From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists

doi:10.1016/j.tips.2013.08.001

Trends in Pharmacological Sciences

Volume 34, Issue 10, October 2013, Pages 560-570

https://doi.org/10.1016/j.tips.2013.08.001 Get rights and content

Highlights

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We propose drug abuse/addiction as a therapeutic target for 5-HT_2C receptor agonists.
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5-HT_2C agonists may exert anti-obesity and anti-addictive effects via shared loci.
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Lorcaserin is a candidate drug in for example smoking-cessation proof-of-concept studies.
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The challenges to conducting such clinical studies are considered.

The recent US Food and Drug Administration (FDA) approval of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT_2C receptor agonist lorcaserin for the treatment of obesity represents a new therapeutic drug class available to the clinic. Preclinical evidence supports the potential for this drug class to treat other related conditions such as substance abuse. In the present article we review this evidence and further suggest that overlapping neurobiological systems may contribute to an anti-addictive and anti-obesity profile. The availability of selective 5-HT_2C agonists provides an opportunity to evaluate their potential as treatments for nicotine dependence or psychostimulant abuse, conditions for which there is significant medical need but only limited available treatment options.

Section snippets

Central serotonin signaling as a therapeutic target

Drugs modulating central 5-HT systems have made a major impact on the treatment of mental health. For example, in 2000 the top five selling central nervous system (CNS) drugs had a modulatory effect on 5-HT function as a recognized part of their mechanism of action [1]. The latest serotonergic therapeutic to reach market – lorcaserin (Lorqess; Belviq®) – was approved by the FDA in 2012 for the treatment of obesity. Lorcaserin is a selective 5-HT_2C receptor agonist, and this drug class has also

Characteristics of the 5-HT_2C receptor

A combination of techniques from pharmacology and molecular biology has provided the framework for the current 5-HT receptor classification scheme which has essentially remained unchanged since 1994 [19]. Fourteen receptor subtypes have been identified, with the three members of the 5-HT₂ subclass (5-HT_2A, 5-HT_2B, 5-HT_2C) characterized by close sequence homology and coupling primarily via the Gq family of G proteins to intracellular signaling pathways such as phospholipase C (PLC) and

Preclinical biology of the 5-HT_2C receptor relating to food and drug motivated behaviors

Given the long-held view that 5-HT is an excellent target candidate for treating obesity, a major research goal has been to identify the mechanisms by which 5-HT_2C receptor agonists alter food intake regulation and energy metabolism. In parallel, a significant effort has been directed towards investigating how 5-HT_2C receptor-mediated neurotransmission modulates forebrain dopamine (DA) systems and their associated networks, which in turn has stimulated interest in determining how manipulating

Clinical experience with 5-HT_2C agonists

Lorcaserin is the most advanced 5-HT_2C receptor agonist, and was approved by the FDA for treatment of obesity in June, 2012. Approval was largely based on outcomes from three Phase III trials of 1–2 year duration, each of which included a dose arm of 10 mg b.i.d. involving a total patient population of 7789. A meta-analysis of these data identified a 3.32 kg weight loss compared to placebo, and a reduction in body-mass index (BMI) of 1.16 kg/m [73]. Benefits on secondary outcome measures including

Opportunities to evaluate lorcaserin for smoking cessation and psychostimulant abuse

Given that 5-HT_2C receptor agonists reduce the behavioral, neurochemical, and electrophysiological effects of nicotine and cocaine, this raises the issue of whether these findings translate to humans. Some of the preclinical findings in cocaine models suggest that 5-HT_2C receptor agonists may be of benefit for the treatment of psychostimulant dependence. Because there are no approved medications for long-term reduction of cocaine dependence, this need is pressing 80, 81. A major clinical

Concluding remarks

Preclinical evidence from behavioral, neurochemical, electrophysiological, and anatomical sources supports a significant modulatory effect of 5-HT_2C receptors on forebrain DA systems that may translate into a therapeutic potential for 5-HT_2C receptor agonists to serve as therapies for drug abuse and addiction. However, there is a major challenge to translate these encouraging preclinical observations into the clinic, although the medical need for effective therapies to treat psychostimulant and

