Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M1 - M5 muscarinic acetylcholine receptors

Bioorg Med Chem Lett. 2019 Feb 1;29(3):471-476. doi: 10.1016/j.bmcl.2018.12.022. Epub 2018 Dec 11.


Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1-M5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (Ki = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1-M5 mAChRs, respectively. Based on results from the [3H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs. The effect of 3c was inhibited by the nonselective mAChR antagonist, scopolamine, and 3c augmented release evoked by oxotremorine. A potent analog from the same scaffold, (±)-quinuclidin-3-yl-(4-methoxyphenethyl)(phenyl)-carbamate (3b) exhibited the greatest selectivity (17-fold) at M3 over M2 mAChRs. These analogs could serve as leads for further discovery of novel subtype-selective muscarinic ligands with the goal of providing therapeutics for substance use disorders and chronic obstructive pulmonary disease.

Keywords: Carbamate; Chronic obstructive pulmonary disease; Muscarinic acetylcholine receptors; Substance use disorders; [(3)H]N-methylscopolamine binding; [(3)H]dopamine release.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Carbamates / chemical synthesis
  • Carbamates / chemistry
  • Carbamates / pharmacology*
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Muscarinic Agonists / chemical synthesis
  • Muscarinic Agonists / chemistry
  • Muscarinic Agonists / pharmacology*
  • Quinuclidines / pharmacology*
  • Rats
  • Receptors, Muscarinic / metabolism*
  • Structure-Activity Relationship


  • Carbamates
  • Ligands
  • Muscarinic Agonists
  • Quinuclidines
  • Receptors, Muscarinic