5-HT₆ Receptor ( Ki = 2.2 nM ); 5-HT₆ Receptor ( EC50 = 6.6 nM )
5-HT6 Receptor: WAY-181187 is a potent and selective 5-HT6 receptor agonist. It displays high affinity binding at the human 5-HT6 receptor (Ki = 2.2 ± 0.3 nM). In a functional cAMP assay, it acts as a full agonist (EC50 = 6.6 ± 0.8 nM; Emax = 93.3% ± 2.1% relative to 5-HT). [1]

WAY-181187 (1 and 10 μM) enhances ERK1/2 activation. WAY-181187 wood increases Fyn Manhattan activity[2]. Western Blot Analysis[2] Cell line: HEK/HA-5-HT6 receptor cell concentration: 1 and 10 μM Incubation time: 5 minutes of pretreatment Results: The activation of ERK1/2 increased at both 1 and 10 μM concentrations.

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Receptor Selectivity: In binding assays against a panel of other monoamine receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C antagonist site, 5-HT2C agonist site, 5-HT7, D2, D3, D4, α1), WAY-181187 demonstrated selectivity for the 5-HT6 receptor. It showed 60-fold selectivity over the 5-HT2C agonist binding site (Ki = 124 nM). At 1 μM, it showed no significant inhibition (0-51%) of binding at most receptors tested, except for 5-HT2B (Ki = 459 nM) and α1 (Ki = 1334 nM). [1]
- Effect on Stimulated Glutamate Release in Hippocampal Slices: In rat hippocampal slice preparations, WAY-181187 (0.1 - 10 μM) was tested for its ability to modulate glutamate release. Sodium azide (10 mM) treatment significantly increased glutamate release. Pretreatment with WAY-181187 dose-dependently attenuated this sodium azide-stimulated increase. Significant effects were observed at concentrations of 0.3 μM (P < 0.0001), 1 μM (P = 0.0492), 3 μM (P < 0.0001), and 10 μM (P < 0.0001). [1]
- Effect on High KCl-Stimulated Glutamate Release in Hippocampal Slices: In rat hippocampal slices, high KCl (50 mM) treatment significantly increased glutamate release. Co-treatment with WAY-181187 (3 - 100 μM) significantly attenuated this KCl-stimulated glutamate release at concentrations of 30 μM (P = 0.0059) and showed a trend at 100 μM (P = 0.0775). [1]

Acute administration of WAY-181187 (3-30 mg/kg, sc) significantly increased extracellular GABA concentrations without altering glutamate or nordepine levels in the FX frontal lobes. Additionally, WAY-181187 (30 mg/kg, sc) modulates but significantly reduces cortical dopamine and 5-HT levels [1]. Animal model: Adult male Sprague-Dawley rat, body weight 280–350 g[1] Dosage: 3, 10 or 30 mg/kg Administration: Acute subcutaneous administration Results: Significant increase in extracellular GABA concentration without alteration Levels of glutamate or norepinephrine.

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Neurochemical Effects in Rat Frontal Cortex: Acute subcutaneous administration of WAY-181187 (3-30 mg/kg) significantly increased extracellular GABA concentrations in a dose-dependent manner (maximal increase of 220% at 30 mg/kg). This effect was blocked by pretreatment with the 5-HT6 antagonist SB-271046 (10 mg/kg, s.c.). WAY-181187 also produced modest but significant decreases in cortical dopamine (27% decrease at 30 mg/kg) and serotonin (37% decrease at 30 mg/kg) levels, which were also blocked by SB-271046 and reversed by local infusion of the GABAA antagonist bicuculline (10 μM). No significant effects were observed on cortical glutamate or norepinephrine levels. [1]
- Neurochemical Effects in Rat Striatum: Acute administration of WAY-181187 (10-30 mg/kg, s.c.) significantly elevated extracellular GABA levels (maximal increase of 518% at 30 mg/kg). It also significantly decreased striatal dopamine levels at 30 mg/kg (34% decrease), an effect blocked by SB-271046 (10 mg/kg, s.c.). No significant effects were observed on norepinephrine, serotonin, or glutamate in this region. [1]
- Neurochemical Effects in Rat Dorsal Hippocampus: Acute treatment with WAY-181187 (10-30 mg/kg, s.c.) significantly elevated extracellular GABA levels (maximal increase of 196% at both doses). No significant effects were reported on other neurotransmitters measured. [1]
- Neurochemical Effects in Rat Amygdala: Acute administration of WAY-181187 (10-30 mg/kg, s.c.) produced robust increases in extracellular GABA levels (up to 215% above baseline). It also significantly increased extracellular norepinephrine levels at 30 mg/kg (42% increase). [1]
- Neurochemical Effects in Rat Nucleus Accumbens and Thalamus: Acute treatment with WAY-181187 had no significant effect on extracellular GABA levels in the nucleus accumbens or thalamus. [1]
- Behavioral Effects in Schedule-Induced Polydipsia (SIP) Model: In the rat SIP model of obsessive-compulsive disorder, acute oral administration of WAY-181187 dose-dependently decreased adjunctive drinking behavior. A significant effect was observed at 178 mg/kg (p.o.). It did not modify drinking behavior under control conditions (all pellets given at start), indicating no nonspecific effects on drinking. [1]

