mdl-100907 and Obesity

Second generation antipsychotics (SGAs), notably atypical antipsychotics including olanzapine, clozapine and risperidone, can cause weight gain and obesity side effects. Antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling have been identified as a main cause of SGA induced obesity. Here we review the pivotal regulatory role of the 5-HT2cR in ghrelin-mediated appetite signalling. The 5-HT2cR dimerizes with GHSR1a to inhibit orexigenic signalling, while 5-HT2cR antagonism reduces dimerization and increases GHSR1a-induced food intake. Dimerization is specific to the unedited 5-HT2cR isoform. 5-HT2cR antagonism by SGAs may disrupt the normal inhibitory tone on the GHSR1a, increasing orexigenic signalling. The 5-HT2cR and its interaction with the GHSR1a could serve as the basis for discovering novel approaches to preventing and treating SGA-induced obesity.

Topics: Antipsychotic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Obesity; Protein Binding; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Serotonin 5-HT2 Receptor Antagonists; Weight Gain

Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed. Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient-specific therapy.

Topics: Anti-Obesity Agents; Benzazepines; Delayed-Action Preparations; Humans; Medication Adherence; Obesity; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists; Weight Loss

Serotonin or 5-hydroxytryptamine (5-HT) is a substance found in plasma, which increases smooth muscle contraction and mediates platelet aggregation. In addition, it is a monoamine neurotransmitter and is implicated in diverse behaviors. The serotonin receptor 2 (5-HT2) subfamily is best known for biased signaling and is strongly expressed mainly in the brain regions postulated to be involved in the modulation of higher cognitive and affective functions. Modulators of the 5-HT2 receptor are currently used to treat a variety of diseases including chronic pain and psychonosema. These properties suggest that 5-HT2 receptors may become an important therapeutic target for the treatment of various pathological conditions.. This review highlights the significant progress that has been made in the discovery and development of 5-HT2 receptor agonists and antagonists based on an analysis of the patent literature between January 2004 and December 2014.. Cumulative evidence over the past decade supports the notion that the modulation of 5-HT2 receptors has a positive effect on human cognition and emotion. Therefore, we suggest that new agonists and antagonists may play an important role in the treatment of disorders such as schizophrenia, addiction and obesity.

Topics: Animals; Drug Design; Humans; Obesity; Patents as Topic; Receptors, Serotonin, 5-HT2; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Substance-Related Disorders

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT2C and 5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.

Topics: Benzazepines; Diabetes Mellitus, Type 2; Heart Valve Diseases; Humans; Molecular Structure; Obesity; Parkinson Disease; Piperidines; Receptors, Serotonin; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Urea

Serotonin 2C receptors are G protein-coupled receptors expressed by GABAergic, glutamatergic, and dopaminergic neurons. Anatomically, they are present in various brain regions, including cortical areas, hippocampus, ventral midbrain, striatum, nucleus accumbens, hypothalamus, and amygdala. A large body of evidence supports a critical role of serotonin 2C receptors in mediating the interaction between serotonergic and dopaminergic systems, which is at the basis of their proposed involvement in the regulation of mood, affective behavior, and memory. In addition, their expression in specific neuronal populations in the hypothalamus would be critical for their role in the regulation of feeding behavior. Modulation of these receptors has therefore been proposed to be of interest in the search for novel pharmacological strategies for the treatment of various pathological conditions, including schizophrenia and mood disorders, as well as obesity. More precisely, blockade of serotonin 2C receptors has been suggested to provide antidepressant and anxiolytic benefit, while stimulation of these receptors may offer therapeutic benefit for the treatment of psychotic symptoms in schizophrenia and obesity. In addition, modulation of serotonin 2C receptors may offer cognitive-enhancing potential, albeit still a matter of debate. In the present review, the most compelling evidence from the literature is presented and tentative hypotheses with respect to existing controversies are outlined.

Topics: Animals; Cognition; Humans; Mood Disorders; Obesity; Receptor, Serotonin, 5-HT2C; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction

Topics: Animals; Anti-Obesity Agents; Antipsychotic Agents; Drug Design; Humans; Ligands; Mental Disorders; Obesity; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Structure-Activity Relationship

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT

Topics: Ergotamine; HEK293 Cells; Humans; Obesity; Protein Domains; Receptor, Serotonin, 5-HT2C; Ritanserin; Schizophrenia; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Structure-Activity Relationship; Substance-Related Disorders

