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 of 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, a preclinical indicator of potential antidepressant activity. However, at equieffective 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 with 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. SIGNIFICANCE STATEMENT: Some clinical studies with the muscarinic antagonist scopolamine document its ability to produce antidepressant effects in patients with mood disorders; however, scopolamine also has well known adverse effects on both autonomic and centrally mediated physiological functions that limit its therapeutic use. This study characterizes the cardiovascular and discriminative stimulus effects of two novel muscarinic antagonists, L-687,306 and CJ2100, that produce antidepressant-like effects in a rodent model (forced swim test) without affecting touchscreen-based cognitive performance (titrating psychomotor vigilance and delayed matching-to-position).

Fig. 1.

Synthesis of L-687,306. TFA=trifluoroacetic acid

Fig. 2.

Synthesis of CJ2100.

Fig. 3.

Antagonism by 0.3 mg/kg CJ2100 (closed triangles), and 1.0 mg/kg CJ2100 (open squares) of the brief, profound bradycardia produced by subcutaneous administration of 10 mg/kg arecoline (closed circles). Saline control data and the effects of the smallest, most effective doses of L-687,306 and scopolamine are shown in the dashed and dotted lines for comparison with CJ2100. The arecoline and saline data were from eight rats (n=8), and the effects of the antagonists came from four rats each (n=4). Data were fitted (R² = 0.77) with a linear mixed model using treatment and time as fixed factors and subject (n = 12) as random factor (Jamovi version 1.2). The effects of treatment [F (4180) = 57.80], time [F (9216) = 20.1], and the treatment × time interaction [F (36,216) = 8.11] were each statistically significant (P < 0.001). Bonferroni-corrected multiple comparisons among the cells means that the results obtained with arecoline were significantly different from saline at 2–5 minutes only (P < 0.001). At 2–4 minutes, the results obtained in all three pretreatment conditions were significantly different from arecoline (P < 0.001) and not from saline. Note that the initial bradycardia is an artifact of handling and injecting the rats and occurs too rapidly to be a drug effect. HR=heart rate; Scopol=Scopolamine

Fig. 4.

Top: the interaction between scopolamine (A), L-687,306 (B), and CJ2100 (C) on the discriminative stimulus effects of arecoline (closed circles). Bottom: simultaneous measures of the interactions of these drugs on the rates at which the rats carried out the discrimination task. The effect of saline on arecoline discrimination and rates of responding are shown as open circles. n = 6-8. Scopol=Scopolamine; Sal=Saline; Sec=Second

Fig. 5.

Effects of several doses of scopolamine (A), L-687,306 (B), and CJ2100 (C) on counts of immobility, swimming, and climbing in the forced swim test. n = 6 rats per dose per drug; *P < 0.05; **P < 0.01; ***P < 0.001. Locomotor activity was evaluated at doses that produced significant decreases in immobility in the FST (D), which demonstrate significant main effects of treatment [F (328) = 6.6, P = 0.002] and time [F (10,280) = 31.6, P < 0.0001]. BL=Baseline

Fig. 6.

(A) Dose-related effects of scopolamine (closed squares), L-687,306 (closed diamonds), and CJ2100 (closed circles) on mean titrated duration in second in the psychomotor vigilance task n = 6. (B) Dose-related effects of the three muscarinic antagonists on the mean titrated delay in the titrating delay matching-to-position task. n = 6; **P < 0.01; ***P < 0.001.Ctrl and C=Control; Sal and S=Saline

Fig. 7.

Antagonism of the effects of 3.2 mg/kg arecoline on the psychomotor vigilance task by a range of doses of scopolamine (A), L-687,306 (B), and CJ2100 (C). n = 6.