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Review

5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators

by
Edmund Przegaliński
1,*,
Kacper Witek
1,
Karolina Wydra
1,
Jolanta H. Kotlińska
2 and
Małgorzata Filip
1
1
Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, Smętna Street 12, 31-343 Krakow, Poland
2
Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodźki Street 4a, 20-093 Lublin, Poland
*
Author to whom correspondence should be addressed.
Nutrients 2023, 15(6), 1449; https://doi.org/10.3390/nu15061449
Submission received: 15 February 2023 / Revised: 9 March 2023 / Accepted: 12 March 2023 / Published: 17 March 2023
(This article belongs to the Special Issue Feature Articles on Obesity and Weight Loss Treatments)
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Abstract

:
Obesity is a substantial health and economic issue, and serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter system involved in the regulation of body weight. The 5-HT2C receptors (5-HT2CRs), one of 16 of the 5-HT receptor (5-HTRs) subtypes, play a significant role in food intake and body weight control. In this review, we focused on the 5-HTR agonists, such as fenfluramines, sibutramine, and lorcaserin, which act directly or indirectly at 5-HT2CRs and have been introduced into the clinic as antiobesity medications. Due to their unwanted effects, they were withdrawn from the market. The 5-HT2CR positive allosteric modulators (PAMs) can be potentially safer active drugs than 5-HT2CR agonists. However, more in vivo validation of PAMs is required to fully determine if these drugs will be effective in obesity prevention and antiobesity pharmacology treatment. Methodology strategy: This review focuses on the role of 5-HT2CR agonism in obesity treatment, such as food intake regulation and weight gain. The literature was reviewed according to the review topic. We searched the PubMed and Scopus databases and Multidisciplinary Digital Publishing Institute open-access scientific journals using the following keyword search strategy depending on the chapter phrases: (1) “5-HT2C receptor” AND “food intake”, and (2) “5-HT2C receptor” AND “obesity” AND “respective agonists”, and (3) “5-HT2C receptor” AND “PAM”. We included preclinical studies (only present the weight loss effects) and double-blind, placebo-controlled, randomized clinical trials published since the 1975s (mostly related to antiobesity treatment), and excluded the pay-walled articles. After the search process, the authors selected, carefully screened, and reviewed appropriate papers. In total, 136 articles were included in this review.

Graphical Abstract

1. Introduction

Overweight and obesity are global epidemics affecting more than 2.5 billion people worldwide. Overweight and obesity are related to a body mass index (BMI) >25 kg/m2 and >30 kg/m2, respectively, and result in substantial health and economic problems. Importantly, obesity is associated with several comorbidities, including chronic diseases, such as diabetes (type 2), cardiovascular pathologies (atherosclerosis, hypertension, and myocardial infarction), stroke, and different kinds of cancers. Thus, obesity is responsible for approximately 15% of human mortality [1]. Therefore, respective medications for obesity are important and are still being investigated in several laboratories.
Serotonin (5-hydroxytryptamine, 5-HT) is a key monoaminergic neurotransmitter in the central nervous system. Mammalian 5-HT is synthesized from the amino acid L-tryptophan by tryptophan hydroxylase to 5-hydroxy-L-tryptophan, and finally by aromatic amino acid decarboxylase enzymes. The 5-HT controls numerous physiological functions, such as thermoregulation, motor activity, wakefulness, cognitive function, and mood [2]. The 5-HT plays a crucial role in food intake modulation and body weight control. In fact, manipulations at a presynaptic level to reduce 5-HT function (e.g., after central administration of 5,7-dihydroxytryptamine, which is a 5-HT neurotoxin) or to enhance 5-HT tone (after 5-hydroxytryptophan, which is the precursor of 5-HT or fenfluramine that releases and inhibits the uptake of 5-HT) provoke an increase or decrease in food intake, respectively [3,4,5].
The multiplicity of 5-HT effects is controlled by a family of 5-HT receptor (5-HTRs) classes, 5-HT1-7R [6]. Preclinical studies using 5-HT2CR knockout demonstrated significantly higher food intake and body weight gain [7,8], while several selective or non-selective 5-HT2CR agonists caused anorectic effects [9]. In addition, the 5-HT2CR antagonist can increase weight gain and food intake [10,11]. This suggests that the 5-HT2CR may be considered the principal therapeutic target of antiobesity drugs among 5-HT signaling.
The 5-HT2CRs are seven transmembrane spanning helices G protein-coupled receptors (GPCRs) with three extracellular, three intracellular loops, and an extracellular amino-terminus. The 5-HT2CRs primarily are distributed postsynaptically in the central nervous system and are especially present in the epithelial cells of the choroid plexus, limbic areas, hippocampal regions, the amygdala, and basal ganglia [12]. The latter receptors are located on neuronal cell types expressed acetylcholine, dopamine, and gamma-aminobutyric acid neurotransmitters. The 5-HT2CRs activate the phospholipase Cβ via Gαq/11 protein and are coupled to phospholipase C in neurons and choroid plexus, and their activation leads to a cellular accumulation of inositol 1,4,5-triphosphate and diglyceride. In addition, 5-HT2CRs have also been shown to regulate ion channels and transport processes as well as activate other downstream effectors [6].
Nowadays, when obesity and overweight are epidemics, the effectiveness of medications is necessary and must be investigated. Whereas the 5-HT system plays a crucial role in food intake and body weight control, 5-HT2CRs are one of the therapeutic targets of antiobesity drugs. Our study aimed to show preclinical research and systematize the obesity treatment efficacy of 5-HT2CR agonists in double-blind, placebo-controlled, and randomized clinical trials. Besides, we focused on the future perspective of newly synthesized pharmaceutical molecules, with 5-HT2CR activity modulation, as a potential antiobesity treatment.

