Description:
Scopolamine, a non-selective muscarinic antagonist, is a rapidly effective antidepressant compound
in humans likely mediated through an antimuscarinic effect. Unfortunately, scopolamine can
produce cognitive impairment including memory disturbances in humans. It is our goal to identify
a muscarinic antagonist that may be able to relieve depression without disrupting cognitive effects.
The 3-exo-1-azabicyclo[2.2.1]heptane, 1-azabicyclo[2.2.2]octane, and N-methyltetrahydropyidine 3-
substituted-1,2,4-oxadiazoles appear to be excellent chemical scaffolds for the generation of potent
muscarinic agonists/antagonists. The addition of a methyl group to the 3-position of the 1,2,4-
oxadiazole yields some of the most potent muscarinic agonists currently known. Yet, addition of a
cyclopropyl group appears to reduce efficacy and confer antagonist action at muscarinic sites.
Previous studies would suggest our lead compound (CJ2100) to act as an antagonist at muscarinic
receptors (old paper attached, Saurberg et al.), and we confirmed this activity.
The novelty is that CJ2100 does act as an antidepressant in the mouse, and does not give rise to
cognitive deficits. The novelty is the fact that the muscarinic
antagonist CJ2100 separates the two effects, to give just the one desired.