Novel Cholinergics for Treatment of Central Nervous System Disorders

Abstract

Approximately 16% of Americans are diagnosed with major depressive disorder, a mental disorder thought be caused by a combination of characterized by genetic, biological, environmental, and psychological factors. It can be accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and diminished quality of life. Between 2-7% of adults with this disorder die by suicide. In addition, almost half of patients who are treated initially with an SSRI do not achieve complete remission, and nearly a third after four different treatment regimens (nimh.nih.gov). While counseling and antidepressant medication can be effective treatments, current selective serotonin re-uptake inhibitors (SSRI's) take weeks before therapeutic effects are observed. This "delay" period of action is not well understood and presents a significant challenge for medical professionals in the management of major depression. Mechanisms of anti-depressants have been a major focus of both current/past research in hopes of developing more effective and faster acting drugs. Directly related to this, clinical data (nimh.nih.gov) that oral and intravenous treatment with the muscarinic cholinergic antagonist scopolamine had rapid anti-depressant effects in humans--likely mediated through an antimuscarinic effect. Unfortunately, scopolamine can produce cognitive impairment including memory disturbances due to its anticholinergic properties. Since major depressive disorder is associated with deficits in cognition, this would produce an undesired additive effect that would only exacerbate the problem. It is our goal to identify a muscarinic antagonist that may be able to relieve depression and have little to no effect on memory or cognition. The 3-exo-1-azabicyclo[2.2.1]heptane, 1-azabicyclo[2.2.2]octane, 1-azabicyclo[3.2.1]octane, and N-methyltetrahydropyidine 3 (and 4)-substituted-1,2,4-oxadiazoles appear to be excellent chemical scaffolds for the generation of potent muscarinic agonists/antagonists. In order to probe the orthosteric site of the mAChRs we designed a large library of compounds and evaluated them via a battery of pharmacological assays to confirm both their antidepressant and cognitive effects. This resulted in the identification of lead compound (CJ2100) that showed potent antidepressant activity without cognitive impairment. (Supported by NIMH Grant 107499)