5-HT2C receptor agonist

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5-HT2C receptor agonists are a class of drugs that activate

psychiatric disorders, sexual dysfunction and urinary incontinence.[1][2][3][4][5]

The 5-HT2C receptors are one of three subtypes that belong to the serotonin 5-HT2 receptor subfamily along with 5-HT2A and 5-HT2B receptors. The development of 5-HT2C agonists has been a major obstacle, because of severe side effects due to a lack of selectivity over 5-HT2A and 5-HT2B receptors. Activation of 5-HT2A receptors can induce hallucinations, and the activation of 5-HT2B receptors has been implicated in cardiac valvular insufficiency and possibly in pulmonary hypertension.[6][7]

Discovery

In the late 1960s, non-selective serotonin

hyperphagia.[9] Studies using pharmacological and genetic tools demonstrated that the 5-HT2C receptor subtype was one of the principal mediators through which serotonin exerts its anorectic effects in rodents. Subsequently, these receptors became a promising pharmacotherapeutic target for further investigation for the treatment of obesity.[10] The development of 5-HT2C receptor knockout mice in the mid-1990s was a hallmark achievement in the identification and development of serotonergic drugs for weight loss. These knockout mice were hyperphagic, which led to obesity, partial Leptin resistance, increased adipose deposition, insulin resistance, and impaired glucose tolerance. As a result of these symptoms, the researchers identified a functional role for the receptors in serotonergic regulation of food intake and body weight.[7][11] Later, 5-HT2C receptors were proposed as a therapeutic target for the treatment of multiple central nervous system (CNS) disorders including: psychiatric disorders, obesity, sexual dysfunction and urinary incontinence.[9]

History

The 5-HT2c receptor agonist

enantiomers, dexfenfluramine and levofenfluramine.[12][13]

In 1994, sales of the combination drug

Fen-phen (fenfluramine and phentermine) increased dramatically, as this combination produced substantial and apparent synergistic effect in promoting weight loss. Subsequently, reports of severe side effects associated with heart valve abnormalities and an increased risk of pulmonary hypertension resulted in a decision to remove products containing fenfluramine from the U.S. market, and then from other markets around the world.[14][15][16]

Dexfenfluramine inhibits serotonin reuptake, stimulating the release of serotonin. In 1996, dexfenfluramine became the first long-term treatment anti-obesity medication approved in the US; adverse effects observed during clinical trials included dry mouth, diarrhea and drowsiness. In the mid-1990s the US FDA approved dexfenfluramine as a weight loss drug. After several reports of adverse cardiovascular effects, the FDA banned dexfenfluramine in 1997.[12][17][18]

It appears that the 5-HT2B receptors, expressed in cardiac valves, are responsible for the valvulopathies reported from the use of fenfluramine and dexfenfluramine.[19]

The serotonin receptor agonist mCPP has a significant affinity for 5-HT2C receptors. mCPP patients experience multiple side effects due to non-selectivity over 5-HT2A and 5-HT2B receptors. The absence of the hypophagic (reduced food consumption) effect of mCPP in 5-HT2C receptor knockout mice suggests that this effect is mediated through 5-HT2C receptor activation. Repeated administration of mCPP to humans might result in decreased food intake and weight loss. mCPP is used as a prototype research tool for drug discovery of selective 5-HT2C receptor agonists.[20][21][22]

Mechanism of action

Figure 1 – Mechanism of action. A hypothetical model for the agonist activation of 5-HT2C receptor. Activation leads to accumulation of inositol phosphate and increase in intracellular Ca2+. Receptor activation also stimulates the ERK pathway and RhoA/PLD pathway.

The

manic-depressive illness stimulated the pathway. This led to the understanding that stimulation of the 5-HT2C receptors could regulate manic-depressive conditions in a manner similar to mood stabilizers.[23][24][25][3]

5-HT2C receptors are located only within the CNS, where they can be found in several locations. The highest density of receptor expression is within the

paraventricular hypothalamic nucleus and the amygdala, all of which are associated with regulation of food intake. This distribution pattern may explain the effect they have in integral function in the control of many physiological and behavioral responses, such as feeding, anxiety, temperature regulation, locomotion, sexual behavior, and the occurrence of seizures.[26][27]

Binding

The 5-HT2C receptors and ligand binding

Figure 2. A schematic representation of the two state-model in which the 5-HT2C receptor are in equilibrium between an active state (R*) and an inactive state (R).

