PRECLINICAL EVALUATION OF ROPANICANT, A NICOTINIC ACETYLCHOLINE α4β2 RECEPTOR ANTAGONIST IN ANIMAL MODELS OF DEPRESSION

Ropanicant is a nicotinic acetylcholine α4β2 receptor antagonist. Based on the literature evidence, it was evaluated in various animal models of depression. To ascertain the antidepressant like property of Ropanicant, a forced swim test was conducted. Ropanicant was evaluated in dominant-submissive studies to ascertain the onset of antidepressant-like properties. To understand the mechanism of action of Ropanicant, various monoamines and brain-derived neurotrophic factor (BDNF) were estimated. As there are reports that an α4β2 receptor antagonist can improve cognition, Ropanicant was assessed in an object recognition task (ORT). Ropanicant reduced the immobility time and increased the duration of swimming in the forced swim test in rats. The doses of Ropanicant, which reduced immobility, had no significant effect on the distance traveled in an open field study. Ropanicant had a rapid onset of action in comparison to reuptake inhibitors in the dominant-submissive assay. Treatment with Ropanicant increased monoamines and BDNF levels in rats, indicating the possible mechanism of action. Unlike tricyclic antidepressants, administration of Ropanicant increased the time spent by rats with the novel object in the ORT. From the ORT, we conclude that Ropanicant has a procognitive like effect. Preliminary toxicity studies showed no safety concerns for further development. Ropanicant has the potential to be a new therapeutic option with unique properties for the treatment of major depressive disorders. Ropanicant is currently undergoing a phase-2 study (NCT06836063) in the United States to evaluate its safety and efficacy in patients with major depressive disorder.