2. 5-HT2C Receptor Action in Food Intake Regulation

The hypothalamus is the most important brain region involved in the central control of feeding and energy expenditure. Within the hypothalamus, the arcuate nucleus controls food intake and metabolism [13]. Functionally, the arcuate nucleus neurons are divided into two antagonistic groups that express specific neuropeptides and elicit disparate physiological actions. The first group consists of orexigenic neurons that express neuropeptide Y and agouti-related peptide to stimulate appetite. The second, anorexigenic group of neurons suppresses appetite with pro-opiomelanocortin (POMC) [14,15]. The modulation of feeding behavior via local 5-HT signaling acts mainly by an anorexigenic effect on POMC neurons. They are controlled by excitatory projections from the raphe nuclei 5-HT-reactive neurons stimulate the POMC-expressing arcuate nucleus neurons [16].
Approximately 25% of adult mouse POMC neurons express the 5-HT2CRs, but activation of POMC neurons via their receptor has been shown to account for the anorexigenic effects of several 5-HT drugs [17]. It has been demonstrated that 5-HT2CRs expressed in hypothalamic POMC/cocaine amphetamine-regulated transcript neurons are required to control energy and glucose homeostasis, implicating POMC neurons as the target for the effect of 5-HT2CR agonists on weight-loss induction and improved glycemic control [6,18]. Moreover, 5-HT2CR activation in POMC neurons both induces the Pomc mRNA expression and increases POMC neuronal activity [19]. Notably, the 5-HT2CR knockout phenotype in POMC neurons provokes hyperphagia, sensitizes mice to diet-induced obesity, and directly dysregulates glucose homeostasis [18]. Moreover, selectively reintroducing the 5-HT2CR to POMC neurons in whole-body 5-HT2CR knockout mice is sufficient to completely negate the knockout phenotype [20]. Finally, 5-HT2CRs re-expression solely in POMC mice neurons is sufficient to mediate the effects of 5-HT drugs on food intake [21].
Food intake is also regulated by the reward brain system (the mesocorticolimbic pathway) structures, such as the ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, and amygdala [22,23]. Changes in reward processing are hypothesized to play a crucial role in the onset and maintenance of binge eating. Binge eating disorder is related to recurrent episodes of frequently consuming unusually large amounts of food and feeling unable to stop eating. Binge eating disorder is also related to its frequent comorbidity, obesity, as well as complications of being overweight [24]. Similar to addictive substances, such as cocaine, food activates the ventral tegmental area–nucleus accumbens pathways and stimulates pleasure by increasing the release of dopamine [25,26]. Moreover, a subset of dopamine neurons of the ventral tegmental area has recently been demonstrated as a key stimulator of binge-like eating behavior in mice [27]. At the same time, 5-HT cell bodies, projecting from the dorsal raphe nuclei to the ventral tegmental area and the nucleus accumbens, and a subset of dopamine and gamma-aminobutyric acid neurons in the ventral tegmental area express the 5-HT2CRs [28,29]. Generally, the activation of 5-HT2CRs plays an inhibitory role in the regulation of reward-related behavior by inhibiting release in certain areas of the brain [30,31]. Activation of ventral tegmental area 5-HT2CR-expressing neurons significantly reduces homeostatic feeding in mice [32].