5-HT6 Receptor Binding Assay: The binding affinity was determined using membrane preparations from HeLa cells expressing the human 5-HT6 receptor. The reaction was conducted in 96-well plates with [3H]LSD as the radioligand in a buffer containing Tris-HCl, MgSO4, and EDTA. Non-specific binding was determined with 10 μM methiothepin. The reaction proceeded in the dark for 120 minutes at room temperature, after which the bound complex was filtered and the radioactivity was measured. Ki values were calculated from IC50 estimates using the Cheng-Prusoff equation. [1]
- 5-HT6 Receptor cAMP Functional Assay: HeLa cells transfected with the human 5-HT6 receptor were washed and incubated in Krebs buffer with IBMX for 5 minutes at 37°C. Cells were then stimulated with various concentrations of WAY-181187 for an additional 10 minutes at 37°C. The assay was terminated with perchloric acid, and intracellular cAMP levels were measured by radioimmunoassay. EC50 and Emax values were determined from log-concentration response curves. [1]

Cell Line: HEK/HA-5-HT6 receptor cells
Concentration: 1 and 10 μM
Incubation Time: Pretreatment 5 minutes
Result: Increased activation of ERK1/2 both at 1 and 10 μM concentrations.

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Cell Culture for cAMP Assay: Human astrocytoma 1321N1 cells stably expressing the human 5-HT6 receptor gene were cultured in DMEM supplemented with 10% FBS, 1 mM sodium pyruvate, and 400 μg/mL G418 at 37°C in a 5% CO2 atmosphere. [2]
- Cell Culture for Calcium, ERK, and Fyn Assays: HEK293 cells stably expressing the HA-5-HT6 receptor were used. They were grown in DMEM supplemented with 10% FBS, penicillin (100 units/mL), streptomycin (100 μg/mL), and G-418 (400 μg/mL) at 37°C in a humidified atmosphere of 5% CO2 and 95% air. For the calcium assay, cells were transiently transfected with Gα15 protein for 24 hours. [2]

Adult male Sprague-Dawley rats weighing 280–350 g
3, 10, or 30 mg/kg
Acute dministered by s.c.

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Acute Microdialysis Studies:** Adult male Sprague-Dawley rats were used. Stereotaxic surgery was performed to implant guide cannulae into various brain regions under halothane anesthesia. Microdialysis probes were implanted and perfused with artificial cerebrospinal fluid at 1 μL/min. After a stabilization period, five baseline samples were collected. Subsequently, animals received either vehicle (2% Tween/0.5% Dextrose in water) or a pretreatment (e.g., SB-271046 at 10 mg/kg, s.c.). Approximately 20 minutes later, WAY-181187 (3, 10, or 30 mg/kg, s.c.) or vehicle was administered. Dialysate samples were collected every 20 minutes. For local infusion studies, the GABAA antagonist bicuculline (10 μM) was infused through the microdialysis probe at 1 μL/min for 1 hour. [1]
- **Chronic Microdialysis Studies:** For chronic treatment with WAY-208466, rats received daily injections (s.c.) of either vehicle or WAY-208466 (10 mg/kg) for 14 days in their home cages. On day 14, they underwent surgery for guide cannula implantation above the frontal cortex. Microdialysis was performed the following day, with an acute challenge of the same compound administered during the experiment. [1]
- **In Vitro Hippocampal Slice Superfusion:** Rat hippocampal slices were prepared and placed in a superfusion apparatus. Tissues were perfused with oxygenated Krebs buffer at 0.4 mL/min. After a 60-minute equilibration, baseline fractions were collected. For sodium azide experiments, tissues were pretreated with WAY-181187 for 30 minutes before and during a 30-minute azide (10 mM) challenge. For KCl experiments, WAY-181187 was co-applied with 50 mM KCl for 30 minutes. Samples were collected for HPLC analysis of amino acids. [1]
- **Schedule-Induced Polydipsia (SIP) Model:** Individually housed male Sprague-Dawley rats, maintained at approximately 85% of free-feeding body weight, were placed in operant chambers with free access to water. One food pellet was delivered every minute of the 120-minute test session, which induced adjunctive drinking. On test days, WAY-181187 (1-178 mg/kg, p.o.) was administered acutely to assess its effect on water intake. [1]

