Effects of allosteric modulators on responses to acetylcholine and stable surrogate acetylcholine receptor agonistsProbe dependence at the screening stage for PAMs aimed at potentiating failing acetylcholine response in Alzheimer’s disease. Stable muscarinic agonists used for screening indicate potentially useful potentiation, but subsequent study with the natural agonist acetylcholine demonstrates antagonism. Data from Jakubíc et al. (1997).
| Target | Modulator | Surrogate Agonist | Effect on Surrogate Agonist | Effect on Natural Agonist (Acetylcholine) |
|---|---|---|---|---|
| Muscarinic m2 | Alcuronium | Pilocarpine | 2.7× potentiation | 10× antagonism |
| Muscarinic m4 | Strychnine | Pentylthio-TZTP | 3× potentiation | 4× antagonism |
| Muscarinic m2 | Brucine | Pentylthio-TZTP | 8× potentiation | 3.5× antagonism |
Pentylthio-TZTP, pentylthio-TZTP, 3-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-4-pentylsulfanyl-1,2,5-thiadiazole.