5-HT2C Receptor (pKi = 9.0)
SB 242084 HCl targets the 5-HT2C receptor, a G protein-coupled receptor that is activated by serotonin (5-hydroxytryptamine, 5-HT). The 5-HT2C receptor is predominantly expressed in the central nervous system, particularly in regions involved in mood, anxiety, appetite, and reward such as the cortex, hippocampus, and limbic system. SB 242084 is a selective antagonist for the 5-HT2C receptor with a pKi of 9.0. It displays 158-fold selectivity over 5-HT2A receptors and 100-fold selectivity over 5-HT2B receptors. The compound has over 100-fold selectivity over a range of other 5-HT, dopamine, and adrenergic receptors. By blocking 5-HT2C receptor activation, SB 242084 modulates serotonin signaling and enhances dopamine signaling in the limbic system.

SB 242084 dihydrochloride (100 nM; 45 min) exhibits antagonism of the 5-HT-stimulated increase in phosphatidylinositol hydrolysis at the human 5-HT2C receptor in SH-SY5Y cells [1]. SB 242084 dihydrochloride (1-100 nM; 24 hours) increases RPTC respiration and PGC-1α mRNA expression [2]. Cell Viability Assay [1] Cell Line: SH-SY5Y Cell Concentration: 100 nM Incubation Time: 45 minutes Results: Antagonizes the concentration-related increase in PI hydrolysis induced by 5-HT. RT-PCR[2] Cell Line: RPTC Cell Concentration: 1-100 nM Incubation Time: 24 hours Results: FCCP uncouples respiration and increases PGC-1α mRNA expression.

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SB 242084 HCl demonstrates potent and selective in vitro activity as a 5-HT2C receptor antagonist. The compound has a pKi of 9.0 for the 5-HT2C receptor, indicating high affinity binding. It displays 158-fold selectivity over 5-HT2A receptors and 100-fold selectivity over 5-HT2B receptors. The compound has over 100-fold selectivity over a range of other 5-HT, dopamine, and adrenergic receptors. This high selectivity makes SB 242084 a valuable tool for studying 5-HT2C receptor-specific functions without off-target effects. In cellular assays, the compound antagonizes 5-HT2C receptor-mediated signaling, blocking the effects of serotonin at this receptor.

SB 242084 dihydrochloride (0.1-1 mg/kg; i.p.; single dose; 20 minutes before testing) improves rat behavior in social interaction tests [1]. SB 242084 dihydrochloride (5 mg/kg; intraperitoneal injection; single dose; 20 minutes before testing) improves mCPP-induced hypophagia in rats [1]. SB 242084 diHClide (5, 10 mg/kg; i.p.; single dose) increases basal dialysate dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens of rats [3]. SB 242084 Dihydrochloride (160-640 µg/kg; IV; single dose) dose-dependently and significantly increases the basal firing rate of VTA (ventral tegmental area) dopaminergic neurons and bursting in the same region in vivo Activity is also enhanced. 3]. Animal model: Male Sprague-Dawley (CD) rat [1]. Dose: 0.1-1 mg/kg Administration: Intraperitoneal injection; singleton; 20 minutes Pre-test results: Rats spent more than 15 minutes in social interaction under bright light conditions and in unfamiliar test box ,A significant increase. Animal model: Male Sprague-Dawley (CD) rat (mCPP-induced hypophagia model) [1]. Dose: 5 mg/kg Administration: Intraperitoneal injection; singleton; 20 min Pre-test results: 23-h food-deprived rats consumed significantly less food during the 1-h test period from the date of food presentation. Animal model: rat[2]. Dosage: 5, 10 mg/kg Administration: intraperitoneal injection; Single result: Significant increase in basal dialysate dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens.

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SB 242084 potently inhibited m-chlorophenylpiperazine (mCPP, 7 mgkg i.p. 20 min pre-test)-induced hypolocomotion in rats, a model of in vivo central 5-HT2C receptor function, with an ID50 of 0.11 mg/kg i.p., and 2.0 mg/kg p.o. SB 242084 (0.1-1 mg/kg i.p.) exhibited an anxiolytic-like profile in the rat social interaction test, increasing time spent in social interaction, but having no effect on locomotion. SB 242084 (0.1-1 mg/kg i.p.) also markedly increased punished responding in a rat Geller-Seifter conflict test of anxiety, but had no consistent effect on unpunished responding. A large acute dose of SB 242084 (30 mg/kg p.o.) had no effect on seizure susceptibility in the rat maximal electroshock seizure threshold test. Also, while SB 242084 (2 and 6 mg/kg p.o. 1 hr pre-test) antagonized the hypophagic response to mCPP, neither acute nor subchronic administration of the drug, for 5 days at 2 or 6 mg/kg p.o. twice daily, affected food intake or weight gain. The results suggest that SB 242084 is the first reported selective potent and brain penetrant 5-HT2C receptor antagonist and has anxiolytic-like activity, but does not possess either proconvulsant or hyperphagic properties which are characteristic of mutant mice lacking the 5-HT2C receptor.[1]