3. 5-HT2C Receptor Agonists in Control over Food Intake Preclinical Research

Functionally, the 5-HTR agonists are drugs that orthosterically bind to one (=selective agonist) or more (=nonselective agonist) subtypes of 5-HTR. Direct or indirect (through additional mechanisms) 5-HTR activation by agonists provides a similar response to the intended activation by endogenous 5-HT (Table 1). In rodents, the 5-HT2CR agonist drugs reduce food intake in a manner consistent with an enhancement of satiety by action in the 5-HT2CR binding site in the brain hypothalamus.

3.1. Piperazine Derivatives

The first reports showing that the stimulation of 5-HT2CRs is responsible for the reduction of food intake were based on experiments performed with piperazine derivatives (m-chlorophenyl piperazine; m-CPP and tri-fluoromethylphenylpiperazine; TFMPP), which are nonselective 5-HT receptor agonists (Table 1). These compounds reduced food intake in rodents, and such an effect did not appear in mice lacking 5-HT2CRs [7] or in rats pretreated with 5-HT2CR antagonists [37]. It has also been shown that piperazine 5-HT receptor agonists (especially m-CPP) reduce hepatic glucose production and insulin tolerance, and both effects are independent of the reduction in food intake [38]. Other authors presented evidence that the effect of m-CPP and other compounds acting via 5-HT2CRs increases satiety, reduces food intake, does not affect energy expenditure, and decreases body weight [39]. It should also be emphasized that hypophagia, an effect depending on the activation of 5-HT2CRs, is also related to an increase in POMC release in the nucleus arcuatus of the hypothalamus and stimulation of melanocortin receptors in the paraventricular nucleus (PVH) [38,40]. In contrast to the above-mentioned piperazine derivatives, several compounds with different chemical structures that have been previously described are selective 5-HT2CR agonists that reduce food intake in rodents. In fact, Org 37684, Ro 60-175, PNU 22394, VER 3323, YM 348, and WAY 163909 have been found to induce hypophagia, which is reduced or blocked by 5-HT2CR antagonists [37,41,42,43,44]. Interestingly, the hypophagia induced by 5-HT2CR agonists seems to be selective. There is a lack of effect on water intake, and tolerance is not induced after chronic administration. Furthermore, some of these compounds (e.g., PNU 22394) appeared to be clinically active [37].

3.2. Fenfluramines

Acting at the presynaptic level, fenfluramine and d-fenfluramine are indirect agonists of 5-HT receptors (Table 1), among which the 5-HT2CR are mostly required for the antiobesity effect. Accordingly, it has been demonstrated that, in 5-HT2CR knockout mice, the anorexic effect of d-fenfluramine was not induced [21,45]. Furthermore, the hypophagic effect of d-fenfluramine was blocked by 5-HT2CR antagonists [39,46]. Preclinical studies show that low (2.5 or 3 mg/kg) and high (10 mg/kg) doses of fenfluramine or d-fenfluramine reduced food intake and decreased body weight in rat models [47,48,49]. Moreover, in the case of cue-induced relapse, d-fenfluramine (3 mg/kg) blocked the reinstatement of lever pressing to food-seeking behavior in male rats [50].

3.3. Sibutramine

Similar to the antiobesity effect of fenfluramines, another selective inhibitor of presynaptic reuptake of the 5-HT and noradrenaline (NA) is β-phenethylamine—sibutramine (Table 1). Sibutramine action has also been suggested to be connected to the activation of 5-HT2CR and enhancement of POMC [51,52]. Sibutramine (3–10 mg/kg) treatment rats showed reduced food intake and decreased body weight [53,54,55,56,57,58]. Interestingly, intraperitoneal injections of sibutramine (0.5–3.0 mg/kg) reduced feeding on a high fat/high sucrose diet across 2-h feeding sessions, but bilateral injections of sibutramine (2.0–10.0 μg) into either the PVN or the medial nucleus accumbens shell increased the food intake of the sweetened fat diet [59].