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Serotonin is a neurotransmitter regulating numerous physiological processes also modulated by drugs, for example, schizophrenia, depression, migraine, and obesity. However, these drugs typically have adverse effects caused by promiscuous binding across 12 serotonin and more than 20 homologous receptors. Recently, structures of the entire serotonin receptor family uncovered molecular ligand recognition. Here, we present a map of 19 ‘selectivity hotspots’, that is, nonconserved binding site residues governing selectivity via favorable target interactions or repulsive ‘off-target’ contacts. Furthermore, we review functional rationale from observed ligand-binding affinities and mutagenesis effects. Unifying knowledge underlying specific probes and drugs is critical toward the functional characterization of different receptors and alleviation of adverse effects.
Effects of 5-HT<inf>2C</inf> receptor stimulation in male mice on behaviour and Fos expression: Feeding, reward and impulsivity
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Serotonin modulates many motivated behaviours via multiple receptor subtypes. Agonists at 5-HT₂_C receptors have potential for treating behavioural problems associated with obesity and drug use. In this work we examined the impact of the 5-HT_2C receptor agonist lorcaserin on several motivated behaviours related to feeding, reward and waiting impulsivity, and on neuronal activation in key brain areas mediating those behaviours. In male C57BL/6J mice effects of lorcaserin (0.2, 1 and 5 mg/kg) were examined on feeding, and on operant responding for a palatable reward. Feeding was reduced only at 5 mg/kg, whereas operant responding was reduced at 1 mg/kg. At a much lower dose range lorcaserin 0.05–0.2 mg/kg also reduced impulsive behaviour measured as premature responding in the 5-choice serial reaction time (5-CSRT) test, without affecting attention or ability to perform the task. Lorcaserin induced Fos expression in brain regions related to feeding (paraventricular nucleus and arcuate nucleus), reward (ventral tegmental area), and impulsivity (medial prefrontal cortex, VTA) although these effects did not show the same differential sensitivity to lorcaserin as the behavioural measures. These results indicate a broad profile of action of 5-HT_2C receptor stimulation on brain circuitry and on motivated behaviours, but with clear evidence of differential sensitivity across behavioural domains. This is exemplified by the fact that impulsive behaviour was reduced at a much lower dose range than was feeding behaviour. Along with previous work, and some clinical observations, this work supports the idea that 5-HT_2C agonists may be useful for behavioural problems associated with impulsivity.
Amberlyst-15 catalysed synthesis of novel indole derivatives under ultrasound irradiation: Their evaluation as serotonin 5-HT<inf>2C</inf> receptor agonists
2021, Bioorganic Chemistry
Citation Excerpt :
The GPCR 5-HT2C being broadly distributed in various regions of brain is largely expressed in the central nervous system (CNS) and involved in numerous physiological functions. Indeed, the modulation of this GPCR has been thought to have beneficial effects in a number of pathological conditions in addition to obesity [4–6]. While agonists and antagonists of 5-HT2C have been studied and reported in the literature the former class of ligands were considered as the most promising agents for the control of food intake thereby body weight reduction mediated by serotonin [7–9].
A series of indole based novel Schiff bases was designed as potential agonists of 5-HT_2C receptor that was supported by docking studies in silico. These compounds were synthesized via Amberlyst-15 catalysed condensation of an appropriate pyrazole based primary amine with the corresponding indole-3-aldehyde under ultrasound irradiation at ambient temperature. A number of target Schiff bases were obtained in good yields (77–87%) under mild conditions within 1 h. Notably, the methodology afforded the corresponding pyrazolo[4,3-d]pyrimidin-7(4H)-one derivatives when the primary amine was replaced by a secondary amine. Several Schiff bases showed agonist activity when tested against human 5-HT_2C using luciferase assay in HEK293T cells in vitro. The SAR (Structure-Activity-Relationship) studies suggested that the imine moiety was more favorable over its cyclic form i.e. the corresponding pyrazolopyrimidinone ring. The Schiff bases 3b (EC₅₀ 1.8 nM) and 3i (EC₅₀ 5.7 nM) were identified as the most active compounds and were comparable with Lorcaserin (EC₅₀ 8.5 nM). Also like Lorcaserin, none of these compounds were found to be PAM of 5-HT_2C. With ∼24 and ∼150 fold selectivity towards 5-HT_2C over 5-HT_2A and 5-HT_2B respectively the compound 3i that reduced locomotor activity in zebrafish (Danio rerio) larvae model emerged as a promising hit molecule for further study.
Serotonin/dopamine interaction: Electrophysiological and neurochemical evidence
