Selective 5-HT2C Agonist Research Articles

Current and future drug targets in weight management.

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed.

New horizons for selective 5-HT2C receptor ligands in psychiatric/neurological disorders.

The serotonin (5-HT) 5-HT2C receptor is a key contributor to obesity, autism, psychiatric (eg, depression, schizophrenia), and neurological diseases (eg, Parkinson's disease). The diversity and regulation of the 5-HT2C receptor signaling pathways are complex and provocatively suggest the importance of this receptor in an array of functions and indications. Therapeutic opportunities for both agonist and antagonist compounds that engage this receptor continue to emerge. The most advanced 5-HT2C receptor agonist in development is lorcaserin, which has completed phase III clinical trials and has submitted an NDA for the treatment of obesity (Pauli and Abdelghany, 2010). In a 12-week obesity trial, approximately 30% of patients at 10 mg b.i.d. showed >5% weight loss with lorcaserin with minimal adverse events. Earlier in development is another 5-HT2C receptor agonist vabicaserin for the treatment of psychiatric indications. Vabicaserin is a highly selective 5-HT2C agonist (Dunlop et al, 2010) with a strong preclinical profile supporting multiple indications. Despite initial concerns regarding potential cardiovascular liabilities, selective 5-HT2C agonists are proving to be devoid of these concerning side effects (Pauli and Abdelghany, 2010). Many different genetically modified animals have been created to improve understanding of the 5-HT2C receptor. Much of the early work focused on the 5-HT2C receptor knockout mouse that showed a hyperphagic obesity phenotype. However, the 5-HT2C receptor is subject to RNA editing leading to different forms of the receptor that are more (unedited) or less (fully edited) sensitive to the functional effects of 5-HT2C agonists. Therefore, more recently, transgenic animals have been developed that lock the 5-HT2C receptor into a fully edited (VGV) or an unedited (INI) isoform. Interestingly, animals locked into the fully edited VGV form of the receptor show failure to thrive, neonatal muscular hypotonia, decreased somatic growth, and reduced fat mass despite hyperphagia, characteristics consistent with Prader–Willi syndrome (Kawahara et al, 2008; Morabito et al, 2010). The link between Prader–Willi syndrome and the 5-HT2C receptor has also been made through regulation of the splicing of the 5-HT2C receptor by HBII-52, a small nucleolar RNA that affects 5-HT2C receptor function (Kishore and Stam, 2006). Patients with Prader–Willi syndrome do not express HBII-52 that regulates alternative splicing of the 5-HT2C receptor by binding to a silencing element in exon Vb (Kishore and Stam, 2006). Moreover, these VGV mice have reduced G-protein-coupling efficiency and agonist binding but show enhanced behavioral sensitivity and serotonergic neurotransmission due to increased cell-surface expression of the 5-HT2C receptor (Kawahara et al, 2008; Olaghere da Silva et al, 2010). Interestingly, both the nonedited INI mice and the fully edited VGV mice show anxiety-like phenotypes with the INI mice showing a depressant-like phenotype and the VGV mice showing an antidepressant-like phenotype (Mombereau et al, 2010). Taken together, these transgenic models continue to show the complexity of the regulation of this receptor and the corresponding complexity of phenotypes. The multitude of ways that the 5-HT2C receptor is regulated through different signaling pathways, RNA editing, and changes in receptor expression coupled with its involvement in multiple psychiatric and neurological illness place this receptor as a critical player in the understanding of CNS disorders.

Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT2C agonists for the treatment of metabolic disorders

The discovery of a novel series of 5-HT2C agonists based on a tricyclic pyrazolopyrimidine scaffold is described. Compounds with good levels of in vitro potency and moderate to good levels of selectivity with respect to the 5-HT2A and 5-HT2B receptors were identified. One of the analogues (7g) was found to be efficacious in a sub-chronic weight loss model. A key limitation of the series of compounds was that they were found to be potent inhibitors of the hERG ion channel. Some compounds, bearing polar side chains were identified which showed a much reduced hERG liability however these compounds were sub-optimal in terms of their in vitro potency or selectivity.

Progressos recentes e novas perspectivas em farmacoterapia da obesidade

Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin.

HTS and rational drug design to generate a class of 5-HT(2C)-selective ligands for possible use in schizophrenia.

Treating neurological conditions: Optimization of a previously identified lead 5-HT2C agonist (left) led to the discovery of a highly selective 5-HT2C agonist (right). Importantly, this compound is a 5-HT2B receptor antagonist. Because of its selective 5-HT2C receptor activity, the compound was further evaluated in the phencyclidine model of disrupted prepulse inhibition, and found to exhibit normalizing effects comparable to those shown by the 5-HT2C agonist vabicaserin, a drug currently in phase II clinical studies for schizophrenia.