3.4. Lorcaserin

A series of new 5-HT2CR agonists, as derivatives of 3-benzazepine, were synthesized by Smith et al. [60]. The most potent and selective compound was (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (APD 356, lorcaserin) (Table 1). The authors performed in vitro (effect on turnover of [3H]phosphoinositol) and in vivo (effect on food intake and body weight after acute or chronic per os administration of lorcaserin) experiments. The results demonstrated its 5-HT2CR selectivity (versus 5-HT2A and 5-HT2B sharing sequence homology) as well as a reduction in food intake after acute administration and reductions in both food intake and body weight after 28 days of treatment. The effect of lorcaserin on food intake has been examined in different animal models of obesity. Some authors used a regular diet [60,61], and other investigators evaluated lorcaserin in rats maintained on a high-fat diet [36,62,63]. Lorcaserin treatment rats (1–2 mg/kg) reduced the percentage of body weight by selective reduction of body fat mass [36,60]. Moreover, Xu et al. performed their experiments using binge-like eating and hunger-driven feeding in mice, where lorcaserin reduced food intake [27]. Lorcaserin also reversed the binge-like feeding observed following stimulation of the nucleus accumbens μ-opioid receptors and blocked nucleus accumbens μ-opioid enhancement of fat intake [64]. The simple antiobesity effect of lorcaserin may be related to the 5-HT2CRs location in brain structures associated with food intake control. It has been shown that the stimulation of such receptors expressed in POMC neurons induces anorexia [20,65], and the stimulation of 5-HT2CRs located on the brain patterning transcription factor single-minded 1 expressing neurons in the PVH increases food intake in mice [66,67].
Other studies showed a reduction in glucose consumption [61] and decreased binge food intake in rats [63] after lorcaserin (1 or 3 mg/kg) treatment. In addition, the above-mentioned antiobesity activity of 5-HT2CR agonists is related to increased satiety and decreased food intake. Such effects of lorcaserin can also be connected with its inhibitory effect on motivation and impulsivity [68]. In some experiments, the effect of lorcaserin on glycemic control has been shown. It reduced the production of glucose and increased the sensitivity to insulin. However, it did not affect the secretion of insulin. The above effects were independent of weight loss [69]. Importantly, single-dose pharmacokinetic studies have shown rapid absorption, high oral bioavailability, and a moderate half-life of lorcaserin [60].

4. Clinical Effects of 5-HT2C Receptor Agonist Drugs

4.1. Fenfluramines

At the beginning of 1970, fenfluramine and d-fenfluramine (an active dextro-rotatory stereoisomer of fenfluramine) were the first antiobesity drugs acting via the 5-HT system to be introduced on the market. In clinical trials, d-fenfluramine showed dose- and time-dependent weight loss (Table 2). In short-term treatment (3–6 months), a higher dose (30–60 mg) of d-fenfluramine led to greater weight loss than low doses (10–15 mg), compared to placebo patients. Long-term treatment (12 months or more) showed greater weight loss in d-fenfluramine patients compared to short-term treatment. Despite the efficacy of fenfluramine or d-fenfluramine in anorexic action, undesirable effects have been observed in obese patients.
In several clinical trials, cardiovascular and heart valve disorders were observed. Echocardiography performed 12 months after the initiation of fenfluramine-phentermine therapy in twenty-four women demonstrated unusual heart valvular morphology and regurgitation in all patients. Moreover, 30% of them also had newly documented pulmonary hypertension [92]. Another study reported that, of 233 obese patients who took appetite suppressants containing d-fenfluramine, 12.7% of them had a prevalence of cardiac valvular insufficiency [93]. Moreover, after the echocardiography of 200 patients with a history of exposure to anorectic medications, significant aortic valve regurgitation was observed in 14% of patients exposed to d-fenfluramine [94].
Other authors showed occurrences of multivalvular disease and pulmonary hypertension after fenfluramine treatment [95,96,97,98]. Nine controlled studies of fenfluramine showed mild or greater aortic valve regurgitation in 9.6% of treated almost 3300 patients compared with 3.9% of 2000 control subjects [99]. Besides the cardiovascular problems, the most common events reported during d-fenfluramine (15 mg twice daily) treatment were diarrhea, asthenia, dry mouth, headache, and tiredness. Side effects were reported significantly more frequently in patients receiving dexfenfluramine 30 mg twice daily than in those receiving 15 mg twice daily [100].
In 1997, fenfluramines were withdrawn from clinical use due to adverse side effects, such as cardiac valvulopathy and pulmonary hypertension. The most likely explanation for fenfluramine-associated valvulopathy is the activation of 5-HT2BRs by norfenfluramine, being a fenfluramine metabolite. Fenfluramines bind weakly to 5-HT2ARs, 5-HT2BRs, and 5-HT2CRs. Norfenfluramine exhibited a high affinity for 5-HT2BRs, and 5-HT2CRs, and a more moderate affinity for 5-HT2ARs [33]. In cells expressing recombinant 5-HT2BRs, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca2+, and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT2BRs. This 5-HT2BRs action is important for heart valvulopathy occurrence. Moreover, the level of 5-HT2BRs and 5-HT2ARs transcripts in heart valves was at least 300-fold higher than the levels of the 5-HT2CR transcript, which were barely detectable [101].