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SB 242084 HCl has been evaluated in vivo for its effects on behavior and neurochemistry. The compound has anxiolytic effects, reducing anxiety-like behavior in animal models. SB 242084 enhances dopamine signaling in the limbic system, a region involved in reward and motivation. The compound has complex effects on dopamine release produced by cocaine, increasing dopamine release in some brain regions while reducing it in others. These findings highlight the role of 5-HT2C receptors in modulating dopaminergic function and reward pathways. SB 242084 is a valuable tool for studying the role of 5-HT2C receptors in psychiatric disorders, addiction, and reward. Detailed in vivo efficacy data, including specific behavioral test results and dosing regimens, are available in the primary literature.

SB 242084 has a high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and 100- and 158-fold selectivity over the closely related cloned human 5-HT2B and 5-HT2A subtypes respectively. SB 242084 had over 100-fold selectivity over a range of other 5-HT, dopamine and adrenergic receptors. In studies of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb of 9.3, which closely resembled its corresponding receptor binding affinity[1].

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The in vitro receptor binding assay for SB 242084 HCl measures the binding affinity of the compound to the 5-HT2C receptor. Membrane preparations from cells expressing the human 5-HT2C receptor are incubated with varying concentrations of SB 242084 HCl (typically ranging from nanomolar to micromolar) in the presence of a radiolabeled 5-HT2C receptor ligand. The amount of bound radioligand is measured by scintillation counting, and Ki values are determined by fitting competition binding curves. The pKi value of 9.0 indicates high affinity binding. The compound is dissolved in DMSO and diluted in assay buffer to achieve the desired final concentrations, with DMSO concentration kept constant across all wells. Appropriate positive controls (known 5-HT2C antagonists) and negative controls (DMSO vehicle) are included in each assay run. Selectivity is assessed by testing the compound against 5-HT2A, 5-HT2B, and other receptors.

The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1α and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) β subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1α mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM[2].

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The in vitro cellular assay for SB 242084 HCl is performed using cells expressing the 5-HT2C receptor, such as HEK293 cells stably transfected with 5-HT2CR. Cells are cultured in appropriate medium and treated with varying concentrations of SB 242084 HCl or vehicle control (DMSO). Cells are stimulated with serotonin to activate the 5-HT2C receptor, and receptor activation is measured by assessing downstream signaling events such as calcium mobilization (5-HT2C is a Gq-coupled receptor that increases intracellular calcium). The inhibition of serotonin-induced calcium mobilization by SB 242084 is quantified, and IC50 or KB values are determined by fitting dose-response curves. The compound's selectivity for 5-HT2C over 5-HT2A and 5-HT2B can be assessed in similar assays using cells expressing these receptor subtypes.

SB242084 was daily dissolved in saline containing 8.0% hydroxypropyl-β-cyclodextrin. All drugs were injected i.p. at a volume of 1ml/kg. SB242084 treatment Twenty-nine animals were separated in HR and LR and used for this experiment. After pre-conditioning, animals in both HR and LR groups received the following treatment during the conditioning phase: SB242084 (0.5 mg/kg, i.p.)-cocaine or vehicle (saline containing 8.0% hydroxypropyl-β-cyclodextrin, 1ml/kg, i.p.)-cocaine (n=6–9 per group). Pretreatments were administered 30 minutes before cocaine (20 mg/kg, i.p.) (Burmeister et al. 2004; Fletcher et al. 2002, 2006, 2008; Nic Dhonnchadha et al. 2009). Effects of MDL100907 or SB242084 on CPP acquisition in absence of cocaine Forty animals were separated according to their locomotor activity and used to test the potential conditioning effects induced by MDL100907 and SB242084 when administered alone, and to control for changes in place preference that might spontaneously occur over time. After pre-conditioning, HR and LR animals were divided into three treatment groups: MDL100907 (0.3 mg/kg, i.p.)-Saline, SB242084 (0.5 mg/kg, i.p.)-Saline and Vehicle (saline containing 8.0% hydroxypropyl-β-cyclodextrin, 1ml/kg, i.p.)-Saline (n=5 per group). A fourth treatment group, vehicle (saline containing 8.0% hydroxypropyl-β-cyclodextrin, 1ml/kg, i.p.) followed by cocaine (20 mg/kg, i.p.) was also run in parallel as an internal control for the experiment (n=5 per group). In all cases, pretreatment was followed by treatment 30 minutes later.Reference: Psychopharmacology (Berl). 2012 Apr; 220(4): 731–740. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314106/

