lorcaserin and Disease-Models--Animal

Lorcaserin, a selective serotonin 5-HT

Topics: Animals; Anticonvulsants; Benzazepines; Disease Models, Animal; Drug Development; Epilepsies, Myoclonic; Humans; Risk Assessment; Serotonin 5-HT2 Receptor Agonists

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

Topics: Animals; Benzazepines; Disease Models, Animal; Ethylamines; Fenfluramine; Indoles; Mice; Piperazines; Pyrazines; Rats; Receptor, Serotonin, 5-HT2C; Seizures; Serotonin 5-HT2 Receptor Agonists; Treatment Outcome

The serotonin (5-HT2c) receptor is known to be involved in the mechanism of urethral closure in a model of stress incontinence. Lorcaserin (Belviq®) has received Food and Drug Administration approval for the treatment of obesity. However, it is unclear whether this selective 5-HT2c receptor agonist enhances urethral closure in stress urinary incontinence (SUI) models. Therefore, we investigated whether lorcaserin could enhance urethral closure in female rats with vaginal distention (VD).. Normal female rats and rats with stress incontinence induced by VD were tested. We evaluated the effect of a single dose of lorcaserin (0.03, 0.3, or 0.9 mg/kg with cumulative administration) on the urethral pressure amplitude during electrical stimulation (A-URE) and on the urethral baseline pressure (UBP). The manual compression-induced leak point pressure (LPP) was also measured.. In VD rats, a single intravenous injection of lorcaserin (0.3 and 0.9 mg/kg) significantly increased both A-URE and LPP compared to saline (P < 0.05). In normal rats, intravenous lorcaserin (0.3 and 0.9 mg/kg) also significantly increased A-URE and LPP compared to saline (P < 0.05). The changes of A-URE and LPP, which are parameters of active urethral closure, were significantly larger in normal rats than in VD rats.. We showed that lorcaserin can activate the external urethral sphincter and pelvic floor muscles, suggesting an influence on active closure mechanisms. 5-HT2c receptors agonists may have dual effects in patients with SUI, not only by reducing obesity but also by enhancing active urethral closure.

Topics: Animals; Benzazepines; Dilatation; Disease Models, Animal; Electric Stimulation; Female; Injections, Intravenous; Pelvic Floor; Pressure; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Agonists; Urethra; Urinary Incontinence, Stress; Vagina

Cocaine use disorder is a serious public health issue for which there is no effective pharmacotherapy. One strategy to speed development of medications for cocaine use disorder is to repurpose drugs already approved for use in humans based on their ability to interact with targets known to be important for addiction. Two such drugs, lorcaserin (Belviq; a drug with serotonin [5-HT]2C receptor agonist properties) and buspirone (Buspar; a drug with 5-HT1A receptor partial agonist and dopamine D3/D4 receptor antagonist properties) can produce modest decreases in cocaine self-administration in rhesus monkeys. The current study evaluated the effectiveness of mixtures of lorcaserin and buspirone (at fixed dose ratios of 3:1, 1:1, and 1:3 relative to each drug's ID50) to reduce responding for 0.032 mg/kg/inf cocaine under a progressive ratio schedule of reinforcement in 2 male and 2 female rhesus monkeys. Dose addition analyses were used to determine if the effects of the drug mixtures differed from those predicted for an additive interaction between lorcaserin and buspirone. Dose-dependent reductions of cocaine self-administration were observed when lorcaserin and buspirone were administered alone, as well as when they were administered as 3:1, 1:1, and 1:3 fixed ratio mixtures of lorcaserin + buspirone. The effects of the 1:1 mixture of lorcaserin + buspirone on cocaine self-administration were supraadditive, whereas the effects of 3:1 and 1:3 mixtures were additive. Together, these results indicate that a combination therapy containing a mixture of lorcaserin and buspirone might be more effective than either drug alone at treating cocaine use disorder. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Topics: Animals; Behavior, Addictive; Benzazepines; Buspirone; Cocaine; Cocaine-Related Disorders; Disease Models, Animal; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Combinations; Female; Macaca mulatta; Male; Serotonin Receptor Agonists

