ding W, Ding JH, Li Y, Wang SH, Ji ZW, Zhao XY, Huo TY, Zhang CF, Liu YM, Sha XY, Gao JR, Zhang WH, Hao Y, Zhang C, Sun JP, Jiao N, Yu X. Nat Metab 5 1726-1746 (2023)
  14. Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor. Wang D, Guo Q, Wu Z, Li M, He B, Du Y, Zhang K, Tao Y. Nat Commun 15 84 (2024)
  15. Muscarinic receptors: from clinic to bench to clinic. Foster DJ. Trends Pharmacol Sci 43 461-463 (2022)
  16. Selective Activation of M1 Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation. Sundel MH, Sampaio Moura N, Cheng K, Chatain O, Hu S, Drachenberg CB, Xie G, Raufman JP. Cancers (Basel) 15 4766 (2023)
  17. The Evaluation of Rac1 Signaling as a Potential Therapeutic Target of Alzheimer's Disease. Wang H, Yamahashi Y, Riedl M, Amano M, Kaibuchi K. Int J Mol Sci 24 11880 (2023)


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