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In vivo animal experiments with SB 242084 HCl are typically conducted using rodent models of anxiety, depression, addiction, or other psychiatric disorders. SB 242084 HCl is administered via intraperitoneal injection at various doses. Behavioral tests relevant to the condition being studied (e.g., elevated plus maze or open field test for anxiety, conditioned place preference for reward, self-administration for addiction) are performed. The effects of SB 242084 on behavior are compared to vehicle-treated controls. Additionally, the compound's effects on dopamine release can be assessed using microdialysis in the limbic system. At the end of the study, brain tissues may be harvested for analysis of receptor occupancy and downstream signaling markers. Detailed experimental protocols, including dosing regimens and endpoints, are described in the primary literature.

Detailed pharmacokinetic (PK) parameters for SB 242084 HCl are not extensively documented in publicly available sources. As a small-molecule 5-HT2C antagonist with a molecular weight of 467.78, the compound is expected to have reasonable oral bioavailability and good central nervous system penetration. SB 242084 HCl has a chemical formula of C21H21Cl3N4O2. The compound is soluble in DMSO for formulation purposes. For in vivo administration, SB 242084 HCl is typically formulated using appropriate vehicles to ensure adequate solubility and stability. The compound should be stored under conditions recommended by the manufacturer to maintain stability and prevent degradation. Detailed PK parameters including half-life, clearance, volume of distribution, and maximum concentration (Cmax) are available in the primary literature and should be consulted for specific experimental planning.

Comprehensive toxicological data for SB 242084 HCl are not extensively documented in publicly available sources. As a research-grade compound, SB 242084 HCl is intended for laboratory research purposes only and is not approved for human therapeutic use. Standard laboratory safety practices should be followed when handling this compound, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound should be stored according to the manufacturer's recommendations to maintain stability and prevent degradation. In animal studies, SB 242084 has been reported to be tolerated at the doses tested for behavioral studies. However, comprehensive toxicological profiling (e.g., LD50, maximum tolerated dose, organ-specific toxicity) is not available from the current search results and would require consultation of the primary literature or safety data sheets.

[1]. Neuropharmacology . 1997 Apr-May;36(4-5):609-20.

[2]. Psychopharmacology (Berl) . 2006 Mar;185(1):45-57.

6-Chloro-5-methyl-N-[6-(2-methylpyridin-3-yl)oxypyridin-3-yl]-2,3-dihydroindole-1-carboxamide dihydrochloride is an organic molecular entity belonging to the indole alkaloids and pyridine compounds. It is a receptor modulator. SB 242084 exhibits high affinity (pKi 9.0) for the cloned human 5-HT2C receptor and selectivity 100-fold and 158-fold higher, respectively, for the closely related cloned human 5-HT2B and 5-HT2A subtypes. SB 242084 also shows selectivity exceeding 100-fold for a range of other 5-HT, dopamine, and adrenergic receptors. In a study of 5-HT-stimulated phosphatidylinositol hydrolysis using SH-SY5Y cells stably expressing the cloned human 5-HT2C receptor, SB 242084 acted as an antagonist with a pKb value of 9.3, exhibiting a very close affinity for the corresponding receptor. SB 242084 effectively inhibited the reduction in rat movement induced by m-chlorophenylpiperazine (mCPP, 7 mg/kg, intraperitoneal injection, 20 minutes in the preliminary test). This model can be used to study central 5-HT2C receptor function in vivo, with ID50 values of 0.11 mg/kg (intraperitoneal injection) and 2.0 mg/kg (oral administration). In rat social interaction tests, SB 242084 (0.1–1 mg/kg, intraperitoneal injection) showed a similar anti-anxiety effect, increasing the duration of social interaction in rats, but had no effect on motor function. SB 242084 (0.1–1 mg/kg, intraperitoneal injection) significantly increased the punishment response in the Geller-Seifter anxiety conflict test in rats, but had no consistent effect on the non-punishment response. High-dose acute SB 242084 (30 mg/kg, oral) had no effect on epilepsy susceptibility in the maximum electroshock epilepsy threshold test in rats. Furthermore, although SB 242084 (2 and 6 mg/kg, oral, 1 hour before testing) antagonized the mCPP-induced anorexia response, acute or subchronic administration at 2 or 6 mg/kg twice daily for 5 consecutive days did not affect food intake or weight gain. These results indicate that SB 242084 is the first reported selective, potent, blood-brain barrier-crossing 5-HT2C receptor antagonist with anxiolytic-like activity, but without the proconvulsant or overfeeding properties characteristic of 5-HT2C receptor deletion mutant mice. [1]

