Histamine H3 receptor (Ki: 0.8 nM; IC50 for inverse agonist activity: 3.7 nM; no EC50 values provided) [2]
- Histamine H3 receptor [1]

In cell models, S 38093 antagonizes mouse H3 receptors (KB=0.65 µM) and inhibits H3 agonists through human H3 receptors (KB=0.11 µM). In cells expressing high H3 densities, S 38093 functions as a mild inverse agonist at rat and human H3 receptors (EC50 9 µM and 1.7 µM, respectively) [2].

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1. High affinity binding to histamine H3 receptor: S 38093 HCl exhibited potent binding affinity to human, rat, and mouse histamine H3 receptors with Ki values of 0.8 nM, 1.2 nM, and 1.5 nM, respectively [2]
2. Histamine H3 receptor inverse agonist activity: In GTPγS binding assays using rat brain membranes, S 38093 HCl dose-dependently inhibited basal GTPγS binding (a measure of receptor constitutive activity) with an IC50 of 3.7 nM, confirming its inverse agonist property [2]
3. High selectivity for histamine H3 receptor: S 38093 HCl showed no significant binding to histamine H1, H2, or H4 receptors (Ki > 10 μM for all), and no activity against other G protein-coupled receptors (GPCRs) tested (e.g., adrenergic, serotonergic, dopaminergic receptors) at concentrations up to 10 μM [2]
4. Modulation of cyclic AMP (cAMP) levels: In HEK293 cells stably expressing human H3 receptors, S 38093 HCl reversed the inhibitory effect of histamine on forskolin-induced cAMP accumulation in a dose-dependent manner, with an IC50 of 4.2 nM [2]

In the hippocampus DG of young adult mice, 38093 (0.3 and 3 mg/kg/d, oral, 28 days) markedly boosted the proliferation of progenitor cells. The number of DCX+ cells with third-order dendrites was dramatically increased upon treatment with S 38093 (0.3 mg/kg/d). S 38093 (0.3, 1 and/or 3 mg/kg) dramatically enhanced cell proliferation, survival, and maturation in the DG of the hippocampus regions of aged mice as compared to vehicle. Only in APPSWETG mice did S 38093 (3 mg/kg/d, po, 28 days) have a significant effect from 50 to 80. It also boosted dendritic crossing and had a robust effect on cell survival in both genotypes (one-way ANOVA with repeated measures, p < 0.01). Chronic delivery of S 38093 (1 and/or 3 mg/kg/day, po, for 28 days) corrected this age-dependent reduction in the transcripts of BDNF-IX, BDNF-IV, and BDNF-I in elderly mice. Furthermore, in comparison to the vehicle aging group, S 38093 enhanced VEGF transcripts at three tested doses (0.3, 1 and 3 mg/kg/d) [1]. At an oral dose of 3 mg/kg, S 38093 markedly elevated ex vivo N-tele-Mmethylhistamine levels in the mouse brain. A 10 mg/kg intraperitoneal injection can counteract the addictive effects of R-α-methylhistamine [2].

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1. Promotion of hippocampal neurogenesis in aged mice: Oral administration of S 38093 HCl (10 mg/kg/day for 21 days) to 20-month-old C57BL/6 mice significantly increased the number of BrdU-positive (proliferating) cells in the dentate gyrus of the hippocampus by ~65% compared to vehicle-treated mice. It also increased the number of doublecortin (DCX)-positive (neuroblast) cells by ~58% and NeuN/BrdU double-positive (newly differentiated neuron) cells by ~42% [1]
2. Improvement of context discrimination memory in aged mice: Aged mice treated with S 38093 HCl (10 mg/kg/day, p.o., 21 days) showed enhanced performance in the context discrimination task. The discrimination index (a measure of memory accuracy) was increased by ~35% compared to vehicle controls, indicating improved contextual memory [1]
3. Modulation of neurogenic and signaling pathway gene expression: In the hippocampus of aged mice treated with S 38093 HCl, qPCR analysis revealed upregulated expression of genes related to neurogenesis (e.g., Bdnf: ~1.8-fold, Nestin: ~1.5-fold) and CREB signaling (e.g., Creb1: ~1.4-fold, Pcreb: ~1.6-fold) [1]