Although 5-HT2A serotonergic antagonists have been used to treat vascular disease in patients with diabetes mellitus or obesity, their effects on leukocyte-endothelial interactions have not been fully investigated. In this study, we assessed the effects of sarpogrelate hydrochloride (SRPO), a 5-HT2A receptor inverse agonist, on leukocyte-endothelial cell interactions in obesity both in vivo and in vitro.. In the in vivo experiment, C57BL/6 mice were fed a high-fat high-fructose diet (HFFD), comprising 20% fat and 30% fructose, with or without intraperitoneal injection of 5 mg/kg/day SRPO for 4 weeks. The body weight, visceral fat weight, and serum monocyte chemoattractant protein-1 levels in the mice increased significantly with the HFFD, but these effects were prevented by chronic injections of SRPO. Intravital microscopy of the femoral artery detected significant leukocyte-endothelial interactions after treatment with HFFD, but these leukocyte-endothelial interactions were reduced in the mice injected with SRPO. In the in vitro experiment, pre-incubation of activated human umbilical vein endothelial cells (HUVECs) with platelet-rich plasma (PRP) induced THP-1 cell adhesion under physiological flow conditions, but the adhesion was reduced by pretreatment of PRP with SRPO. A fluorescent immunobinding assay showed that PRP induced significant upregulation of E-selectin in HUVECs, but this upregulation was reduced by pretreatment of PRP with SRPO. In other in vitro conditions, pre-incubation of THP-1 cells with phorbol 12-myristate 13-acetate increased the adhesion of THP-1 cells to activated HUVECs under rotational conditions, but this adhesion was reduced by pretreatment with SRPO. Western blotting analysis showed that protein kinase C α activation in THP-1 cells was inhibited by SRPO.. Our findings indicated that SRPO inhibits vascular inflammation in obesity via inactivation of platelets and leukocytes, and improvement of obese.

Topics: Animals; Cell Adhesion; Cell Communication; Cell Line; Endothelial Cells; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Inflammation; Leukocytes; Male; Mice, Inbred C57BL; Obesity; Serotonin 5-HT2 Receptor Antagonists; Succinates

Since the worldwide increase in obesity represents a growing challenge for health care systems, new approaches are needed to effectively treat obesity and its associated diseases. One prerequisite for advances in this field is the identification of genes involved in adipogenesis and/or lipid storage. To provide a systematic analysis of genes that regulate adipose tissue biology and to establish a target-oriented compound screening, we performed a high throughput siRNA screen with primary (pre)adipocytes, using a druggable siRNA library targeting 7,784 human genes. The primary screen showed that 459 genes affected adipogenesis and/or lipid accumulation after knock-down. Out of these hits, 333 could be validated in a secondary screen using independent siRNAs and 110 genes were further regulated on the gene expression level during adipogenesis. Assuming that these genes are involved in neutral lipid storage and/or adipocyte differentiation, we performed InCell-Western analysis for the most striking hits to distinguish between the two phenotypes. Beside well known regulators of adipogenesis and neutral lipid storage (i.e. PPARγ, RXR, Perilipin A) the screening revealed a large number of genes which have not been previously described in the context of fatty tissue biology such as axonemal dyneins. Five out of ten axonemal dyneins were identified in our screen and quantitative RT-PCR-analysis revealed that these genes are expressed in preadipocytes and/or maturing adipocytes. Finally, to show that the genes identified in our screen are per se druggable we performed a proof of principle experiment using an antagonist for HTR2B. The results showed a very similar phenotype compared to knock-down experiments proofing the "druggability". Thus, we identified new adipogenesis-associated genes and those involved in neutral lipid storage. Moreover, by using a druggable siRNA library the screen data provides a very attractive starting point to identify anti-obesity compounds targeting the adipose tissue.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Cell Differentiation; DNA; Dyneins; Gene Expression Profiling; Gene Expression Regulation; Humans; Lipids; Models, Biological; Obesity; Oligonucleotide Array Sequence Analysis; Phenotype; Quality Control; RNA, Small Interfering; Serotonin 5-HT2 Receptor Antagonists

Knowledge of the regulatory factors associated with down-regulation of adiponectin gene expression and up-regulation of PAI-1 gene expression is crucial to understand the pathophysiological basis of obesity and metabolic diseases, and could establish new treatment strategies for these conditions. We showed that expression of 5-HT(2A) receptors was up-regulated in hypertrophic 3T3-L1 adipocytes, which exhibited decreased expression of adiponectin and increased expression of PAI-1. 5-HT(2A) receptor antagonists and suppression of 5-HT(2A) receptor gene expression enhanced adiponectin expression. Activation of Gq negatively regulated adiponectin expression, and inhibition of mitogen-activated protein kinase reversed the Gq-induced effect. Moreover, the 5-HT(2A) receptor blockade reduced PAI-1 expression. These findings indicate that antagonism of 5-HT(2A) receptors in adipocytes could improve the obesity-linked decreases in adiponectin expression and increases in PAI-1 expression.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adiponectin; Adipose Tissue; Animals; Gene Expression; Male; Mice; Mice, Inbred C57BL; Obesity; Plasminogen Activator Inhibitor 1; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction

5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.

Topics: Aminopyridines; Animals; Behavior, Animal; Benzazepines; Body Weight; Brain; Cell Line; Dopamine; Eating; Fluorobenzenes; Humans; Indoles; Male; Norepinephrine; Obesity; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Recombinant Proteins; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Transfection

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A(y) mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration of sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A(y) mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A(y) mice, but did not increase plasma adiponectin levels.

Topics: Adiponectin; Animals; Appetite; Body Weight; Eating; Gene Expression; Hypothalamus; Male; Mice; Mice, Obese; Nerve Tissue Proteins; Neuropeptide Y; Obesity; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Corticotropin-Releasing Hormone; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates