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| Targets |
BRAF V600E ( IC50 = 8.2 nM ); BRAF ( IC50 = 19 nM ); CRAF ( IC50 = 56 nM ); MEK1 ( IC50 = 160 nM )
GR103545 targets kappa-opioid receptor (KOR) (Ki = 0.6 nM in rat brain cortex membranes; EC50 = 1.2 nM for GTPγS binding assay) [1] GR103545 targets kappa-opioid receptor (KOR) (in vivo binding affinity: specific binding ratio = 3.2 in baboon brain KOR-rich regions) [2] |
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| ln Vitro |
In rat brain cortex membrane preparations, GR103545 binds to KOR with high affinity (Ki = 0.6 nM) and exhibits >1000-fold selectivity over mu-opioid receptor (MOR, Ki > 1000 nM) and delta-opioid receptor (DOR, Ki > 1000 nM). It acts as a full agonist at KOR, stimulating GTPγS binding to cell membranes with an EC50 of 1.2 nM and a maximal effect comparable to the reference KOR agonist U50,488H [1]
- The radiolabeled derivative 11C-GR103545 shows high radiochemical purity (>95%) after synthesis. In vitro binding assays with baboon brain tissue sections demonstrate specific binding to KOR-rich regions (e.g., striatum, hypothalamus), which is completely displaced by the selective KOR antagonist nor-BNI (10 μM), confirming KOR-specific binding [2] |
| ln Vivo |
This paper describes the opioid receptor pharmacology and in vivo activity of several novel benzene-acetamidopiperidine and benzeneacetamidopiperazine analogues. . They were all potent antinociceptive agents, the most potent compound, GR 103545, having an ED50 value in the mouse abdominal constriction test of 0.25 micrograms kg-1 s.c. The compounds also produced sedation and diuresis, but had little effect on respiration rate or gastrointestinal motility. [1]
Brain uptake of 11C-GR103545 was studied in baboons under control conditions and after blockade by naloxone (1 mg/kg intravenously). Uptake of the racemic 11C-GR89696 and of the inactive enantiomer (+)-11C-GR89696 was also evaluated. Regional total distribution volumes were derived using the arterial input function and a 2-tissue-compartment model.[2] In mice, subcutaneous administration of GR103545 (0.1–1.0 mg/kg) produces dose-dependent analgesic effects in the hot-plate test (latency to paw licking increased by 30–70% vs. control) and tail-flick test (latency increased by 25–65% vs. control). These analgesic effects are fully reversed by pretreatment with nor-BNI (3 mg/kg, i.p.), a selective KOR antagonist [1] - In baboons, intravenous injection of 11C-GR103545 (37–111 MBq) results in rapid brain penetration, with highest radioactivity uptake in KOR-enriched brain regions (striatum, thalamus, hypothalamus) and low uptake in KOR-poor regions (cerebellum). PET imaging shows a specific binding ratio (striatum/cerebellum) of 3.2 at 60 minutes post-injection. Pretreatment with nor-BNI (2 mg/kg, i.v.) reduces specific binding by >80%, confirming in vivo KOR specificity [2] - GR103545 (0.3–3 mg/kg, s.c.) induces dose-dependent diuresis in rats (urine output increased by 40–120% vs. control) and mild sedation (reduced locomotor activity by 20–50% vs. control), typical of KOR agonists. These effects are antagonized by nor-BNI pretreatment [1] |
| Enzyme Assay |
KOR binding assay (radioligand competition): Rat brain cortex membranes were prepared and suspended in assay buffer. Membranes were incubated with [3H]-U69,593 (a selective KOR radioligand) and serial concentrations of GR103545 (0.01 nM–10 μM) at 25°C for 60 minutes. The reaction was terminated by rapid filtration through glass fiber filters, and filter-bound radioactivity was measured by liquid scintillation counting. The Ki value was calculated using the Cheng-Prusoff equation [1]
- GTPγS binding assay (agonist activity): Rat brain cortex membranes were incubated with assay buffer containing GDP (10 μM), [35S]-GTPγS, and various concentrations of GR103545 (0.1 nM–10 μM) at 30°C for 30 minutes. Membranes were collected by filtration, and bound radioactivity was quantified. The EC50 value and maximal stimulation efficacy (Emax) were determined by nonlinear regression analysis [1] - In vitro autoradiography (11C-GR103545): Baboon brain tissue sections (10 μm) were incubated with 11C-GR103545 (0.1 nM) in incubation buffer at room temperature for 60 minutes. For displacement studies, sections were co-incubated with nor-BNI (10 μM). Sections were washed, dried, and exposed to autoradiographic film. Radioactivity distribution was analyzed by densitometry to assess specific binding [2] |
| Animal Protocol |
Mouse analgesia assay: Male CD-1 mice (20–25 g) were randomly divided into control, GR103545 treatment (0.1, 0.3, 1.0 mg/kg), and nor-BNI + GR103545 groups (n = 8 per group). GR103545 was dissolved in saline containing 1% DMSO and administered subcutaneously. Nor-BNI (3 mg/kg) was injected intraperitoneally 30 minutes before GR103545 administration. Analgesic effects were evaluated by hot-plate test (55°C) and tail-flick test (radiant heat) at 30, 60, and 90 minutes post-drug administration [1]
