TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding.

Objective: Metabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator of metabolic control.

Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity Mouse Model.

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as tool compounds.

Investigation of impulsivity in binge-eating rats in a delay-discounting task and its prevention by the d-amphetamine prodrug, lisdexamfetamine.

Freely-fed, female, rats were trained in a two-lever, delay-discounting task: one lever delivered a single chocolate-flavoured pellet immediately and the other a three-pellet reward after increasing delay (0, 4, 8, 16, 32 s). Rats were divided into two groups (i.e.

Lisdexamfetamine reduces the compulsive and perseverative behaviour of binge-eating rats in a novel food reward/punished responding conflict model.

Compulsive and perseverative behaviour in binge-eating, female, Wistar rats was investigated in a novel food reward/punished responding conflict model. Rats were trained to perform the conditioned avoidance response task. When proficient, the paradigm was altered to a food-associated conflict test by placing a chocolate-filled jar (empty jar for controls) in one compartment of the shuttle box.

A sustained release formulation of novel quininib-hyaluronan microneedles inhibits angiogenesis and retinal vascular permeability in vivo.

Pathologic neovascularisation and ocular permeability are hallmarks of proliferative diabetic retinopathy and age-related macular degeneration. Current pharmacologic interventions targeting VEGF are effective in only 30-60% of patients and require multiple intraocular injections associated with iatrogenic infection. Thus, our goal is to develop novel small molecule drugs that are VEGF-independent are amenable to sustained ocular-release, and which reduce retinal angiogenesis and retinal vascular permeability.

Effects of lisdexamfetamine in a rat model of binge-eating.

Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter.

Characterisation of pain responses in the high fat diet/streptozotocin model of diabetes and the analgesic effects of antidiabetic treatments.

Chronic pain is a common complication of diabetes. The aim of the present study was to characterise pain behaviour in a high fat diet/streptozotocin (HFD/STZ) model of diabetes in the rat, investigate spinal mechanisms, and determine the effects of antidiabetic interventions. Three-week consumption of a high fat diet followed by single injection of STZ (45 mgkg(-1)) produced sustained changes in plasma insulin and glucose until day 120.

Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet.

The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days.

Effect of linagliptin, alone and in combination with voglibose or exendin-4, on glucose control in male ZDF rats.

The effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, alone and in combination with voglibose or exendin-4, on glycaemic control and body weight were assessed in an animal model of type 2 diabetes. Voglibose is an α-glucosidase inhibitor but also increases glucagon-like peptide 1 (GLP-1). Exendin-4 is a GLP-1 receptor agonist.

Effects of the DPP-4 inhibitor, linagliptin, in diet-induced obese rats: a comparison in naive and exenatide-treated animals.

Background: To assess the chronic effect of the DPP-4 inhibitor, linagliptin, alone, in combination with exenatide, and during exenatide withdrawal, in diet-induced obese (DIO) rats.

Methods: Female Wistar rats were exposed to a cafeteria diet to induce obesity. Animals were then dosed with vehicle or linagliptin (3 mg/kg PO) orally once-daily for a 28 day period.

Animal models to explore the effects of CNS drugs on food intake and energy expenditure.

Obesity has reached epidemic proportions globally with an increasing incidence not just in Western cultures but also Mexico, Brazil, China and parts of Africa. In terms of pharmacological intervention, the track record of drug treatments for obesity is poor, especially in the case of centrally acting medicines, and there remains an unmet need for the development of safer compounds delivering superior efficacy. Animal models are of importance not only in detecting changes in food intake, energy expenditure and body weight but also providing confidence that these changes are behaviourally specific and not a result of drug-induced side effects.

The utility of animal models to evaluate novel anti-obesity agents.

The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.

5-(pyridinon-1-yl)indazoles and 5-(furopyridinon-5-yl)indazoles as MCH-1 antagonists.

A new series of 5-(pyridinon-1-yl)indazoles with MCH-1 antagonist activity were synthesized. Potential cardiovascular risk for these compounds was assessed based upon their interaction with the hERG potassium channel in a mini-patch clamp assay. Selected compounds were studied in a 5-day diet-induced obese mouse model to evaluate their potential use as weight loss agents.

Tetrahydrocarboline analogs as MCH-1 antagonists.