5-HT2 receptors are

inverse agonists and reduce the effector activity. Agonists preferentially bind to and stabilize the R* state, thereby increasing effector activity. Neutral antagonists show equal affinity for both conformations and do not alter the equilibrium between the two states, however they occupy the receptor and can block the effect of both agonists and inverse agonists.[28][29]

5-HT2C and 5-HT2A receptors have a similar

postsynaptic cell.[28]

The 5-HT2C receptors are the only G-protein coupled receptors known to undergo a post-transcriptional process of RNA editing. The 5-HT2C receptor gene is found on the

X-chromosome, Xq24. This gene product undergoes an RNA editing process leading to a decrease in agonist binding affinity, however antagonist binding remains unaltered. This process of RNA editing generates 14 unique receptor isoforms of the 5-HT2C receptor that differ in three amino acids in the second intracellular loop.[28][30]

Serotonin binding to 5-HT2C

Serotonin is an

Van der Waals interaction with residues F223 in TM 5 and F328 in TM 6. The ring falls tight into the receptor pocket, stacked between two phenylalanines. Amine of the indole group forms a hydrogen bond with S219 residue in TM 5 and hydroxide substituent of the indole forms hydrogen bonds both with residue S131 in TM 3 and I332 in TM 6. There is also a strong Van der Waals interaction between the indole and I332 in TM 6.[31]

Figure 3. Outline of the 5-HT2C receptor. The most important contacts when serotonin binds are with residues in TM helixes 3, 5, and 6.

Pharmacophore

Figure 4. The best fit mapped with the four features of the pharmacophore.

In the drug discovery process of a 5-HT2C agonist, a pharmacophore module has been used to discover novel 5-HT2C receptor ligands. The pharmacophore has four features; one aromatic ring, two hydrophobic features and one positive ionizable feature. Figure 4 shows an example of a compound that fits the agonist pharmacophore perfectly. The nitrogen atom of piperazine fits the positive ionizable feature, the benzofuran part fits the aromatic ring and one hydrophobic, and the trifluoromethane part fits another hydrophobic feature of the pharmacophore.[32]

Structure-activity relationships

In a

aliphatic- or cyclic groups reduces potency as well (derivatives 5 and 6 in figure 5).[32]

Pyrazolo[3,4-d]pyrimidine core
Pyrazolo[3,4-d]pyrimidine core
Derivative 1
Derivative 1
Derivative 2
Derivative 2
Derivative 3
Derivative 3
Derivative 4
Derivative 4
Derivative 5
Derivative 5
Figure 5. Pyrazolo[3,4-d]pyrimidine derivatives.
Figure 6. Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine).
mCPP (meta-chlorophenylpiperazine)
A potent mCPP derivative (4-(3-chlorophenyl)-1,2,3,6-tetrahydropyridine)
Figure 7. mCPP and a potent derivative.

A series of 3-benzazepine derivatives, such as Lorcaserin (Figure 6) have been evaluated for their potency and selectivity for the 5-HT2C receptors. Lorcaserin is a very potent agonist, but the potency is dependent on the presence of a chloro substituent in position 8.[7][33][34]

Arylpiperazine-containing compounds such as mCPP (Figure 7), show good potency toward the 5-HT2C receptors, but do not have sufficient selectivity for the 5-HT2C receptors over the other two receptor subtypes. Many derivatives have been examined in an attempt to increase the selectivity. Derivatives lacking the arylpiperazine core, such as 4-aryl-1,2,3,6-tetrahydropyridinum chlorine analogues, are more favorable for potency and selectivity over the other two receptors (Figure 7).[35]

Functional selectivity

In 2016 the discovery of novel G protein biased 5-HT2C receptor agonists was published.[36]

Drug development

Obesity

Obesity is a global epidemic health problem and has received considerable attention as a major public hazard. Obesity is a chronic pathological and costly disease of abnormal or excessive fat accumulation in the body.[37]

Studies indicate that 5-HT2C receptor activation will regulate appetite and food consumption, most likely by promoting satiety through appetite suppression by activation of 5-HT2C. Consequently, selective agents with high affinity for this receptor over 5-HT2B and 5-HT22A are being developed for the treatment of obesity.[38][6]

Pumosetrag was the example set by Mitsubishi Chemical Corporation.

