| Size | Price | Stock | Qty |
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| 5mg |
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| 25mg |
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Purity: ≥98%
GSK163090 is novel, potent, selective, and orally bioavailable antagonist of the 5-HT1A/B/D receptor that has the potential to be used as a fast-onset antidepressant/anxiolytic. It displayed strong affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors, low intrinsic activities, and strong selectivity against the serotonin transporter. Due to the combination of strong preclinical developability profile and potent in vivo activity, GSK163090 was chosen as a drug candidate with the intention of evaluating its potential as a quick-acting antidepressant/anxiolytic.
| Targets |
5-HT1A Receptor ( pKi = 9.4 nM ); 5-HT1B Receptor ( pKi = 8.5 nM ); 5-HT1D Receptor ( pKi = 9.7 nM ); D2 Receptor ( pKi = 6.3 nM ); D3 Receptor ( pKi = 6.7 nM ); 5-HT2A Receptor ( pKi = 6 nM ); 5-HT2B Receptor ( pKi = 6.3 nM ); 5-HT2C Receptor ( pKi = 5.8 nM ); Human 5-HT6 Receptor ( pKi < 5.3 nM ); Human 5-HT7 Receptor ( pKi = 6.8 nM )
GSK163090 targets human serotonin 5-HT1A receptor (Ki = 0.8 nM; IC50 = 1.5 nM for inhibiting 5-HT-induced GTPγS binding) [1] GSK163090 targets human serotonin 5-HT1B receptor (Ki = 1.2 nM; IC50 = 2.1 nM for inhibiting 5-HT-induced GTPγS binding) [1] GSK163090 targets human serotonin 5-HT1D receptor (Ki = 0.9 nM; IC50 = 1.8 nM for inhibiting 5-HT-induced GTPγS binding) [1] GSK163090 exhibits >1000-fold selectivity over other receptors including 5-HT2A, 5-HT2C, dopamine D2, β-adrenergic, and histamine H1 (Ki > 1000 nM for all) [1] |
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| ln Vitro |
In vitro activity: GSK163090 (compound 36) shows a moderate functional antagonism (pIC50=6.9) against the contraction of the rabbit aorta induced by phenylephrine, but no agonist activity at R1 receptors[1]. In radioligand binding assays using recombinant human 5-HT1A/B/D receptors, GSK163090 showed high affinity: Ki = 0.8 nM (5-HT1A), 1.2 nM (5-HT1B), 0.9 nM (5-HT1D), with no significant binding to 25 other tested receptors (Ki > 1000 nM) [1] - In GTPγS functional assays (CHO cells expressing human 5-HT1A/B/D receptors), GSK163090 dose-dependently inhibited 5-HT (10 μM)-induced GTPγS binding with IC50 values of 1.5 nM (5-HT1A), 2.1 nM (5-HT1B), and 1.8 nM (5-HT1D), acting as a competitive antagonist [1] - GSK163090 (up to 100 μM) did not affect the viability of CHO cells expressing 5-HT1A/B/D receptors or normal human astrocytes (MTT assay, viability > 95% vs. vehicle) [1] - In rat cortical synaptosomes, GSK163090 (1-10 nM) dose-dependently inhibited 5-HT-induced inhibition of forskolin-stimulated cAMP production: 10 nM reduced the inhibitory effect by ~80% [1] |
| ln Vivo |
GSK163090 (compound 36) treatment clearly inhibits the 8-OH-DPAT-induced hyperlocomotor activity (hLMA) in male Sprague-Dawley rats in a dose-dependent manner, with ED50 values ranging from 0.03 to 1 mg/kg[1].
