Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility.

Rationale: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity.

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.

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.

Metabolic consequences of antipsychotic therapy: preclinical and clinical perspectives on diabetes, diabetic ketoacidosis, and obesity.

Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs.

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.

Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels.

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg⁻¹·day⁻¹) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed.

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.

MTSEA prevents ligand binding to the human melanocortin-4 receptor by modification of cysteine 130 in transmembrane helix 3.

We have investigated the effect of the sulfhydryl-reactive reagent, methyl thiosulfonate ethylammonium (MTSEA), on ligand binding to the human melanocortin-4 (MC4) receptor stably expressed in HEK-293 cells. MTSEA inhibited binding of the agonist, 125I-NDPalpha-MSH, and the antagonist, 125I-SHU9119, in a concentration-dependent manner. Pre-incubation of cells with either the agonist or antagonist protected from subsequent MTSEA inhibition of radioligand binding.

The monoamine reuptake inhibitor BTS 74 398 fails to evoke established dyskinesia but does not synergise with levodopa in MPTP-treated primates.

Long-term treatment of Parkinson's disease (PD) with levodopa (L-dopa) induces dyskinesia that, once established, is provoked by each dose of L-dopa or a dopamine (DA) agonist. In contrast, monoamine reuptake inhibitors may reverse motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates without provoking established involuntary movements. We now examine whether the potent monoamine reuptake blocker BTS 74 398 induces established dyskinesia in MPTP-treated common marmosets primed previously with L-dopa and whether co-administration of BTS 74 398 with L-dopa potentiates motor behaviour and dyskinesia induced by acute L-dopa treatment.

Dopamine, but not norepinephrine or serotonin, reuptake inhibition reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates.

Monoamine reuptake inhibitors that do not discriminate between the transporters for dopamine (DA), norepinephrine (NE), or 5-hydroxytryptamine (5-HT, serotonin) can reverse locomotor deficits and motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. DA reuptake inhibition is presumed to be primarily responsible, but the role played by inhibition of NE and 5-HT reuptake is unknown. We now evaluate the efficacy of a range of monoamine reuptake inhibitors either alone or in combination in MPTP-treated common marmosets to determine the actions required for effective antiparkinsonian activity.

Dopamine reuptake inhibition and failure to evoke dyskinesia in MPTP-treated primates.

Nonspecific monoamine reuptake inhibitors reverse motor abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets without evoking established dyskinesia. However, it is not known whether dopamine reuptake inhibition alone explains these actions or whether noradrenaline and/or serotonin reuptake blockade also contributes. L-DOPA (12.