Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists.
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Rajeswaran WG, Cao Y, Huang XP, Wroblewski ME, Colclough T, Lee S, Liu F, Nagy PI, Ellis J, Levine BA, Nocka KH, Messer WS Jr
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.
- PubMed ID
- 11741475 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Acetylcholine Muscarinic acetylcholine receptor M1 EC 50 (nM) 20000 N/A N/A Details Carbamoylcholine Muscarinic acetylcholine receptor M1 Ki (nM) 20000 N/A N/A Details Carbamoylcholine Muscarinic acetylcholine receptor M1 EC 50 (nM) 130000 N/A N/A Details Carbamoylcholine Muscarinic acetylcholine receptor M1 EC 50 (nM) 13000 N/A N/A Details Carbamoylcholine Muscarinic acetylcholine receptor M4 EC 50 (nM) 290 N/A N/A Details