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The interaction between serotonin (5-HT) and dopamine (DA) in the central nervous system (CNS) plays an important role in the adaptive properties of living animals to their environment. These are two modulatory, divergent systems shaping and regulating in a widespread manner the activity of neurobiological networks and their interaction. The concept of one interaction linking these two systems is rather elusive when looking at the mechanisms triggered by these two systems across the CNS. The great variety of their interacting mechanisms is in part due to the diversity of their neuronal origin, the density of their fibers in a given CNS region, the distinct expression of their numerous receptors in the CNS, the heterogeneity of their intracellular signaling pathway that depend on the cellular type expressing their receptors, and the state of activity of neurobiological networks, conditioning the outcome of their mutual influences. Thus, originally conceptualized as inhibition of 5-HT on DA neuron activity and DA neurotransmission, this interaction is nowadays considered as a multifaceted, mutual influence of these two systems in the regulation of CNS functions. These new ways of understanding this interaction are of utmost importance to envision the consequences of their dysfunctions underlined in several CNS diseases. It is also essential to conceive the mechanism of action of psychotropic drugs directly acting on their function including antipsychotic, antidepressant, antiparkinsonian, and drug of abuse together with the development of therapeutic strategies of Alzheimer's diseases, epilepsy, obsessional compulsive disorders. The 5-HT/DA interaction has a long history from the serendipitous discovery of antidepressants and antipsychotics to the future, rationalized treatments of CNS disorders.
Constitutive activity of 5-HT receptors: Factual analysis
2020, Neuropharmacology
The constitutive activity of different serotonin receptors (5-HTRs) toward intracellular signaling pathways has been proposed to have physiological and pathological importance. Inverse agonists block the constitutive activity and can be used to probe and silence such a spontaneous activity. The constitutive activity of 5-HTRs can be observed in various heterologous systems of expression in vitro (very high for 5-HT_2CR; very low for 5-HT_2AR). The demonstration of the existence of this activity in native tissues and ultimately in integrative neurobiology and behavior is a real pharmacological challenge. Irrespective of the existence of mutants or polymorphisms that could alter the constitutive activity of 5-HTRs, evidence suggests that spontaneous activity of 5-HT_2CR could impact the activity of neurobiological networks and that of 5-HT₆R and 5-HT₇R the developmental morphogenesis. Some findings exist for 5-HT_2BR and 5-HT_2AR in diverse though rare conditions. The existence of a constitutive activity for 5-HT_1AR, 5-HT_1B/1DR, and 5-HT₄R is still poorly supported. When identified, the constitutive activity may differ according to brain location, state of activity (phasic in nature), and intracellular signaling pathways. A very few studies have reported aberrant constitutive activity of 5-HTRs in animal models of human diseases and patients. The purpose of this review is a critical examination of the available neuropharmacological data on the constitutive activity of 5-HTRs to determine whether this activity is an essential component of the serotonergic system transmission and it may be a possible target for CNS drug development.
Lorcaserin bidirectionally regulates dopaminergic function site-dependently and disrupts dopamine brain area correlations in rats
2020, Neuropharmacology
Lorcaserin, which is a selective agonist of serotonin2C receptors (5-HT_2CRs), is a new FDA-approved anti-obesity drug that has also shown therapeutic promise in other brain disorders, such as addiction and epilepsy. The modulation of dopaminergic function might be critical in the therapeutic effect of lorcaserin, but its exact effect is unknown. Here, we studied the effect of the peripheral administration of lorcaserin on the ventral tegmental area (VTA), the substantia nigra pars compacta (SNc) dopaminergic neural activity, dopamine (DA) dialysis levels in the nucleus accumbens and striatum and on DA tissue levels in 29 different rat brain regions. Lorcaserin (5–640 μg/kg, i.v.) moderately inhibited only a subpopulation of VTA DA neurons, but had no effect on the SNc neurons. Lorcaserin (0.3, 3 mg/kg, i.p.) did not change VTA and SNc DA population neural activity but slightly decreased the firing rate and burst firing of the spontaneously active VTA neurons, without altering DA extracellular dialysate levels in both the nucleus accumbens and the striatum. Quantitative analysis of DA and metabolites tissue contents of the 29 areas studied revealed that lorcaserin (0.3 or 3 mg/kg, i.p.) only affected a few brain regions, i.e., increased DA in the central amygdala, ventral hypothalamus and nucleus accumbens core and decreased it in the ventromedial striatum. On the other hand, lorcaserin dramatically changed the direction and reduced the number of correlations of DA tissue content among several brain areas. These effects on DA terminal networks might be significant in the therapeutic mechanism of lorcaserin.
This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.