Topics: Animals; Anti-Obesity Agents; Anticonvulsants; Benzazepines; Benzimidazoles; Disease Models, Animal; Drug Discovery; Epilepsies, Myoclonic; High-Throughput Screening Assays; Humans; United States; United States Food and Drug Administration; Zebrafish

The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT. Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control.. Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R. These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

Topics: Animals; Benzazepines; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Disease Models, Animal; Eating; Energy Metabolism; Glucose; Glucose Tolerance Test; Homeostasis; Humans; Insulin Resistance; Melanocortins; Mice; Mice, Transgenic; Obesity; Receptor, Serotonin, 5-HT2C; Receptors, Melanocortin; Weight Loss

Dravet syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics. We demonstrate that clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways e.g. trazodone and lorcaserin. Coincident with these zebrafish findings, we treated five medically intractable Dravet syndrome patients with a clinically-approved serotonin receptor agonist (lorcaserin, Belviq®) and observed some promising results in terms of reductions in seizure frequency and/or severity. Our findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet syndrome.

Topics: Adolescent; Animals; Animals, Genetically Modified; Anticonvulsants; Benzazepines; Benzimidazoles; Child; Disease Models, Animal; Epilepsies, Myoclonic; Female; Gene Expression Regulation, Developmental; Humans; Larva; Male; NAV1.1 Voltage-Gated Sodium Channel; Protein Binding; Receptors, Serotonin; Seizures; Serotonin; Signal Transduction; Treatment Outcome; Zebrafish

Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT(2C) receptor (5-HT(2C)R) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT(2C)R agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT(2C)R activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT(2C)R agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT(2C)R antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT(2C)R protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT(2C)R can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT(2C)R may represent a new avenue for the treatment of opioid addiction.

Topics: Aminopyridines; Analgesics, Opioid; Animals; Benzazepines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Indoles; Locomotion; Male; Mice; Mice, Inbred Strains; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Reaction Time; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Substance Withdrawal Syndrome; Time Factors

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety-depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.

Topics: Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Chickens; Depression; Disease Models, Animal; Humans; Monoamine Oxidase; Protein Binding; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Structure-Activity Relationship; Tryptophan

Compared to the general population, individuals with psychiatric illness, especially serious and chronic mood and psychotic disorders, are more likely to be overweight or obese, have higher rates of weight-related medical conditions, and have greater non-suicide mortality rates. Lorcaserin (Belviq(®)), phentermine/topiramate combination (Qsymia(®)), and bupropion/naltrexone combination have been demonstrated to be effective for the treatment of obesity, as an adjunct to a reduced-calorie diet and physical activity, although their absolute safety has yet to be established with more widespread use or longer use. Bariatric surgery is an effective approach for morbid obesity, but careful psychiatric assessment before and follow up after surgery is necessary. Behavioral lifestyle interventions to promote weight loss are effective and should be implemented along with or instead of drug therapies or surgery.

Topics: Animals; Appetite Depressants; Bariatric Surgery; Benzazepines; Bupropion; Chronic Disease; Combined Modality Therapy; Diet, Reducing; Disease Models, Animal; Drug Combinations; Exercise; Fructose; Humans; Mood Disorders; Naltrexone; Obesity; Overweight; Phentermine; Psychotic Disorders; Randomized Controlled Trials as Topic

New pyrimido[4,5-d]azepines 7 are disclosed as potent 5-HT(2C) receptor agonists. A preferred example, 7b had minimal activation at either the 5-HT(2A) or 5-HT(2B) receptors combined with robust efficacy in a preclinical canine model of stress urinary incontinence (SUI) and attractive pharmacokinetic and safety properties. Based on this profile, 7b (PF-3246799) was identified as a candidate for clinical development for the treatment of SUI. In addition, it proved to be critical to build an understanding of the translation between recombinant cell-based systems, native tissue preparations and in vivo preclinical models. This was a significant undertaking and proved to be crucial in compound selection.

Topics: Animals; Azepines; Disease Models, Animal; Dogs; Male; Molecular Structure; Pyrimidines; Rats; Serotonin 5-HT2 Receptor Agonists; Urinary Incontinence

We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model.

Topics: Animals; Benzazepines; Cell Line; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Humans; Male; Molecular Structure; Obesity; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Agonists; Structure-Activity Relationship