Approximately 16% of Americans are diagnosed with major depressive disorder, a mental illness thought to be caused by a combination of genetic, biological, environmental, and psychological factors. 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 managing major depression.<br/>     Mechanisms of antidepressants have been a significant focus of both current/past research to develop more effective and faster-acting drugs. Directly related, clinical data demonstrated that oral and intravenous treatment with the muscarinic cholinergic antagonist scopolamine had rapid antidepressant effects in humans, likely mediated through an antimuscarinic effect. Unfortunately, a significant disadvantage to using scopolamine in treating depression is its detrimental effects on cognition, which might aggravate cognitive deficits that occur with depression itself. Therefore, the identification of antimuscarinic drugs that are free of such adverse effects may provide an essential avenue for the development of novel therapeutics to manage depression.<br/>     The present data in rats show that a known muscarinic antagonist, L-687,306, and a muscarinic antagonist of our design, CJ2100, were as effective as scopolamine in antagonizing the bradycardia effects of the muscarinic agonist arecoline in cardiovascular studies, its discriminative-stimulus effects, and rate-decreasing effects in behavioral studies. Additionally, both antagonists were equally effective to scopolamine in decreasing immobility in the forced swim test (FST), a preclinical indicator of potential antidepressant activity. However, they were much less disruptive at equally effective or even larger doses than scopolamine in assays of cognition-related behavior. All three drugs displayed high specificity for the mAChRs with few off-target binding sites, and CJ2100 showed modest affinity across the mAChRs compared to L-687,306 and scopolamine. These data emphasize the different pharmacological profiles evident across antimuscarinic compounds and novel mAChR antagonists' utility for the improved treatment of depression.

Novel antimuscarinic antidepressants with reduced effects on cognition

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.