A new series of tetrahydrocarbolines with potent MCH-1 antagonist activity were synthesized, using a conformationally constrained design approach towards optimizing pharmacokinetic properties. Two compounds from this series were progressed to a 5-day diet-induced obesity mouse screening model to evaluate their potential as weight loss agents. Both compounds produced a highly significant reduction in weight, which was attributed to their improved pharmacokinetic profile.

Synthesis and SAR of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones as MCH-1 antagonists for the treatment of obesity.

A new series of 4-aryl-1-(indazol-5-yl)pyridin-2(1H)ones possessing MCH-1 receptor antagonism is presented. Suzuki coupling of boronic acids with key triflate 6 allowed rapid generation of a range of analogs. The SAR of the MCH-1 receptor was explored with a variety of aryl and heterocyclic moieties.

Prokineticin 2 is a hypothalamic neuropeptide that potently inhibits food intake.

Objective: Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.

Research Design And Methods: We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody.

Mixed valence Creutz-Taube ion analogues incorporating thiacrowns: synthesis, structure, physical properties, and computational studies.

A series of nine new complexes incorporating [Ru(II)Cl([n]aneS(3))] (n = 12, 14, 16) metal centers bridged by three ditopic ligands containing two monodentate sites (pyrazine, 4,4'-bipyridine, and 3,6-bis(4-pyridyl)-1,2,4,5-tetrazine) have been synthesized and fully characterized. The solid-state structures of three of the complexes have been further characterized by X-ray crystallography studies. Intermetallic interactions within the new systems have been probed using electrochemistry and optical spectroscopy.

A comparison of the effects of the CB(1) receptor antagonist SR141716A, pre-feeding and changed palatability on the microstructure of ingestive behaviour.

Rationale: The cannabinoid CB(1) receptor inverse agonist SR141716A (rimonabant) is known to cause hypophagia and this study uses microstructural data to elucidate the relevant behavioural mechanisms.

Objectives: The aim of these studies was to determine the behavioural changes induced by SR141716A in animals consuming either a fat or carbohydrate solution. These behavioural changes were directly compared with those induced by behavioural manipulations that modify motivational state and palatability.

The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake.

The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss.

Kinetically locked, trinuclear Ru(II) metallo-macrocycles--synthesis, electrochemical, and optical properties.

Using a [Ru(II)([9]aneS3)] templating moiety, kinetically-locked, metallomacrocycles incorporating adenine based ligands have been synthesised through self-assembly. The kinetically robust nature of these structures is confirmed by electrochemical studies: each can be reversibly oxidised in a four-member redox series, containing two formally mixed valence states. Unusually, the electrochemically derived comproportionation constants for these mixed valence states are very different, suggesting that intermetallic coupling differs between the two states.

Structure and properties of Dinuclear [RuII([n]aneS4)] complexes of 3,6-Bis(2-pyridyl)-1,2,4,5-tetrazine.

The synthesis of dinuclear [Ru(II)([n]aneS(4))] (where n = 12, 14) complexes of the bridging ligand 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine are reported. The X-ray structures of both of the new complexes are compared to a newly obtained structure for a dinuclear [Ru(II)([9]aneS(3))]-based analogue, whose synthesis has previously been reported. A comparison of the electrochemistry of the three complexes reveals that the first oxidation of the [Ru(II)([n]aneS(4))]-based systems is a ligand-based couple, indicating that the formation of the radical anion form of the bridging ligand is stabilized by metal center coordination.

Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists.

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported.

The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food.

Rationale: The CB1 receptor antagonist SR141716A reduces food intake in rats. This effect is likely to depend on modulation of reward related processes.

Objective: To investigate the effects of SR141716A on responding for food under a second order instrumental task in which responding and consumption of food can be separated, and on Pavlovian responding for a stimulus predictive of food reward.

Serotonin receptor ligands and the treatment of obesity.

It was first established in the 1970s that the brain serotonin (5-HT) system was involved in the control of eating. Subsequent progress in the molecular pharmacology of 5-HT receptors, and the development of selective 5-HT receptor ligands, has clarified our understanding of the role of 5-HT in the regulation of ingestive behavior. Of the 14 5-HT receptor subtypes currently described, 5-HT1A, 5-HT1B and 5-HT2C receptors have been of principal interest in the regulation of food intake.