4.2. Sibutramine

Sibutramine was approved by the U.S. Food and Drug Administration (FDA) in 1997 for weight loss in the short- and long-term treatment of obesity. Sibutramine has dose- and time- dependent antiobesity effectiveness, as evidenced in clinical studies (Table 2). Compared to placebo-treated patients, higher doses (15–30 mg) of sibutramine result in greater weight loss than low doses (10 mg). Moreover, sibutramine efficacy in reducing body weight in a long-term period (over one year) was greater than in short-term treatment (six months). However, the Sibutramine Cardiovascular Outcomes (SCOUT) trial showed that, at 12 months but not six months of sibutramine treatment, patients with marked lower baseline blood pressure had the tendency to increase [102]. In some other clinical studies, sibutramine did not increase blood pressure in obese patients [103,104]. Besides, patients taking sibutramine experienced a significant increase in heart rate [83,105,106,107,108,109], but without difference in the overall status of the cardiac valves compared to placebo subjects [105,110,111,112]. Otherwise, sibutramine’s most frequently encountered adverse effects were constipation, dry mouth, headache, insomnia, and nausea.
In 2010, the FDA decided to withdraw sibutramine from the market as a consequence of increased primary outcome events (POEs), such as nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death. Indeed, the risk of POEs was increased by 16% in the sibutramine treatment group as compared with the placebo [80]. Nevertheless, other results from SCOUTs did not show an overall deleterious effect of treatment but an increase in POEs in subjects with a history of cardiovascular disease and type 2 diabetes [113,114]. Unexpectedly, sibutramine therapy in obese or overweight high-risk patients induced significant mean reductions for all blood lipids [115]. Although sibutramine and its metabolites exhibit low affinity for 5-HT1A-BRs and 5-HT2ARs, these receptors are reported as a possible target for the causation of unwanted cardiovascular effects [116].

4.3. Lorcaserin

In 2012, the FDA approved lorcaserin on the market as a weight loss medication. The results of several clinical studies have shown its antiobesity effect (Table 2). Despite the time of treatment, lorcaserin (10 mg once and twice daily) caused greater weight loss than with a placebo. The most commonly reported adverse effects were headache, nausea, dizziness, and fatigue, but generally, lorcaserin was well-tolerated. In contrast, the unwanted effects of fenfluramines and sibutramine, in randomized, double-blind, placebo-controlled, multinational clinical trials of lorcaserin treatment, were not associated with any increase in cardiovascular events among patients with high cardiovascular risk [88]. Interestingly, lorcaserin treatment for 6–13 months showed an improvement in metabolic and cardiovascular parameters in obese patients [91,117,118]. It has also been reported that this drug decreases the risk of developing diabetes [119]. At the same time, compared to a placebo, lorcaserin did not affect blood pressure, heart rate, or heart valves [120,121,122].
However, the US Food and Drug Administration Adverse Event Reporting System (FAERS) database scrutinization identified that lorcaserin medication was associated with a significantly greater valvular disorder [123]. Only in overweight and obese patients with renal dysfunction, lorcaserin treatment barely increased cardiovascular disease risk [124]. At the same time, the results of several clinical studies have shown its modest antiobesity effects, and lorcaserin’s position on the market slowly declined. Moreover, patients treated with lorcaserin were diagnosed with more frequent occurrences of cancer. Indeed, incidences of malignancies during lorcaserin pharmacotherapy (though not different from the respective placebo groups) were the reason that it was withdrawn as an antiobesity medication in 2020 [125,126,127].