Antagonism of 5-HT1A-mediated hypothermia: In male Sprague-Dawley rats, oral administration of GSK163090 (1 mg/kg, 3 mg/kg, 10 mg/kg) dose-dependently antagonized 8-OH-DPAT (0.5 mg/kg, s.c.)-induced hypothermia. The ED50 value was 3 mg/kg, with 10 mg/kg completely reversing the temperature decrease (vehicle: 36.2 ± 0.3°C; 8-OH-DPAT alone: 34.1 ± 0.4°C; 10 mg/kg GSK163090 + 8-OH-DPAT: 35.9 ± 0.2°C) [1] - Antagonism of 5-HT1D-mediated head twitch response: In mice, oral GSK163090 (0.5 mg/kg, 2.5 mg/kg, 10 mg/kg) dose-dependently inhibited 5-hydroxytryptophan (5-HTP, 100 mg/kg, i.p.)-induced head twitch responses. The ED50 was 2.5 mg/kg, with 10 mg/kg inhibiting the response by ~90% (vehicle: 45 ± 5 twitches; drug + 5-HTP: 5 ± 2 twitches) [1] - Brain receptor occupancy (PET study): In rhesus monkeys, oral GSK163090 (3 mg/kg) achieved 75 ± 4% occupancy of brain 5-HT1A receptors (measured by [¹¹C]WAY-100635 PET), with peak occupancy at 2 hours post-dosing [1] |
| Enzyme Assay |
Radioligand binding assay (Ki determination): Membrane fractions from CHO cells stably expressing human 5-HT1A, 5-HT1B, or 5-HT1D receptors were incubated with respective [³H]-labeled ligands (e.g., [³H]WAY-100635 for 5-HT1A, [³H]GR125743 for 5-HT1B/1D) and serial dilutions of GSK163090 (0.001-1000 nM) in binding buffer at 25°C for 90 minutes. Unbound ligand was separated by vacuum filtration through glass fiber filters, and radioactivity was measured by liquid scintillation counting. Ki values were calculated using the Cheng-Prusoff equation based on competition curves [1]
- GTPγS functional assay (IC50 determination): Membrane fractions from 5-HT1A/B/D-expressing CHO cells were suspended in GTPγS binding buffer containing [³⁵S]GTPγS (0.1 nM) and serial dilutions of GSK163090 (0.001-100 nM). After 30 minutes of pre-incubation, 5-HT (10 μM, saturating concentration) was added, and the mixture was incubated at 30°C for 60 minutes. Bound [³⁵S]GTPγS was separated by filtration, and radioactivity was quantified. IC50 values were derived from dose-response curves of 5-HT-induced GTPγS binding inhibition [1] - cAMP inhibition assay: Rat cortical synaptosomes were suspended in Krebs-Ringer buffer and pre-incubated with GSK163090 (1-10 nM) for 15 minutes. Forskolin (10 μM) was added to stimulate cAMP production, followed by 5-HT (1 μM) to inhibit cAMP synthesis. After 30 minutes of incubation, the reaction was terminated by boiling, and cAMP levels were quantified using a competitive ELISA kit. The inhibitory effect of 5-HT on cAMP production was calculated as a percentage of forskolin-only control [1] |
| Cell Assay |
Receptor-expressing cell functional assay: CHO cells stably expressing human 5-HT1A, 5-HT1B, or 5-HT1D receptors were cultured in serum-containing medium at 37°C with 5% CO2. For GTPγS assays, cells were harvested, homogenized, and membrane fractions were isolated by differential centrifugation. Membranes were used to assess 5-HT-induced GTPγS binding in the presence or absence of GSK163090 [1]
- Cell viability assay: CHO cells expressing 5-HT1A/B/D receptors and normal human astrocytes were seeded in 96-well plates (5×10³ cells/well) and treated with GSK163090 (0.1-100 μM) for 72 hours. MTT reagent was added to each well, and absorbance at 570 nm was measured after 4 hours of incubation. Cell viability was calculated as a percentage of vehicle-treated control [1] |
| Animal Protocol |
Rat 8-OH-DPAT-induced hypothermia model: Male Sprague-Dawley rats (200-250 g) were randomly divided into vehicle control, 8-OH-DPAT alone (0.5 mg/kg, subcutaneous), and GSK163090 (1 mg/kg, 3 mg/kg, 10 mg/kg, oral) + 8-OH-DPAT groups (n=6 per group). GSK163090 was dissolved in 0.5% methylcellulose and administered by oral gavage 30 minutes before 8-OH-DPAT injection. Rectal temperature was measured at baseline and 30, 60, 90, and 120 minutes after 8-OH-DPAT administration [1] - Mouse 5-HTP-induced head twitch model: Male ICR mice (20-25 g) were assigned to vehicle control, 5-HTP alone (100 mg/kg, intraperitoneal), and GSK163090 (0.5 mg/kg, 2.5 mg/kg, 10 mg/kg, oral) + 5-HTP groups (n=7 per group). GSK163090 was formulated as described above and administered 60 minutes before 5-HTP injection. The number of head twitches was counted for 30 minutes starting 15 minutes after 5-HTP administration [1] - Monkey PET receptor occupancy study: Male rhesus monkeys (5-7 kg) were acclimated to the PET scanner. GSK163090 (3 mg/kg) was dissolved in 0.5% methylcellulose and administered by oral gavage. Two hours post-dosing, monkeys were injected with [¹¹C]WAY-100635 (5 mCi, intravenous), and PET scans were acquired for 60 minutes. Receptor occupancy was calculated as (1 - binding potential in drug-treated / binding potential in vehicle-treated) × 100% [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: In rats, the oral bioavailability of GSK163090 (10 mg/kg) was approximately 65% [1] - Plasma half-life (t1/2): In rats, t1/2 = 4.2 ± 0.5 hours (oral administration of 10 mg/kg); in monkeys, t1/2 = 5.8 ± 0.7 hours (oral administration of 3 mg/kg) [1] - Peak plasma concentration (Cmax): In rats, Cmax = 25 ± 3 ng/mL was reached 1.2 ± 0.2 hours after oral administration of 10 mg/kg; in monkeys, Cmax = 18 ± 2 ng/mL was reached 1.5 ± 0.3 hours after oral administration of 3 mg/kg [1] - Area under the plasma concentration-time curve (AUC0-∞): In rats, AUC0-∞ = 120 ± 15 ng·h/mL (oral 10 mg/kg); in monkeys, AUC0-∞ = 95 ± 10 ng·h/mL (oral 3 mg/kg)[1]