Sizing Up Pharmacotherapy for Obesity

Obesity has increased over the last 20 years, from a condition affecting only a small portion of populations in developed countries, into a global pandemic.1 The impact of obesity can be appreciated in the context of the populations at risk, and it is estimated that >1 billion adults worldwide are overweight (BMI >25 kg/m2), 300 million of whom are clinically obese (BMI >30 kg/m2).2 In the United States, 65% of adults are overweight, and 32.2% of them are obese, a prevalence that has doubled over 20 years.3 In industrialized countries, obesity rates have tripled, coinciding with adoption of a Western lifestyle.4 Further, the growing worldwide rates of childhood obesity have reached epidemic values in developed countries.5 This global obesity pandemic reflects genetic susceptibility, availability of high-energy foods, and decreased physical activity. Accelerating rates of obesity have profound health and economic consequences. Obesity is associated with a myriad of co-morbidities, including type II diabetes, coronary artery disease, obstructive sleep apnea, stroke, cancer, hypertension, osteoarthritis, and liver and biliary disease which collectively increase mortality.6 Indeed, the health care impact of chronic obesity exceeds that of smoking or alcohol abuse.7 National health care costs of obesity are $70–100 billion, and if this trend continues, in 15 years 20% of health care costs in the United States will be attributed to the chronic diseases associated with obesity.8 Collectively, these considerations underscore the health and economic imperative to develop novel therapeutic approaches to combat obesity and its co-morbidities. In that context, overweight and obese individuals who receive assistance from their health care providers to lose weight are three times more likely to attempt weight loss.9 The most common approach to medical weight management is counseling and lifestyle modification. However, while patients enrolled in these programs initially lose weight, they usually regain 30–35% of their lost weight within one year following treatment, and >50% of patients return to their baseline weight by five years.10, 11 At present, only two drugs, orlistat and sibutramine, are approved for the long-term treatment of obesity. However, due to their inherent cardiovascular and gastrointestinal adverse effects, respectively, these drugs are often only utilized as rescue therapy for patients who fail diet and exercise. The scope of the obesity problem and the absence of available long-term solutions highlights the unmet clinical need for safe and effective pharmacotherapeutics to induce and maintain weight loss.

Orally active and brain permeable proline amides as highly selective 5HT2c agonists for the treatment of obesity

Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered.

Design and synthesis of orally-active and selective azaindane 5HT2c agonist for the treatment of obesity

Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose-responsive in vivo efficacy in our pre-clinical food intake model.

Stimulation of 5-HT2A and 5-HT2C receptors blocks the reward-facilitating effect of cocaine in the rat

Event Abstract Back to Event Stimulation of 5-HT2A and 5-HT2C receptors blocks the reward-facilitating effect of cocaine in the rat Vicky Katsidoni1* and George Panagis1 1 University of Crete, Greece Serotonin (5-HT) appears to play a modulatory role in the behavioral effects of cocaine, although the impact of specific 5-HT receptors in this control has not been fully established. In the present study, the efficacy of selective ligands for the 5-HT2A and 5-HT2C receptors in altering the reward-facilitating effect of cocaine was examined in rats. Male Sprague-Dawley rats were implanted with a monopolar stimulating electrode into the medial forebrain bundle at the level of the lateral hypothalamus. Rate-frequency functions were determined by logarithmically decreasing the number of cathodal pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After brain reward threshold stabilized rats received systemic injections with the selective 5-HT2A agonist TCB-2 (0.3mg/kg), the selective 5-HT2A antagonist R-96544 (0.3mg/kg), the selective 5-HT2C agonist WAY-161503 (0.3mg/kg) and the selective 5-HT2C antagonist SB-242084 (0.5mg/kg), followed by acute administration of cocaine (5mg/kg). Systemic injections of the 5-HT2A and 5-HT2C agonists blocked the reward-facilitating effect of cocaine. These effects were reversed by pretreatment with selective 5-HT2A and 5-HT2C antagonists, respectively. Interestingly, the 5-HT2C antagonist appeared to act synergistically with cocaine increasing further its reward-facilitating effect. To the contrary, the 5-HT2A antagonist did not have an effect. The present data support the hypothesis that serotonin through 5-HT2A and 5-HT2C receptors exerts an inhibitory influence on the reward-facilitating effect of cocaine. Intracranial microinjections of these drugs into specific brain regions of the mesocorticolimbic dopaminergic system expressing high levels of 5-HT2A and 5-HT2C receptors could reveal the specific neuroanatomical substrate of the present actions. Supported by a grant from the Research Committee of the University of Crete (KA 2581) Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Katsidoni V and Panagis G (2009). Stimulation of 5-HT2A and 5-HT2C receptors blocks the reward-facilitating effect of cocaine in the rat. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.187 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 10 Jun 2009; Published Online: 10 Jun 2009. * Correspondence: Vicky Katsidoni, University of Crete, Crete, Greece, panagis@uoc.gr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Vicky Katsidoni George Panagis Google Vicky Katsidoni George Panagis Google Scholar Vicky Katsidoni George Panagis PubMed Vicky Katsidoni George Panagis Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Stimulation of serotonin2C receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats

