Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1

Br J Pharmacol. 2008 Jul;154(5):1104-15. doi: 10.1038/bjp.2008.152. Epub 2008 May 5.


Background and purpose: M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs.

Experimental approach: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology.

Key results: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration.

Conclusions and implications: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.

Publication types

  • Comparative Study

MeSH terms

  • Action Potentials
  • Animals
  • CHO Cells
  • Calcium Signaling / drug effects
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Humans
  • Injections, Intraperitoneal
  • Injections, Subcutaneous
  • Inositol Phosphates / metabolism
  • Muscarinic Agonists / administration & dosage
  • Muscarinic Agonists / pharmacokinetics
  • Muscarinic Agonists / pharmacology*
  • Patch-Clamp Techniques
  • Permeability
  • Piperidines / administration & dosage
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Quinolones / administration & dosage
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / genetics
  • Receptors, Muscarinic / metabolism
  • Recombinant Proteins / agonists
  • Time Factors
  • Transfection


  • 4-n-butyl-1-(4-(2-methylphenyl)-4-oxo-1-butyl)-piperidine hydrogen chloride
  • 77-LH-28-1
  • CHRM1 protein, human
  • Inositol Phosphates
  • Muscarinic Agonists
  • Piperidines
  • Quinolones
  • Receptor, Muscarinic M1
  • Receptors, Muscarinic
  • Recombinant Proteins