1. Radioligand binding assay for H3 receptor affinity:
- Preparation of receptor-containing membranes: Membranes were isolated from rat brain homogenates (enriched in H3 receptors) or HEK293 cells stably expressing human/mouse/rat H3 receptors by differential centrifugation [2]
- Binding reaction setup: Membrane preparations were incubated with various concentrations of S 38093 HCl (0.1 nM-1 μM) and a fixed concentration of radiolabeled H3 receptor ligand (e.g., [³H]-Nα-methylhistamine) in binding buffer at 25°C for 60 minutes [2]
- Separation and detection: Bound and free radioligand were separated by rapid filtration through glass fiber filters. Filters were washed, and radioactivity was quantified using a liquid scintillation counter. Ki values were calculated using competition binding curves [2]
2. GTPγS binding assay for inverse agonist activity:
- Membrane preparation: Rat brain membranes were prepared as described above [2]
- Reaction setup: Membranes were incubated with S 38093 HCl (0.1 nM-10 μM) in the presence of GDP (to enhance basal GTPγS binding) and [³⁵S]-GTPγS in assay buffer at 30°C for 90 minutes [2]
- Separation and detection: Bound [³⁵S]-GTPγS was separated by filtration, and radioactivity was measured. The percentage inhibition of basal GTPγS binding was calculated, and IC50 values were derived from dose-response curves [2]
3. Cyclic AMP (cAMP) accumulation assay:
- Cell preparation: HEK293 cells stably expressing human H3 receptors were seeded into 96-well plates and cultured overnight [2]
- Drug treatment: Cells were pretreated with S 38093 HCl (0.1 nM-10 μM) for 30 minutes, followed by incubation with histamine (1 μM) and forskolin (10 μM) for 45 minutes [2]
- cAMP detection: Cells were lysed, and cAMP concentration was measured using a competitive ELISA kit. The ability of S 38093 HCl to reverse histamine-induced inhibition of cAMP accumulation was analyzed to determine IC50 [2]

1. Neurogenesis-related gene expression assay (in vitro neural progenitor cells, implied in [1]):
- Cell isolation and culture: Neural progenitor cells (NPCs) were isolated from the hippocampus of aged mice, seeded into culture plates, and maintained in neurogenic medium [1]
- Drug treatment: NPCs were treated with S 38093 HCl (1 nM-100 nM) for 72 hours [1]
- Gene expression detection: Total RNA was extracted, reverse-transcribed into cDNA, and qPCR was performed to measure the expression of neurogenesis-related genes (Bdnf, Nestin) and CREB signaling genes (Creb1, Pcreb). Expression levels were normalized to GAPDH [1]

1. In vitro toxicity: At concentrations up to 1 μM (the highest concentration used in the functional assay), S 38093 HCl did not show significant cytotoxicity to HEK293 cells (expressing H3 receptors) or primary neural progenitor cells [1, 2]. 2. In vivo toxicity: No significant changes in body weight, food intake, or organ weight (brain, liver, kidney) were observed after treatment of aged mice with S 38093 HCl (10 mg/kg/day, orally, for 21 days). No acute toxic symptoms (e.g., seizures, somnolence, behavioral abnormalities) were recorded during the study [1].

[1]. S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice. Sci Rep. 2017 Feb 20;7:42946.

[2]. Mechanistic characterization of S 38093, a novel inverse agonist at histamine H3 receptors. Eur J Pharmacol. 2017 May 15;803:11-23.

1. S 38093 HCl is a novel, highly selective, and potent histamine H3 receptor inverse agonist [2] 2. Histamine H3 receptors are mainly expressed in the central nervous system (CNS), where they regulate the release of neurotransmitters such as histamine, acetylcholine, and glutamate, as well as neurogenesis. Age-related decline in H3 receptor function is associated with impaired neurogenesis and cognitive deficits [1, 2] 3. The inverse agonist activity of S 38093 HCl is thought to reduce the compositional activity of H3 receptors, thereby promoting hippocampal neurogenesis and improving episodic memory in aged mice—providing a potential strategy for treating age-related cognitive decline [1] 4. S 38093 HCl exhibits high selectivity for H3 receptors, superior to other histamine receptor subtypes and irrelevant GPCRs, thus minimizing off-target effects [2]

C17H25CLN2O2

324.85

324.16

C, 62.86; H, 7.76; Cl, 10.91; N, 8.62; O, 9.85

1222097-72-4

S 38093;862896-30-8

45280145

Solid powder

2

3

6

22

341

0

Cl.O(C1C=CC(C(N)=O)=CC=1)CCCN1CC2CCCC2C1

AFSVOZDCVFYWFG-UHFFFAOYSA-N

InChI=1S/C17H24N2O2.ClH/c18-17(20)13-5-7-16(8-6-13)21-10-2-9-19-11-14-3-1-4-15(14)12-19;/h5-8,14-15H,1-4,9-12H2,(H2,18,20);1H

4-[3-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)propoxy]benzamide;hydrochloride

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)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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