Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists

J Med Chem. 2001 Dec 20;44(26):4563-76. doi: 10.1021/jm0102405.


Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.

Publication types

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

MeSH terms

  • Binding, Competitive
  • Cell Line
  • Drug Design
  • Humans
  • Ligands
  • Models, Molecular
  • Muscarinic Agonists / chemical synthesis*
  • Muscarinic Agonists / chemistry
  • Muscarinic Agonists / pharmacology
  • Phosphatidylinositols / metabolism
  • Protein Structure, Tertiary
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Radioligand Assay
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M3
  • Receptor, Muscarinic M5
  • Receptors, Muscarinic / metabolism
  • Solubility
  • Structure-Activity Relationship
  • Thiadiazoles / chemical synthesis*
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology
  • Transfection


  • Ligands
  • Muscarinic Agonists
  • Phosphatidylinositols
  • Pyridines
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M3
  • Receptor, Muscarinic M5
  • Receptors, Muscarinic
  • Thiadiazoles