3-Heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives as muscarinic antagonists. Synthesis and structure-activity relationships

J Med Chem. 1995 Feb 3;38(3):473-87. doi: 10.1021/jm00003a011.


A number of 3-heteroaryl-substituted quinuclidin-3-ol and quinuclidin-2-ene derivatives have been prepared and evaluated for muscarinic and antimuscarinic properties. The affinities of the new compounds (13, 14, 16-32, and 36-52a,b) were tested in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate [(-)-[3H]QNB] as the radioligand and in a functional assay using isolated guinea pig urinary bladder. The present compounds behaved as competitive muscarinic antagonists in the urinary bladder. The highest receptor binding affinity, Ki (cortex) = 9.6 nM, was observed for 3-(2-benzofuranyl)quinuclidin-2-ene (31). The corresponding 3-benzofuranyl (36) and 3-benzothienyl (37) homologues had about 3.5-fold lower affinity for cortical muscarinic receptors. All quinuclidin-3-ol derivatives (14 and 16-25) had lower binding affinities for the different muscarinic receptor subtypes than the corresponding quinuclidin-2-ene analogues when examined in the various tissue homogenates. In general, the new compounds showed low subtype selectivity. The structure-affinity relationships are discussed in terms of differences in proton basicity of the azabicyclic nitrogen and differences in geometric, conformational, and/or electronic properties of the compounds. The cortical antimuscarinic potency is also related to the complementarity of the compounds to the putative binding site of the muscarinic m1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cerebral Cortex / metabolism
  • Electrochemistry
  • Guinea Pigs
  • In Vitro Techniques
  • Male
  • Models, Molecular
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / metabolism
  • Muscarinic Antagonists / pharmacology
  • Myocardium / metabolism
  • Parotid Gland / metabolism
  • Quinuclidines / chemical synthesis*
  • Quinuclidines / pharmacology
  • Spectrophotometry, Ultraviolet
  • Structure-Activity Relationship
  • Urinary Bladder / metabolism


  • Muscarinic Antagonists
  • Quinuclidines