5. Positive-Allosteric Modulators of the 5-HT2CR

The 5-HT2CR is not only an antiobesity drug target, but also a binding site for positive-allosteric modulators (PAMs). PAMs are groups of substances that increase the affinity and/or efficacy of respective receptor ligands (Figure 1). A potential PAM therapeutic role is the ability to potentiate the effect of an endogenous cognate ligand or other probes interacting orthosterically by binding at a distinct, allosteric, receptor recognition site [128]. Thereafter, several new molecules related to 5-HT2CR PAMs were pharmacologically evaluated. Recently, there have been a few papers showing 5-HT2CR PAM to be potentially safer antiobesity drugs. Garcia-Carceles et al. [129] screened a chemical library from Vivia Biotech using the ExviTech platform and validated and synthesized analogues of Compound 5 (VA240). Among 35 synthesized akins, the most interesting was Compound 11 (PAM 11: (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012). This compound dose-dependently enhanced 5-HT efficacy (highest potentiation—by 35% at 10 µM—of 5-HT-induced inositol monophosphate release in 5-HT2CR HeLa cells), displayed low binding competition with 5-HT or other orthosteric ligands, and did not exhibit significant off-target activities. Importantly, PAM 11 and WAY 161503 (an agonist of 5-HT2CRs used as a reference drug) were administered acutely to reduce food intake in rats, and PAM 11 acted with higher efficacy and with more prolonged action. Moreover, PAM 11-evoked food intake inhibition was not eliminated after pretreatment with the 5-HT2AR antagonist ketanserin. These findings indicate that the effect of PAM 11 was not related to the activation of 5-HT2ARs and suggest that it has no direct action at the orthosteric site of the 5-HT2CR. Furthermore, PAM 11 administered subchronically (seven days) in a restricted food access model also reduced both food intake and body weight gain in rats. Finally, after combined treatment with PAM 11 and sertraline (a 5-HT reuptake inhibitor) administered in a dose-induced mild feeding suppression, potentiation of feeding reduction was demonstrated. This is clear evidence for the allosteric potentiation of 5-HT-induced anorexia, especially 5-HT2CR-induced anorexia [129]. Another study synthesized a series of N-heterocycle imidazole-linked phenyl cyclopropyl methanone molecules. One of three active 5-HT2CR allosteric modulator molecules, Compound 58, showed unique and beneficial dual characteristics. Compound 58 selectively exhibited PAM response at 5-HT2CRs and negative-allosteric modulator at 5-HT2BRs, which is rarely reported for allosteric modulators. From the point of view of 5-HT2CR agonist’s unwanted cardiovascular effects (depending on 5-HT2BRs activation), the negative 5-HT2BRs modulation is a unique property. Besides, at the same dose, both Compound 58 and lorcaserin reduced food intake in rats [130].

6. Conclusions and Perspectives

This paper reviews the preclinical and clinical efficacy of 5-HT2CR agonists in obesity treatment. Moreover, we showed evidence of new therapeutic molecules, based on 5-HT2CR targets, as potential antiobesity drugs.
In preclinical studies, nonselective or more selective 5-HT2CR agonists showed effectiveness in decreasing body weight, reducing food intake, and inhibiting food seeking-behavior. Consequently, 5-HT2CR drugs, such as fenfluramines, sibutramine, and lorcaserin, were approved in the trade as obesity pharmacology medications. Clinical trials confirmed 5-HT2CR agonist’s action in reduced food intake and decreased body weight in patients with BMI >25 kg/m2 or an ideal body weight of 120–180%. However, after a few years, the 5-HT2CR agonist’s position on the market slowly declined, until being withdrawn from the market due to unwanted effects (higher risk of cardiac valvular abnormalities) occurrence. Nonetheless, the above-mentioned drugs have contributed to understanding the mechanisms of 5-HTR action that permitted the design of new selective molecules. Herein, we showed that 5-HT2CR PAM intensifies 5-HT action for reduced food intake and decreased weight loss in a few in vivo studies. Moreover, we presented selective 5-HT2CR PAM without 5-HT2BR-linked cardiac valve affinity that offers a new angle into the pharmacological potential safer in obesity treatment.
Nowadays, more attention is being paid to precision medicine that offers new grounds for obesity prevention and targeting correct treatment based on genetic, pharmacogenomic, and environmental factors [131,132,133]. Recent human studies underline the connectivity between 5-HT availability and BMI as a predictor of obesity treatment success [134]. Furthermore, the loss of 5-HT2CR function due to mutation can predispose humans to obesity. Thus, sequencing genes encoding the 5-HT2CR should be included in diagnostic panels for obesity [135]. Currently, a series of highly specific 5-HT2CR PAM selectively increase in vitro 5-HT efficacy [136]. This elevates the possibility of 5-HT2CR PAM being used in a more directed way as precision medicine.
In conclusion, we underline the role of 5-HT2CR as a crucial therapeutic target in obesity treatment. Further, 5-HT2CR PAM discovery and syntheses are recommended. Furthermore, 5-HT2CR PAM optimization and clinical weight loss validation are necessary for successful antiobesity treatment and to reveal the full therapeutic potential of PAM.

