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Comment
. 2022 Jun;43(6):461-463.
doi: 10.1016/j.tips.2022.01.006. Epub 2022 Jan 31.

Muscarinic receptors: from clinic to bench to clinic

Daniel J Foster  1
Affiliations
Comment

Muscarinic receptors: from clinic to bench to clinic

Daniel J Foster. Trends Pharmacol Sci. 2022 Jun.

Abstract

Efforts to target muscarinic acetylcholine receptors in the brain have been hampered by dose-limiting side effects. In a tour de force of team science, Brown and colleagues have designed a muscarinic agonist that has been optimized to possess properties that could position it to succeed where other agonists have failed.

Keywords: behavioral pharmacology; clinical trials; drug discovery; molecular pharmacology; neuroscience; structural biology.

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Conflict of interest statement

Declaration of interests The author declares no conflicts of interest.

Figures

Figure 1.
Figure 1.
Flowchart of the discovery and validation of HTL9936, a drug with great potential for treating cognitive disturbances in Alzheimer’s disease. Insights from previous clinical studies guided efforts employing structural biology to obtain drugs with enhanced selectivity for the M1 muscarinic receptor. Compounds were then optimized to contain partial agonist activity and a pharmacological profile that demonstrated pro-cognitive efficacy in multiple pre-clinical models with little to no adverse side effects. The lead compound HTL9936 was then moved into clinical trials where it was well tolerated and produced changes in brain activity that are associated with cognition enhancement.
See this image and copyright information in PMC

Comment on

  • 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. Brown AJH, et al. Cell. 2021 Nov 24;184(24):5886-5901.e22. doi: 10.1016/j.cell.2021.11.001. Cell. 2021. PMID: 34822784 Free PMC article. Clinical Trial.

References

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