Further exploration of M1 allosteric agonists: Subtle structural changes abolish M1 allosteric agonism and result in pan-mAChR orthosteric antagonism

Douglas J. Sheffler, Christian Sevel, Uyen Le, Kimberly M. Lovell, James C. Tarr, Sheridan J.S. Carrington, Hyekyung P. Cho, Gregory J. Digby, Colleen M. Niswender, P. Jeffrey Conn, Corey R. Hopkins, Michael R. Wood, Craig W. Lindsley

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


This letter describes the further exploration of two series of M 1 allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M1 allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M1 allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M1 activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism.

Original languageEnglish (US)
Pages (from-to)223-227
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number1
StatePublished - Jan 1 2013
Externally publishedYes


  • Allosteric agonist
  • M1
  • Muscarinic receptor
  • TBPB

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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