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Background: To investigate the functional relationship between 5-HT1B receptor (5-HT1B-R) and 5-HT2C receptor (5-HT2C-R) in the regulation of food intake. Objective: To compare the appetite-suppressing effects of the 5-HT(2C/1B)-R agonist m-chlorophenylpiperazine (mCPP) and the selective 5-HT1B-R agonist CP-94,253 in wild-type (WT) and 5-HT2C knockout (KO) mice. Methods: The appetite-suppressing effects of mCPP (1, 3, and 5.6 mg/kg) and CP-94,253 (5, 10, and 20 mg/kg) were evaluated in wild-type (WT) and 5-HT2C receptor knockout (KO) mice using a behavioral satiety sequence paradigm. The effects of pretreatment with the selective 5-HT2C receptor antagonist SB 242,084 (0.5 and 1.5 mg/kg) were evaluated in two groups of wild-type (WT) mice, with each group receiving either mCPP or CP-94,253 alone. Results: Both the 5-HT(2C/1B) receptor agonist mCPP and the selective 5-HT1B receptor agonist CP-94,253 suppressed food intake in WT mice. 5-HT2C KO mice were insensitive to the anorexia induced by mCPP, but were more sensitive than the wild-type control group to CP-94,253-induced anorexia. mCPP significantly increased postprandial activity in 5-HT2C KO mice, but this effect disappeared in 5-HT2C KO mice treated with CP-94,253. Data from wild-type mice pretreated with the 5-HT2C receptor antagonist SB 242,084 and then stimulated with mCPP or CP-94,253 were similar to those from 5-HT2C KO mice. Conclusion: Activation of both 5-HT2C and 5-HT1B receptors was sufficient to induce anorexia. However, concurrent 5-HT2C-R inactivation enhanced the anorexia induced by 5-HT1B-R activation, consistent with the inhibitory role of 5-HT2C-R in behaviors mediated by other 5-HT receptor activations. These results also confirm that 5-HT1B-R activation alone is insufficient to explain the overactive response of 5-HT2C KO mice to mCPP. [2]

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SB 242084 HCl is a research compound developed for studying the role of 5-HT2C receptors in psychiatric disorders, addiction, and reward. The compound is a selective 5-HT2C receptor antagonist with a pKi of 9.0, displaying 158-fold selectivity over 5-HT2A and 100-fold selectivity over 5-HT2B receptors. SB 242084 has anxiolytic effects and enhances dopamine signaling in the limbic system. The compound has complex effects on dopamine release produced by cocaine. SB 242084 HCl is not currently in clinical trials nor approved for therapeutic use; it remains an investigational tool compound for preclinical neuroscience research. The compound is available from various chemical suppliers for research purposes. Its utility lies in its ability to selectively antagonize 5-HT2C receptors and probe their role in mood, reward, and addiction.

C21H21CL3N4O2

467.7760

466.07

C, 53.92; H, 4.53; Cl, 22.74; N, 11.98; O, 6.84

1049747-87-6

SB 242084; 181632-25-7

16219981

Off-white to light yellow solid powder

1.4±0.1 g/cm3

620.1±55.0 °C at 760 mmHg

328.8±31.5 °C

0.0±1.8 mmHg at 25°C

1.671

3.76

3

4

3

30

551

0

ClC1C(C([H])([H])[H])=C([H])C2=C(C=1[H])N(C(N([H])C1=C([H])N=C(C([H])=C1[H])OC1C([H])=C([H])C([H])=NC=1C([H])([H])[H])=O)C([H])([H])C2([H])[H].Cl[H].Cl[H]

GCMNSEILNIPNSX-UHFFFAOYSA-N

InChI=1S/C21H19ClN4O2.2ClH/c1-13-10-15-7-9-26(18(15)11-17(13)22)21(27)25-16-5-6-20(24-12-16)28-19-4-3-8-23-14(19)2;;/h3-6,8,10-12H,7,9H2,1-2H3,(H,25,27);2*1H

6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yl)oxypyridin-3-yl]-2,3-dihydroindole-1-carboxamide;dihydrochloride

SB-242084 HCl; SB 242084; SB242084; 6-Chloro-5-methyl-N-(6-((2-methylpyridin-3-yl)oxy)pyridin-3-yl)indoline-1-carboxamide dihydrochloride; SB 242084 hydrochloride; SB 242084 (hydrochloride); SB-242084 Dihydrochloride; SB 242084 dihydrochloride; SB 242084 dihydrochloride hydrate; SB-242084

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~213.78 mM)

Solubility in Formulation 1: ≥ 5 mg/mL (10.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 5 mg/mL (10.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 5 mg/mL (10.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)