2-(2-(5-bromo-1h-indol-3-yl)ethyl)-3-(1-methylethoxyphenyl)-4-(3h)-quinazolinone 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

Brain cholecystokinin (CCK) and its receptor CCK(2) have been implicated in the etiology of anxiety. CCK(2) antagonists, however, fail to ameliorate anxiety in humans. In this study, a role for CCK in adaptation to stress is investigated by testing carry-over effects of Ly225.910, a potent CCK(2) antagonist, in a rat model of individual differences in novelty-induced emotionality. Novelty-seeking behavior in the rat is thought to model some aspects of sensation-seeking, a personality trait closely associated with risk activities including substance abuse. Animals were categorized as high-responders (HR) and low-responders (LR) based on the activity response to an inescapable novel environment. High-responders exhibit increased exploration and proactive behavior while low-responders are less exploratory and deemed to behave more anxiously. We analyzed the effects of the CCK(2) antagonist Ly225.910 (0.1 mg/kg or 0.5 mg/kg, i.p.) on the anxiety displayed by HR and LR rats in the light-dark (LD) box test (Day 1). Treatment and phenotype effects were not acutely evident. LD-experienced rats were then re-exposed to drug-free LD-box (Days 4 and 11) and elevated plus-maze (EPM) test (Day 14). Drug-naïve HR rats behaved less anxiously than drug-naïve LR rats while exploring the open arms. Previous exposure to the antagonist curtailed these differences. The emotional responses in drug-naïve HR and LR rats to the EPM test could reflect different degrees of adaptation to anxiety-like training. Long-term effects of Ly225.910 on EPM-induced risk assessment in HR and LR rats suggest that CCK-system may be involved in modulating preparedness to arousing environmental changes.

Topics: Adaptation, Physiological; Animals; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Male; Maze Learning; Quinazolinones; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Cholecystokinin; Stress, Psychological

Cholecystokinin (CCK) has been implicated in anxiety disorders. The midbrain periaqueductal gray (PAG), which modulates anxiety and panic reactions, contains CCK-immunoreactive fibers and CCK(2) receptors. The present study investigated the involvement of CCK(2) receptors of the PAG dorsolateral subdivision (dlPAG) in the regulation of inhibitory avoidance and escape, two defensive behaviors that have been related in terms of psychopathology to generalized-anxiety and panic disorders, respectively. Male Wistar rats were microinjected in the dlPAG with the CCK(2) receptor agonist cholecystokinin-tetrapeptide (CCK-4; 0.08-0.32 nmol/0.2 microL), the CCK(2) receptor antagonist LY-225910 (0.05-0.20 nmol/0.2 microL) or LY-225910 prior to CCK-4. Inhibitory avoidance and escape behaviors were evaluated in the elevated T-maze. Whereas CCK-4 facilitated escape, indicating a panic-like action, LY-225910 had the opposite effect. Pretreatment with a non-effective dose of LY-225910 prevented the panic-eliciting action of CCK-4. Neither CCK-4 nor LY-225910 affected inhibitory avoidance acquisition. The present results substantiate the view that dlPAG CCK(2) receptors modulate panic-related behaviors.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cholecystokinin; Disease Models, Animal; Exploratory Behavior; Fear; Male; Maze Learning; Motor Activity; Neural Pathways; Panic Disorder; Periaqueductal Gray; Quinazolines; Quinazolinones; Rats; Rats, Wistar; Receptor, Cholecystokinin B; Tetragastrin