ABSTRACT
RATIONALE: Ropanicant (SUVN-911) (3-(6-Chloropyridine-3-yloxymethyl)-2-azabicyclo (3.1.0) hexane hydrochloride) is a novel α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist being developed for the treatment of depressive disorders. OBJECTIVES: Pharmacological and neurochemical characterization of Ropanicant to support a potential molecule for the treatment of depressive disorders. METHODS: Ropanicant was assessed for antidepressant-like activity using the rat forced swimming test (FST) and differential reinforcement of low rate -72 s (DRL-72 s). Alleviation of anhedonia was assessed in chronic mild stress model using sucrose preference test. To understand the mechanism of action, serotonin levels, ionized calcium-binding adaptor molecule 1 (Iba1), and brain-derived neurotrophic factor (BDNF) were determined. The onset of antidepressant-like activity was determined using the reduction in submissive behavior assay. The effects on cognition and sexual functions were assessed using the object recognition task and sexual dysfunction assay respectively. Interaction of Ropanicant, TC-5214, and methyllycaconitine (MLA) with citalopram was investigated individually in mice FST. RESULTS: Ropanicant exhibited antidepressant like properties in the FST and DRL-72 s. A significant reduction in anhedonia was observed in the sucrose preference test. Oral administration of Ropanicant produced a significant increase in serotonin and BDNF levels, with a reduction in the Iba1 activity. The onset of antidepressant like effect with Ropanicant was within a week of treatment, and was devoid of cognitive dulling and sexual dysfunction. While Ropanicant potentiated the effect of citalopram in FST, such an effect was not observed with MLA or TC-5214. CONCLUSIONS: Preclinical studies with Ropanicant support the likelihood of its therapeutic utility in the treatment of depressive disorders.
Subject(s)
Antidepressive Agents , Depressive Disorder , Nicotinic Antagonists , Anhedonia , Animals , Antidepressive Agents/pharmacology , Brain-Derived Neurotrophic Factor , Citalopram/pharmacology , Depressive Disorder/drug therapy , Disease Models, Animal , Mice , Nicotinic Antagonists/pharmacology , Rats , Receptors, Nicotinic , Serotonin , Sucrose , SwimmingABSTRACT
A series of oxadiazole derivatives were synthesized and evaluated as 5-hydroxytryptamine-4 receptor (5-HT4R) partial agonists for the treatment of cognitive deficits associated with Alzheimer's disease. Starting from a reported 5-HT4R antagonist, a systematic structure-activity relationship was conducted, which led to the discovery of potent and selective 5-HT4R partial agonist 1-isopropyl-3-{5-[1-(3-methoxypropyl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate (Usmarapride, 12l). It showed balanced physicochemical-pharmacokinetic properties with robust nonclinical efficacy in cognition models. It also showed disease-modifying potential, as it increased neuroprotective soluble amyloid precursor protein alpha levels, and dose-dependent target engagement and correlation of efficacy with oral exposures. Phase 1 clinical studies have been completed and projected efficacious concentration was achieved without any major safety concerns. Phase 2 enabling long-term safety studies have been completed with no concerns for further development.
Subject(s)
Alzheimer Disease/drug therapy , Cognition Disorders/drug therapy , Drug Discovery , Neuroprotective Agents/pharmacology , Receptors, Serotonin, 5-HT4/metabolism , Serotonin 5-HT4 Receptor Agonists/pharmacology , Alzheimer Disease/metabolism , Cognition Disorders/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Serotonin 5-HT4 Receptor Agonists/chemical synthesis , Serotonin 5-HT4 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
In the present study, we investigated the performance of adult and juvenile rats in the Object Recognition Task (ORT). While it is well known that the performance of rat in ORT differs with age, the reason for the difference as well as the underlying neurotransmitter that may have led to these differences were investigated. In the present study, juvenile rats of postnatal day 40-45 (PND 40-45) and adult rats of postnatal day 60+ (PND 60+) were subjected to a two trial ORT. The juvenile rats did not discriminate between the novel object and the familiar object, while the adult rats discriminated the novel from the familiar object. On estimating brain concentrations of norepinephrine (NE), it was observed that the NE level in MTL (medial temporal lobe) of adult experimental rats was significantly higher than the adult non-experimental rats. In juvenile rats, no significant difference was observed in the NE levels of experimental rats in comparison to its non-experimental counterparts. Administration of yohimbine (α(2A) adrenergic receptor antagonist) enhanced the level of NE in juvenile rats and reversed the difference seen with age. From the present study, we conclude that the deficit in memory seen is likely due to the difference in NE levels with task and this can be reversed by yohimbine which enhance NE levels.
