Discovery of VU6077564: A Selective M1 Antagonist That Promotes Neurite Outgrowth in Adult Sensory Neurons

  • ACS Chem Neurosci. 2026 Jul 15;17(14):2739-2751. doi: 10.1021/acschemneuro.6c00367.
Tomayo I Berida  1  2 ,  Cayden J Dodd  1  2 ,  Joshua C Wilkinson  1  2  3 ,  Darrell R Smith  4 ,  Sichen Chang  1  2  3 ,  Christopher C Presley  1  2  3 ,  Li Peng  1  2 ,  Snehal Sant  1  2  3 ,  Srinivasan Krishnan  1  2  3 ,  Irene Zagol-Ikapitte  1  2  3 ,  Katherine J Watson  1  2 ,  Analisa Thompson Gray  1  2  3 ,  Alice L Rodriguez  1  2  3 ,  Hyekyung P Cho  1  2  3 ,  Carrie K Jones  1  2  3  5 ,  Olivier Boutaud  1  2  3 ,  Colleen M Niswender  1  2  3  5  6 ,  Darren W Engers  1  2  3 ,  Paul Fernyhough  4  7 ,  Craig W Lindsley  1  2  3  8  9 ,  Elizabeth S Childress  1  2  3
Affiliations
  • 1. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3. Vanderbilt Institute for Therapeutic Advances, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4. Division of Neurodegenerative & Neurodevelopmental Disorders, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg R3T 2N2, Canada.
  • 5. Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 6. Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 7. Department of Pharmacology & Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg R3E 0T6, Canada.
  • 8. Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 9. Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
PMID: 42411178 DOI: 10.1021/acschemneuro.6c00367
Abstract

Previously, we reported the potent and highly selective M1 antagonists VU0415248 and VU0452865; however, these compounds were limited by high predicted hepatic clearance in rat. This work reports the development of cyclobutylsulfonamide-based analogs of VU0415248 and VU0452865. From this exercise, we identified VU6077564, a peripherally restricted and selective M1 antagonist. Furthermore, we demonstrate the ability of VU6077564 to promote neurite outgrowth in adult rat dorsal root ganglia sensory neurons, highlighting the potential of selective M1 antagonists for the treatment of peripheral neuropathy.

Keywords
M1; Muscarinic acetylcholine receptor (mAChR); VU6077564; antagonist; neurite outgrowth; neuropathy; peripheral; pharmacokinetics.
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