amibegron and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The involvement of the noradrenergic system, particularly the beta1 and beta2 receptors, in depressive disorders has been frequently shown. Recently, however, it has been shown that the beta3 receptor may also contribute since amibegron (SR58611A), a selective beta3 receptor agonist, has antidepressant-like effects. The present experiment sought to confirm the antidepressant potential of amibegron by studying its effects in an animal model of depression, the Flinders Sensitive Line (FSL) rat. The FSL rat is innately highly immobile in the forced swim test and exhibits a decrease in immobility after chronic, not acute antidepressant treatment. FSL rats were treated for 14 consecutive days with amibegron (0.3, 1.0, or 3.0 mg/kg), fluoxetine (5 mg/kg) or desipramine (5 mg/kg) as positive controls, and vehicle, while the control strain, the Flinders Resistant Line (FRL) rats, was given either vehicle or 1.0 mg/kg amibegron. About 23-25 h after the last injection the rats were tested in the forced swim test. All doses of amibegron and the two active controls, fluoxetine and desipramine, significantly reduced immobility in the FSL rats. Thus, amibegron had a selective antidepressant-like effect in this study, confirming its antidepressant potential.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Antidepressive Agents; Behavior, Animal; Depression; Disease Models, Animal; Motor Activity; Rats; Social Behavior; Tetrahydronaphthalenes

A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (5HT) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the 5HT antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that 5HT transmission is strictly involved in its action.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Adrenergic beta-Antagonists; Analysis of Variance; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Behavior, Animal; Clomipramine; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Grooming; Injections, Intraperitoneal; Male; Maze Learning; Methysergide; Mice; Motor Activity; Propanolamines; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Serotonin Antagonists; Swimming; Tetrahydronaphthalenes