Novel Antimuscarinic Antidepressant-like Compounds with Reduced Effects on Cognition

Abstract

The cholinergic nervous system has been implicated in mood disorders, evident in the fast-onset antidepressant effects of scopolamine, a potent muscarinic antagonist, in clinical studies. One prominent disadvantage to the use of scopolamine in the treatment of depression is its detrimental effects on cognition, especially as such effects might aggravate cognitive deficits that occur with depression itself. Thus, the identification of antimuscarinic drugs that are free of such detrimental effects may provide an important avenue for the development of novel therapeutics for the management of depression. The present data in rats indicate that a historical muscarinic antagonist, L-687,306, and a muscarinic antagonist of our own design, CJ2100, were as or more effective than scopolamine in antagonizing both the bradycardic effects of the muscarinic agonist arecoline in cardiovascular studies and its discriminative-stimulus and rate-decreasing effects in behavioral studies. Additionally, both novel muscarinic antagonists were as effective as scopolamine in decreasing immobility in the forced swim test (FST), a preclinical indicator of potential antidepressant activity. However, at equi-effective or even larger doses, they were considerably less disruptive 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 when compared to L-687,306 and scopolamine. These data emphasize the dissimilar pharmacological profiles that are evident across antimuscarinic compounds and the potential utility of novel antagonists for the improved treatment of depression.

Nicotinic aspects of the discriminative stimulus effects of arecoline

“…1, bottom, closed circles). The muscarinic antagonist, L 687 306 (Freedman et al ., 1992; Winger et al ., 2020; Johnson et al ., 2021) antagonized the discriminative stimulus effects of arecoline (Fig. 1, top, open squares) and to a lesser degree relieved the rate-suppressing effects of arecoline (Fig.…”

“…Rats were trained to report the discriminative stimulus effects of 1.0 mg/kg s.c. arecoline by responding on one lever following administration of arecoline and to respond on another lever following administration of saline. The fundamental muscarinic effects of arecoline in this assay were established initially by evaluating the effects of a muscarinic antagonist, L 687 306 (Freedman et al ., 1992; Freedman et al ., 1993; Winger et al ., 2020; Johnson et al ., 2021), as well as two nicotinic antagonists on the discriminative stimulus effects of arecoline. Subsequently, the ability of nicotine to produce an arecoline stimulus was evaluated.…”

Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders

“…Aside from studies on scopolamine, there has been little published on muscarinic antagonists as potential antidepressants. In the past year, Johnson et al [ 291 ] reported the development of two potential lead compounds (L-687306 and CJ2100, Figure 8 ) targeting the orthosteric site acting as rapid-acting antidepressants that lack cognitive deficits. Additionally, L-687306 was synthesized and evaluated as a possible treatment of AD in the early 1990s by Merck [ 292 , 293 , 294 ] to identify a more selective mAChR agonist with reduced efficacy (hence reduced cholinergic side-effect profile), and CJ2100 is a cyclopropyl oxadiazole derivative of arecoline.…”

“…* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Reproduced with permission from Johnson CR et al [ 291 ].…”

Open science and data sharing in cognitive neuroscience with MouseBytes and MouseBytes+

“…Hence, current data-sharing platforms for conventional behavioral data lack information on standardization decreasing the potential for re-use of data. The development of computerized and automated behavioral testing is a game-changing opportunity in cognitive behavioral data collection and analysis [13][14][15][16][17] . Touchscreen technology 18 has enabled the automation of multiple high-level cognitive tests and the generation of data in digital formats that lend themselves to deposition in FAIR-compliant data repositories.…”