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Acute Microdialysis Studies: Adult male Sprague-Dawley rats were used. Stereotaxic surgery was performed to implant guide cannulae into various brain regions under halothane anesthesia. Microdialysis probes were implanted and perfused with artificial cerebrospinal fluid at 1 μL/min. After a stabilization period, five baseline samples were collected. Subsequently, animals received either vehicle (2% Tween/0.5% Dextrose in water) or a pretreatment (e.g., SB-271046 at 10 mg/kg, s.c.). Approximately 20 minutes later, WAY-181187 (3, 10, or 30 mg/kg, s.c.) or vehicle was administered. Dialysate samples were collected every 20 minutes. For local infusion studies, the GABAA antagonist bicuculline (10 μM) was infused through the microdialysis probe at 1 μL/min for 1 hour. [1]
- Chronic Microdialysis Studies: For chronic treatment with WAY-208466, rats received daily injections (s.c.) of either vehicle or WAY-208466 (10 mg/kg) for 14 days in their home cages. On day 14, they underwent surgery for guide cannula implantation above the frontal cortex. Microdialysis was performed the following day, with an acute challenge of the same compound administered during the experiment. [1]
- In Vitro Hippocampal Slice Superfusion: Rat hippocampal slices were prepared and placed in a superfusion apparatus. Tissues were perfused with oxygenated Krebs buffer at 0.4 mL/min. After a 60-minute equilibration, baseline fractions were collected. For sodium azide experiments, tissues were pretreated with WAY-181187 for 30 minutes before and during a 30-minute azide (10 mM) challenge. For KCl experiments, WAY-181187 was co-applied with 50 mM KCl for 30 minutes. Samples were collected for HPLC analysis of amino acids. [1]
- Schedule-Induced Polydipsia (SIP) Model: Individually housed male Sprague-Dawley rats, maintained at approximately 85% of free-feeding body weight, were placed in operant chambers with free access to water. One food pellet was delivered every minute of the 120-minute test session, which induced adjunctive drinking. On test days, WAY-181187 (1-178 mg/kg, p.o.) was administered acutely to assess its effect on water intake. [1]

[1]. Neuropharmacological Profile of Novel and Selective 5-HT6 Receptor Agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology. 2008 May;33(6):1323-35.

[2]. ST1936 Stimulates cAMP, Ca2+, ERK1/2 and Fyn Kinase Through a Full Activation of Cloned Human 5-HT6 Receptors. Eur J Pharmacol. 2011 Jul 1;661(1-3):8-14.

Background: WAY-181187 is a novel, selective, and potent full agonist at the 5-HT6 receptor. It was developed to investigate the biological consequences of 5-HT6 receptor stimulation, an area previously hampered by the lack of suitable agonists for in vivo study. [1]
- Mechanism of Action: WAY-181187 activates the 5-HT6 receptor, a G-protein-coupled receptor that positively stimulates adenylate cyclase. Its activation leads to region-specific increases in extracellular GABA levels in corticlimbic brain structures. The resulting GABAergic tone can indirectly modulate glutamatergic and monoaminergic (dopamine, serotonin, norepinephrine) neurotransmission. The neurochemical effects are mediated by 5-HT6 receptors, as they are blocked by the selective antagonist SB-271046. [1]
- Therapeutic Potential: Based on its ability to elevate GABA levels and attenuate stimulated glutamate release, WAY-181187 is suggested to have potential therapeutic utility in the treatment of anxiety-related disorders, such as obsessive-compulsive disorder, as demonstrated by its efficacy in the SIP model. The authors also hypothesize that 5-HT6 receptor agonists may have antidepressant-like activity, potentially by increasing BDNF expression and offering an acute onset of action. [1]

C15H13CLN4O2S2

380.87232

380.017

554403-49-5

WAY-181187 oxalate; 1883548-85-3; WAY-181187 hydrochloride; 554403-08-6

10150497

White to yellow solid powder

4.523

1

5

4

24

572

0

RYBOXBBYCVOYNO-UHFFFAOYSA-N

InChI=1S/C15H13ClN4O2S2/c16-13-14(19-7-8-23-15(19)18-13)24(21,22)20-9-10(5-6-17)11-3-1-2-4-12(11)20/h1-4,7-9H,5-6,17H2

2-[1-(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonylindol-3-yl]ethanamine

WAY-181187; WAY 181187; WAY181187; SAX187; SAX-187; SAX187

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: ~100 mg/mL (~262.6 mM）

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.56 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 (6.56 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 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: ≥ 2.5 mg/mL (6.56 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.)