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Trends in Pharmacological Sciences

ReviewFrom obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists

Highlights

Section snippets

Central serotonin signaling as a therapeutic target

Characteristics of the 5-HT2C receptor

Preclinical biology of the 5-HT2C receptor relating to food and drug motivated behaviors

Clinical experience with 5-HT2C agonists

Opportunities to evaluate lorcaserin for smoking cessation and psychostimulant abuse

Concluding remarks

Pharmacol. Biochem. Behav.

Prog. Med. Chem.

Pharmacol. Ther.

Prog. Brain Res.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Pharmacol. Ther.

Neuropharmacology

Front. Neuroendocrinol.

Trends Neurosci.

Curr. Opin. Neurobiol.

Pharmacol. Ther.

Brain Res.

Neuropharmacology

Pharmacol. Biochem. Behav.

Neuropharmacology

Eur. J. Pharmacol.

Behav. Brain Res.

Neuropharmacology

Neuropharmacology

Neuropharmacology

Behav. Brain Res.

Trends Pharmacol. Sci.

Neuropsychopharmacology

Lancet

Neurobiol. Dis.

Neurobiol. Dis.

Neuropharmacology

Eur. J. Pharmacol.

5-HT2C receptor modulators: a patent survey

Expert Opin. Ther. Pat.

Common cellular and molecular mechanisms in obesity and drug addiction

Nat. Rev. Neurosci.

How can drug addiction help us understand obesity?

Nat. Neurosci.

Issues for DSM-V: should obesity be included as a brain disorder?

Am. J. Psychiatry

Smoking cessation drugs market

Nat. Rev. Drug Discov.

Pharmacological targeting of the serotonergic system for the treatment of obesity

J. Physiol.

Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine

Int. J. Obes. Relat. Metab. Disord.

Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders

Br. J. Clin. Pharmacol.

Antidepressants for smoking cessation

Cochrane Database Syst. Rev.

The treatment of obesity and its co-occurrence with substance use disorders

J. Addict. Med.

Serotonin modulation of cortical neurons and networks

Front. Integr. Neurosci.

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin)

Pharmacol. Rev.

Regulation of serotonin-2C receptor G-protein coupling by RNA editing

Nature

5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential

J. Pharmacol. Exp. Ther.

6-Chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (SB-242084): the first selective and brain penetrant 5-HT2C receptor antagonist

J. Med. Chem.

Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors

Nature

Reversal of sibutramine-induced anorexia with a selective 5-HT2C receptor antagonist

Psychopharmacology (Berl.)

Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice

Psychopharmacology (Berl.)

Anatomy and regulation of the central melanocortin system

Nat. Neurosci.

Review
From obesity to substance abuse: therapeutic opportunities for 5-HT_2C receptor agonists

Characteristics of the 5-HT_2C receptor

Preclinical biology of the 5-HT_2C receptor relating to food and drug motivated behaviors

Clinical experience with 5-HT_2C agonists

5-HT_2C receptor modulators: a patent survey

5-HT_2C receptor agonists: pharmacological characteristics and therapeutic potential

6-Chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline (SB-242084): the first selective and brain penetrant 5-HT_2C receptor antagonist

Eating disorder and epilepsy in mice lacking 5-HT_2C serotonin receptors

Reversal of sibutramine-induced anorexia with a selective 5-HT_2C receptor antagonist

Reduced satiating effect of d-fenfluramine in serotonin 5-HT_2C receptor mutant mice