It has been suggested that the increase in serotonin transmission induced by indirect agonists such as fenfluramine and fluoxetine attenuates cue-elicited reinstatement of cocaine-seeking in rats through a 5-HT2C receptor-dependent mechanism. We investigated whether Ro 60-0175, a nonselective 5-HT2B-2C agonist, influences cue-elicited reinstatement of cocaine-seeking behavior. We evaluated the 5-HT2C receptor's role in Ro 60-0175 by studying its interaction with SB-242,084, a selective 5-HT2C antagonist. The study also explored whether Ro 60-0175 influences cue-elicited seeking behavior associated with sucrose, a highly palatable nutritive reinforcer. Different groups of free-feeding rats were trained to associate discriminative stimuli (SDs) with the availability of cocaine or a sucrose pellet or no-reward in two-lever operant cages. Cocaine and sucrose pellets were available under an FR1 schedule of reinforcement, and each reinforcer was followed by a 20-s timeout signaled by a cue light coming above the active lever. After extinction of reinforced responding in the absence of cue, the reinforcer-associated stimuli were reintroduced in reinstatement sessions in which reinforcers were withheld. Ro 60-0175, at IP doses from 0.1 to 1 mg/kg, dose-dependently reduced cocaine-seeking behavior, while 1 mg/kg had no such effect for the sucrose pellet. Pretreatment with 1 mg/kg SC SB-242,084 completely prevented the effect on cocaine-seeking behavior. These findings, provided they can be extrapolated to abstinent human addicts, suggest therapeutic potential for the selective 5-HT2C agonist in preventing cue-controlled cocaine-seeking and relapse.

Discovery of (R)-9-Ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a Selective, Orally Active Agonist of the 5-HT2CReceptor

Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.

5-HT receptor subtypes involved in the anxiogenic-like action and associated Fos response of acute fluoxetine treatment in rats

We have recently reported that acute treatment with the selective serotonin reuptake inhibitor fluoxetine exacerbates escape responses to airjet and facilitates airjet-induced activation of locus coeruleus (LC) neurons. Here we aimed to identify the 5-HT receptor subtype(s) mediating the anxiogenic-like effects of acute fluoxetine in this paradigm and to study whether chronic fluoxetine treatment would alter these responses. The expression of the immediate early gene c-fos was used as a marker of neuronal activation. Acute fluoxetine increased the airjet-induced escape behaviour and Fos expression in the LC of saline-pretreated rats. Pretreatment with the 5-HT(2C/2B) antagonist SB 206553, but not with the 5-HT1A antagonist WAY 100635, the 5-HT1B antagonist SB 224289 or the 5-HT3 antagonist Y-25130 inhibited the fluoxetine-induced increase in escape behaviour and the associated elevated LC Fos response. The selective 5-HT2C agonist MK-212 mimicked the anxiogenic response of fluoxetine. Chronic treatment with fluoxetine abolished the anxiogenic-like effect and led to a normalization of the enhanced fluoxetine-induced Fos response to airjet. Taken together, the results indicate that the anxiogenic-like effect as well as the facilitated neuronal reactivity induced by acute fluoxetine in the airjet model is mediated primarily by activation of 5-HT2C receptors.

The potential use of selective 5-HT2C agonists in treating obesity

Activation of central 5-HT2C receptors as a strategy for appetite suppression and weight control is supported by animal pharmacology and human clinical studies. Considerable evidence comes from the weight-loss effects of fenfluramine, a non-selective 5-HT2C agonist. Advances in molecular pharmacology have led to an understanding of the effects of 5-HT2C receptor activation on food intake and satiety, in addition to providing insight into the causes of cardiac valvular insufficiency and pulmonary hypertension associated with the use of fenfluramine. However, clinically validated animal models of drug-induced disease and knowledge of the molecular mechanisms of these safety issues is lacking. For this reason, the development of selective 5-HT2C agonists for the treatment of obesity has remained a challenge.

SAR of Psilocybin Analogues: Discovery of a Selective 5‐HT2C Agonist.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Multiple serotonin receptors: opportunities for new treatments for obesity?

Recent progress in the molecular pharmacology of 5-HT receptors and the development of selective ligands for various 5-HT receptor subtypes has advanced our understanding of the role of 5-HT mechanisms in the control of food intake and bodyweight. The most intensively investigated 5-HT receptor subtypes have been the 5-HT1A receptor, the 5-HT1B receptor and the 5-HT2C receptor. The overall pattern of results to date suggests that selective 5-HT2C agonists may be novel anorectic drugs and prove useful in the treatment of obesity. However, a number of issues remain unresolved, particularly regarding potential side-effects, as the 5-HT2C receptor agonist mCPP has been reported to induce anxiety and nausea in humans, actions that would clearly limit its therapeutic utility. In addition, the possible role of recently cloned 5-HT receptor subtypes such as 5-ht5, 5-ht6 and 5-ht7, remains unexplored and the development of selective ligands for these sites has the potential to lead to new treatments for obesity.