5-HT2C Receptor (pKi = 9.0)

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.

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]

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].

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].

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/

[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]

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.)