Author Contributions

Conceptualization and supervision, E.P. and M.F.; methodology, K.W. (Kacper Witek); writing—original draft preparation, E.P., K.W. (Kacper Witek), K.W. (Karolina Wydra), J.H.K. and M.F.; writing—review and editing, E.P. and K.W. (Kacper Witek). All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the statutory fund of the Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Nutrients 15 01449 g001 550
Figure 1. Mechanisms of the 5-HT2CR function modulation by agonists and positive-allosteric modulators (PAMs). The 5-HT2CR agonists bind to the same orthosteric sites as endogenous serotonin (5-HT) at the 5-HT2CR to evoke a response. Opposed to the 5-HT2CR agonists, the 5-HT2CR PAMs bind to allosteric sites at the 5-HT2CR, enhancing the affinity and efficacy of the 5-HT2CR response by 5-HT.
Figure 1. Mechanisms of the 5-HT2CR function modulation by agonists and positive-allosteric modulators (PAMs). The 5-HT2CR agonists bind to the same orthosteric sites as endogenous serotonin (5-HT) at the 5-HT2CR to evoke a response. Opposed to the 5-HT2CR agonists, the 5-HT2CR PAMs bind to allosteric sites at the 5-HT2CR, enhancing the affinity and efficacy of the 5-HT2CR response by 5-HT.
Nutrients 15 01449 g001
Table
Table 1. Description of antiobesity drugs affinity to 5-HT1-2 receptor (5-HT1-2R) subtypes, type of binding and mechanisms of 5-HT2C receptor (5-HT2CR) activation.
Table 1. Description of antiobesity drugs affinity to 5-HT1-2 receptor (5-HT1-2R) subtypes, type of binding and mechanisms of 5-HT2C receptor (5-HT2CR) activation.
DrugAffinity to 5-HT1-2R Subtypes *Selectivity to 5-HT2CRMechanism of 5-HT2CR Activation
piperazine
derivatives
(e.g., m-chlorophenyl piperazine)		5-HT2B ≥ 5-HT2C > 5-HT2A > 5-HT1A ≥ 5-HT1B [33]nonselective
ligand		indirect agonism
(affinity to 5-HT transporter and followed by 5-HT reuptake inhibition or 5-HT release enhancement)
fenfluramines5-HT2B ≥ 5-HT2C > 5-HT2A [34]nonselective
ligand		indirect agonism
(affinity to 5-HT transporter and followed by 5-HT reuptake inhibition)
sibutramine5-HT1A = 5-HT1B = 5-HT2A = 5-HT2C [35]nonselective
ligand		indirect agonism
(affinity to 5-HT transporter and followed by 5-HT reuptake inhibition)
lorcaserin5-HT2C > 5-HT2A > 5-HT2B [36]selective
ligand		direct agonism
* mostly important for food intake and unwanted effects.
Table
Table 2. Efficacy of 5-HT2C receptor agonist properties in double-blind, placebo-controlled, randomized clinical obesity trials. The patient’s inclusion criteria are increased body mass index (BMI; >25 kg/m2) or ideal body weight (IBW; 120–180%). The mean weight loss (kg or %) of the drug group (D) is compared to the placebo group (P). Multicenter studies were marked by an asterisk (*). QD—once-a-day treatment; BID—two times-a-day treatment.