Lorcaserin

clinical trials, and achieved US Food and Drug Administration (FDA) approval. However it was later withdrawn from the market in February 2020 due to a higher risk of malignancy in a randomized trial of lorcaserin.[39] Previously approved agents were subsequently removed from the US market.[6]

Lorcaserin is a full agonist for 5-HT2C and 5-HT2B receptors and

oxidation.[11] Lorcaserin has a high affinity for the 5-HT2C receptors, with 18-fold selectivity over 5-HT2A receptors and 104-fold over 5-HT2B receptors.[7] The predicted blood concentration to stimulate 2A and 2B receptors is approximately 1400-fold for 2B and 250-fold for 2A, above the blood concentration that is required to stimulate the 2C receptors. This functional selectivity is critical to prevent potential side effects and suggests that the theoretical risk of cardiac valvulopathy is very low. Clinical trials have supported this theory since they have not revealed any side effects on heart valves or pulmonary artery pressure like the former obesity drugs. Lorcaserin is well tolerated in general, but the most frequent adverse effect are headache, nausea and dizziness.[7][11]

Psychiatric disorders

Serotonin plays an important role in numerous physiological conditions. 5-HT2 receptor antagonists have long been known, but recently 5-HT2 receptor agonists are becoming promising agents in the development for new

forced swim test) in rats in a manner comparable to SSRIs. In the 1990s 5-HT2C receptors have received more attention as many studies have shown that selective 5-HT2C receptor agonists may be more suited in the treatment for psychotic indications.[40][41]

A 5-HT2C agonist may be expected to reduce positive symptoms of schizophrenia by reducing dopamine release in the

mesolimbic dopamine pathway. Vabicaserin (SCA-136) is a 5-HT2C agonist that has shown promise in preliminary testing for the treatment of schizophrenia.[42]

Vabicaserin and aripiprazole

Vabicaserin has a high affinity for 5-HT2C receptors and low affinity for 5-HT2B and 5-HT2A receptors. Vabicaserin is a full agonist with approximately 4-fold greater selectivity for 5-HT2C over these related receptors, in terms of binding affinity. Vabicacserin is a full agonist in stimulating the 5-HT2C receptor; it was discovered when a class of tetrahydroquinoline-fused diazepines were being researched as possible potent 5-HT2C receptor agonists.[43]

As of 2012, vabicaserin is in clinical trials for the treatment of schizophrenia. Long-term administration of vabicaserin significantly decreased the number of spontaneously active mesocorticolimbic dopamine neurons without affecting

nigrostriatal dopamine neurons, consistent with effects of atypical antipsychotic agents. The outcome of clinical studies for vabicaserin may reveal whether 5-HT2C receptors can be possible targets for the treatment of schizophrenia.[44]

Aripiprazole is also a mild partial agonist of 5HT2C receptor.

Sexual dysfunction

Activation of 5-HT2C receptor subtype has been reported to mediate numerous effects, such as penile erection.

SB-242,084. Therefore, results suggest that YM348 is a potent and orally active 5-HT2C receptor agonist.[49][50]

Urinary incontinence

Serotonin plays a key role in mechanisms involved in

stress urinary incontinence (SUI).[50]

Current status

Many

SB-243,213. Evidence supports a therapeutic potential of 5-HT2C receptor modulation in the treatment of a variety of pathological conditions, including schizophrenia, obesity, urinary incontinence and sexual dysfunction.[42]

Compound name Chemical name Mode of action Company Phase of development Indication Reference
PRX-00933 N/A 5-HT2C agonist Proximager Phase III (2011) Obesity and diabetes [51]
Vabicaserin (9aR,12aS)-4,5,6,7,9,9a,10,11,12,12a- decahydrocyclopenta[c] [1,4]diazepino[6,7, 1-ij]quinoline 5-HT2C agonist Pfizer Phase I (February, 28th,2012) Schizophrenia [52]
Lorcaserin 1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl- 1H-3-benzazepine 5-HT2C agonist Arena Pharmaceuticals FDA approved (June 27, 2012) Obesity [53]

See also

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