5-HT2C Receptor (pKi = 9.0)

Multiple antagonistic effects of SB 242084 (100 nM; 45 min) on the increase in phosphatidylinositol workstation of 5-HT in human 5-HT2C workstation in SH-SY5Y cells have been reported [1]. SB 242084 (1–100 Nm; twenty-four hours)

In social interaction tests, SB 242084 (0.1–1 mg/kg; i.p.; single dosage; 20 min pretest) improves behavior [1]. SB 242084 (160-640 μg/kg; IV; single dose) dose-dependently and significantly increases basal current rates in dopaminergic neurons in the VTA (ventral tegmental area), as well as intrabody (DOPAC) levels. SB 242084 (5 mg/kg; i.p.; single dose; 20 minutes) SB 242084 (5, 10 mg/kg; i.p.; single dose) increases basal dialysate dopamine (DA) and hexaphenyl forms in the nucleus accumbens [ 3]. The same region also experiences increased burst activity [3].

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].

Cell Viability Assay[1]
Cell Types: SH-SY5Y cells
Tested Concentrations: 100 nM
Incubation Duration: 45 min
Experimental Results: Antagonizes 5-HT-induced concentration-related increase) Increases RPTC in RPTC Respiration and PGC-1α mRNA expression [2]. In PI hydrolysis.

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RT-PCR[2]
Cell Types: RPTC Cell
Tested Concentrations: 1-100 nM
Incubation Duration: 24 hrs (hours)
Experimental Results: FCCP uncouples respiration and increases PGC-1α mRNA expression.

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) (CD) rat [1].
Doses: 0.1-1 mg/kg
Route of Administration: intraperitoneal (ip) injection; single; 20 minutes Pre-test
Experimental Results: Rats spent Dramatically more time in social interactions over 15 minutes under bright light conditions and in unfamiliar test boxes.

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Animal/Disease Models: Male SD (SD (Sprague-Dawley)) (CD) rats (mCPP-induced Hypophagia model) [1].
Doses: 5 mg/kg
Route of Administration: intraperitoneal (ip) injection; single; 20-minute pre-test
Experimental Results: 23 hrs (hrs (hours)) of food deprivation during a 1-hour test period from the date of food presentation The amount of food consumed by rats was Dramatically diminished.

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Animal/Disease Models: Rat [2].
Doses: 5, 10 mg/kg
Route of Administration: intraperitoneal (ip) injection; Single
Experimental Results:Basal dialysate dopamine (DA) and diamine in the nucleus accumbens Hydroxyphenylacetic acid (DOPAC) was Dramatically increased.

[1]. SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist. Neuropharmacology. 1997 Apr-May;36(4-5):609-20.

[2]. 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists. J Pharmacol Exp Ther. 2016 Apr;357(1):1-9.

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 100-fold and 158-fold higher selectivity, 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 overeating characteristics specific to mutant mice lacking the 5-HT2C receptor. [1]

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In acute organ injury, mitochondrial function is often impaired, and recent studies have shown that inducing mitochondrial biosynthesis (MB) can accelerate the recovery of mitochondrial and renal function. We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl)prop-2-amine] can induce MB production in proximal renal tubular cells (RPTCs). This study aimed to investigate the role of the 5-HT2 receptor in the regulation of renal mitochondrial gene expression and oxidative metabolism. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and the antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide dihydrochloride] were used to investigate the induction and oxidative metabolism of RPTC and rat kidney mitochondrial genes in the presence or absence of 5-HT2C receptors. Unexpectedly, both CP-809,101 and SB-242,084 at concentrations of 1–10 nM increased respiration in the paratubular nucleus (RPTC) and the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA. Furthermore, CP-809,101 and SB-242,084 increased the mRNA expression of PGC-1α and mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) β subcomplex 8 in the paratubular nucleus of mouse renal cells. These compounds increased mitochondrial gene expression in RPTC cells with 5-HT2C receptor downregulated by small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. Conversely, in RPTC cells treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist epfanserin, the ability of these compounds to increase PGC-1α mRNA and respiration was blocked. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased respiration in RPTC cells at concentrations ranging from 1 to 100 nM. These results indicate that 5-HT2A receptor agonists can induce mitochondrial membrane potential (MB), and that the classic 5-HT2C receptor agonists CP-809,101 and antagonist SB-242,084 can increase mitochondrial gene expression and oxidative metabolism through the 5-HT2A receptor. To our knowledge, this is the first report to link 5-HT2A receptor agonists with mitochondrial function. [2]

C21H19N4O2CL.2[HCL]

467.77604

466.073

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

181632-25-7

SB 242084 dihydrochloride;1049747-87-6

3644637

Off-white to pink 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

1

4

3

28

551

0

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

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;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ≥ 44 mg/mL (~111.43 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.33 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 25.0 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: ≥ 2.5 mg/mL (6.33 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 25.0 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.)