Table 2. Efficacy of 5-HT2C receptor agonist properties in double-blind, placebo-controlled, randomized clinical obesity trials. The patient’s inclusion criteria are increased body mass index (BMI; >25 kg/m2) or ideal body weight (IBW; 120–180%). The mean weight loss (kg or %) of the drug group (D) is compared to the placebo group (P). Multicenter studies were marked by an asterisk (*). QD—once-a-day treatment; BID—two times-a-day treatment.
DrugDosage (mg)Duration (Months)Patients Completed Study
D|P		Key Inclusion Criteria
(BMI > 25 kg/m2 or IBW 120–180%)		Mean Weight Loss
D vs. P (kg or %)		Ref.
d-fenfluramine10 BID385|85 *120–180%2.79 vs. 2.83 kg[70]
15 BID168|169120–180%5.84 vs. 1.85 kg[71]
12|1228–35 kg/m23.1 ± 2.3 vs. 0.1 ± 1.2 kg[72]
12404|418 *≥120%9.82 vs. 7.15 kg[73]
30 QD
or
BID		382|85 *120–180%5.63 vs. 2.83 kg[70]
30|30120–180%4.6 ± 1.6 kg vs. no changed[74]
1236|39≥135%12.8 vs. 8.6 kg[75]
60 BID387|85 *120–180%7.23 vs. 2.83 kg[70]
Sibutramine5 QD219|20130–180%2.9 ± 2.3 vs. 1.4 ± 2.1 kg[76]
356|59 *27–40 kg/m22.4 ± 0.5 vs. 1.4 ± 0.5 kg[77]
6107|87 *30–40 kg/m23.7 vs. 1.3 kg[78]
10 QD359|59 *27–40 kg/m25.1 ± 0.5 vs. 1.4 ± 0.5 kg[77]
699|87 *30–40 kg/m25.7 vs. 1.3 kg[78]
104|94 *≥30 and ≤40 kg/m28.2 vs. 3.9 kg[79]
402933|2825 *25–45 kg/m21.7 vs. +0.7 kg[80]
15 QD362|59 *27–40 kg/m22 4.9 ± 0.5  vs. 1.4 ± 0.5 kg[77]
698|87 *30–40 kg/m27.0 vs. 1.3 kg[78]
12281|80±44 kg/m26.5 ± 0.31 vs. 1.9 ± 0.56 kg[81]
68|64 *>27 kg/m25.5 ± 0.6 vs. 0.2 ± 0.5 kg[82]
~14114|103 *≥30 and <40 kg/m28.1 ± 8.2 vs. 5.1 ± 6.5 kg[83]
20 QD221|20130–180%5.0 ± 2.7 vs. 1.4 ± 2.1[76]
696|87 *30–40 kg/m28.2 vs. 1.3 kg[78]
151|152 *≥27 kg/m24.9 vs. 0.6 kg[84]
1262|64 *>27 kg/m28.0 ± 0.9 vs. 0.2 ± 0.5 kg[82]
30 QD6101|87 *30–40 kg/m29.0 vs. 1.3 kg[78]
Lorcaserin10 QD
or
10 BID		~229|2827–45 kg/m23.8 ± 0.4 vs. 2.2 ± 0.5 kg[85]
386 or 77|88 *30–45 kg/m21.8 or 3.6 vs. 0.3 kg[86]
659|53 *≥33 and ≤55 kg/m22.4 ± 0.8 vs. +0.6 ± 0.8 kg[87]
12748|243 *≥27 kg/m24.2 vs. 1.4 kg[88]
1275 or 169|157 *27–45 kg/m244.7 or 37.5 vs. 16.1%[89]
275|684 *27–45 kg/m25.81 ± 0.16 vs. 2.16 ± 0.14%[90]
131800|155030–45 kg/m247.1 vs. 22.6%[91]
24564|684 *27–45 kg/m27.0 ± 0.2 vs. 3.0 ± 0.2%[90]
40748|243 *≥27 kg/m24.0 kg vs. 2.1 kg[88]
15 QD382|88 *30–45 kg/m22.6 vs. 0.3 kg[86]
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Przegaliński, E.; Witek, K.; Wydra, K.; Kotlińska, J.H.; Filip, M. 5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators. Nutrients 2023, 15, 1449. https://doi.org/10.3390/nu15061449

AMA Style

Przegaliński E, Witek K, Wydra K, Kotlińska JH, Filip M. 5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators. Nutrients. 2023; 15(6):1449. https://doi.org/10.3390/nu15061449

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Przegaliński, Edmund, Kacper Witek, Karolina Wydra, Jolanta H. Kotlińska, and Małgorzata Filip. 2023. "5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators" Nutrients 15, no. 6: 1449. https://doi.org/10.3390/nu15061449

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