Synthesis and pharmacological evaluation of dimeric muscarinic acetylcholine receptor agonists

J Pharmacol Exp Ther. 2001 Sep;298(3):1260-8.

Abstract

Two dimeric analogs of the muscarinic acetylcholine receptor (mAChR) agonist phenylpropargyloxy-1,2,5-thiadiazole-quinuclidine (NNC 11-1314) were synthesized and pharmacologically evaluated. In radioligand binding assays on Chinese hamster ovary (CHO) cell membranes expressing the individual human M(1) to M(5) mAChR subtypes, both dimers [(3S)-1,4-bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1,2,5-thiadiazol-4-yloxy]-1-propyn-1-yl)benzene,2-L-(+)-tartrate (NNC 11-1607) and (3S)-1,3-bis-(3-[(3-azabicyclo[2.2.2]octanyl)-1,2,5-thiadiazol-4-yloxy]-1-propyn-1-yl)benzene,2-L-(+)-tartrate (NNC 11-1585)] exhibited higher binding affinities than the monomeric NNC 11-1314. Only NNC 11-1585, however, displayed significant selectivity for the M(1) and M(2) mAChRs relative to the other subtypes. Although binding studies in rat brain homogenates supported the selectivity profile of NNC 11-1585 observed in the CHO membranes, rat heart membrane experiments revealed complex binding behavior for all three agonists that most likely reflected differences in species and host cell environment between the heart and CHO cells. Subsequent functional assays with phosphatidylinositol hydrolysis revealed that all three novel ligands were partial agonists relative to the full agonist oxotremorine-M at the CHO M(1), M(3), and M(5) mAChRs, with NNC 11-1607 displaying the highest functional selectivity. In the CHO M(2) and M(4) mAChR cells, agonist-mediated effects on forskolin-stimulated cAMP accumulation were characterized by bell-shaped concentration-response curves, with the exceptions of NNC 11-1607, which had no discernible effects at the M(2) mAChR, and NNC 11-1585, which could only inhibit cAMP accumulation at the M(4) mAChR. Thus, we identified NNC 11-1607 as a novel functionally selective M(1)/M(4) mAChR agonist. Our data suggest that dimerization of mAChR agonists is a viable approach in designing more potent and functionally selective agonists, as well as in providing novel tools with which to probe the nature of agonism at these receptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms
  • Animals
  • Binding, Competitive / drug effects
  • CHO Cells
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetinae
  • Cyclic AMP / metabolism
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Muscarinic Agonists / chemical synthesis*
  • Muscarinic Agonists / pharmacology*
  • Phosphatidylinositols / metabolism
  • Quinuclidines / pharmacology*
  • Receptors, Muscarinic / drug effects*
  • Structure-Activity Relationship
  • Thiadiazoles / pharmacology*

Substances

  • 1,4-bis(3-((3-azabicyclo(2.2.2)octanyl)-1,2,5-thiadiazol-4-yloxy)-1-propyn-1-yl)benzene
  • Ligands
  • Muscarinic Agonists
  • Phosphatidylinositols
  • Quinuclidines
  • Receptors, Muscarinic
  • Thiadiazoles
  • Cyclic AMP
  • NNC 11-1314