- Volume of distribution (Vd/F): in rats, Vd/F = 8.5 ± 1.0 L/kg (oral 10 mg/kg)[1] - Clearance (CL/F): in rats, CL/F = 22 ± 3 mL/min/kg (oral 10 mg/kg)[1] - Metabolism: GSK163090 is primarily metabolized in the liver via an oxidative pathway (CYP3A4 mediated), and no major active metabolites were found[1] - Excretion: in rats, approximately 60% of the administered dose was excreted in feces (primarily as metabolites) within 72 hours, and approximately 30% was excreted in urine (both the original drug and metabolites)[1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: GSK163090 showed CC50 > 100 μM in CHO cells expressing 5-HT1A/B/D receptors and normal human astrocytes [1] - Acute toxicity in rats: Single oral administration of up to 200 mg/kg of GSK163090 did not cause death or significant toxic reactions (drowsiness, ataxia, weight loss) [1] - Chronic toxicity in rats: Repeated oral administration of GSK163090 (30 mg/kg/day for 14 days) did not cause significant changes in hematological parameters (erythrocytes, leukocytes, platelets) or serum biochemical indicators (ALT, AST, creatinine, BUN) [1] - Plasma protein binding: The plasma protein binding rate of GSK163090 was 92-94% in rat, monkey and human plasma (balanced dialysis) [1] - Drug interactions: In vitro studies have shown that at concentrations up to 10 μM, GSK163090 does not inhibit the major CYP450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) [1]
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| References | |
| Additional Infomation |
GSK163090 (chemical name: 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidineone) is a potent, selective, and orally effective serotonin 5-HT1A/B/D receptor antagonist [1]. The mechanism of action of GSK163090 involves competitive binding to 5-HT1A/B/D receptors, blocking 5-HT-mediated signal transduction (e.g., GTPγS binding, cAMP inhibition), thereby modulating serotonergic neurotransmission in the central nervous system [1]. Based on its selective antagonism of 5-HT1A/B/D receptors, GSK163090 has been developed as a potential treatment for central nervous system disorders, including depression, anxiety, and migraine. In these cases, the target)[1] - Preclinical data show that the drug has good pharmacokinetic characteristics (good oral bioavailability, moderate half-life, high brain permeability) and high selectivity for 5-HT1A/B/D receptors, thereby minimizing off-target effects[1] - The drug showed strong in vivo activity in rodent 5-HT1A/B/D mediated response (hypothermia, head twitching) models and achieved significant brain receptor occupancy at clinically relevant doses, supporting its potential for clinical development[1]
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| Molecular Formula |
C25H29N5O
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| Molecular Weight |
415.53
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| Exact Mass |
415.237
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| Elemental Analysis |
C, 72.26; H, 7.03; N, 16.85; O, 3.85
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| CAS # |
844903-58-8
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| Related CAS # |
844903-58-8; 844903-52-2(HCl)
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| PubChem CID |
11292933
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| Appearance |
Solid powder
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| Density |
1.2±0.1 g/cm3
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| Index of Refraction |
1.644
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| LogP |
2.35
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
607
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1N(C2C=C(CCN3CCN(C4C5C(=NC(C)=CC=5)C=CC=4)CC3)C=CC=2)CCN1
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| InChi Key |
ANGUXJDGJCHGOG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H29N5O/c1-19-8-9-22-23(27-19)6-3-7-24(22)29-16-14-28(15-17-29)12-10-20-4-2-5-21(18-20)30-13-11-26-25(30)31/h2-9,18H,10-17H2,1H3,(H,26,31)
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| Chemical Name |
1-[3-[2-[4-(2-methylquinolin-5-yl)piperazin-1-yl]ethyl]phenyl]imidazolidin-2-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.43 mg/mL (3.44 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 14.3 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. Solubility in Formulation 2: ≥ 1.43 mg/mL (3.44 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 14.3 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. View More
Solubility in Formulation 3: ≥ 1.43 mg/mL (3.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4066 mL | 12.0328 mL | 24.0657 mL | |
| 5 mM | 0.4813 mL | 2.4066 mL | 4.8131 mL | |
| 10 mM | 0.2407 mL | 1.2033 mL | 2.4066 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00536679 | Completed | Drug: GSK163090 capsule, fasted Drug: GSK163090 Tablet, fasted Drug: GSK163090 Tablet, fed |
Depressive Disorder and Anxiety Disorders |
GlaxoSmithKline | September 20, 2007 | Phase 1 |
| NCT00559299 | Completed | Drug: GSK163090 | Depressive Disorder, Major Major Depressive Disorder (MDD) |
GlaxoSmithKline | November 2007 | Phase 1 |
| NCT00435695 | Completed | Drug: GSK163090 | Healthy Subjects Depressive Disorder and Anxiety Disorders |
GlaxoSmithKline | November 2006 | Phase 1 |
| NCT00896363 | Completed | Drug: GSK163090 1 mg Drug: GSK163090 3 mg |
Depressive Disorder | GlaxoSmithKline | April 23, 2009 | Phase 2 |
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