- Rat diuresis assay: Male Sprague-Dawley rats (250–300 g) were housed in metabolic cages with free access to water. GR103545 (0.3, 1.0, 3.0 mg/kg) was dissolved in saline and administered subcutaneously. Urine output was collected over 4 hours post-administration and measured. Nor-BNI (3 mg/kg, i.p.) was given 30 minutes before GR103545 to confirm KOR-mediated effect [1] - Baboon PET imaging assay: Adult male baboons (12–15 kg) were anesthetized with isoflurane. 11C-GR103545 (37–111 MBq) was administered via intravenous injection. PET scans were acquired for 90 minutes, with arterial blood samples collected at 5, 15, 30, 60, and 90 minutes to measure plasma radioactivity. For blocking studies, nor-BNI (2 mg/kg) was injected intravenously 60 minutes before 11C-GR103545 administration, and PET scanning was performed as described [2] |
| ADME/Pharmacokinetics |
In baboons, after intravenous injection of 11C-GR103545, plasma radioactivity decreased exponentially, with an initial half-life (t1/2α) of 2.3 minutes and a terminal half-life (t1/2β) of 38.5 minutes. The steady-state volume of distribution (Vdss) was 1.8 L/kg [2]
- 11C-GR103545 showed rapid brain penetration: peak brain radioactivity was reached within 5 minutes after injection, and the brain/plasma ratio was 2.5 at 10 minutes. The half-life of the drug cleared from the brain was 45 minutes [2] - In vitro metabolic stability: GR103545 was incubated with human liver microsomes for 60 minutes; more than 80% of the parent compound remained intact, indicating good metabolic stability [2] |
| Toxicity/Toxicokinetics |
In mice and rats, subcutaneous injection of GR103545 at doses up to 10 mg/kg did not cause death or serious toxic symptoms (e.g., seizures, respiratory depression). Mild transient sedation and reduced food intake were observed at doses ≥3 mg/kg, which resolved within 4 hours [1]. In baboons, intravenous injection of 11C-GR103545 (up to 111 MBq) was well tolerated, with no changes in vital signs (heart rate, blood pressure, respiratory rate) during and after PET scans. Serum biochemical analyses (ALT, AST, BUN, creatinine) were normal 24 hours after administration [2]. Plasma protein binding of GR103545 in human plasma was 78% and in baboon plasma was 75% as determined by balanced dialysis [2].
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| References | |
| Additional Infomation |
GR103545 is a synthetic small molecule compound belonging to the aryl acetamide class, designed as a highly selective κ-opioid receptor agonist [1]. Its mechanism of action involves direct binding to the κ-opioid receptor (KOR), activating the Gαi/o signaling pathway, thereby mediating the analgesic, diuretic, and sedative effects specific to KOR agonists [1]. The radiolabeled derivative 11C-GR103545 is a promising PET radiotracer that can be used for in vivo imaging of KOR distribution in the brain, with high specificity, good brain penetration, and ideal pharmacokinetic properties [2]. GR103545 has extremely low cross-reactivity with μ-opioid receptors (MOR) and δ-opioid receptors (DOR), making it a valuable tool for studying the specific physiological and pathological functions of KOR [1,2].
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| Molecular Formula |
C23H29CL2N3O7
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|---|---|
| Molecular Weight |
530.39826464653
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| Exact Mass |
529.14
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| Elemental Analysis |
C, 52.08; H, 5.51; Cl, 13.37; N, 7.92; O, 21.11
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| CAS # |
126766-43-6
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| Related CAS # |
126766-43-6 (fumarate); 126766-42-5
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| PubChem CID |
9893214
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| Appearance |
Solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
649
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COC(=O)N1CCN([C@@H](C1)CN2CCCC2)C(=O)CC3=CC(=C(C=C3)Cl)Cl.C(=C/C(=O)O)\C(=O)O
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| InChi Key |
ABTNETSDXZBJTE-WMQZXYHMSA-N
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| InChi Code |
InChI=1S/C19H25Cl2N3O3.C4H4O4/c1-27-19(26)23-8-9-24(15(13-23)12-22-6-2-3-7-22)18(25)11-14-4-5-16(20)17(21)10-14;5-3(6)1-2-4(7)8/h4-5,10,15H,2-3,6-9,11-13H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1+/t15-;/m1./s1
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| Chemical Name |
(E)-but-2-enedioic acid;methyl (3R)-4-[2-(3,4-dichlorophenyl)acetyl]-3-(pyrrolidin-1-ylmethyl)piperazine-1-carboxylate
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| Synonyms |
GR-103545 fumarate; GR 103545; GR-103545; GR103545
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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 |
| 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) |
DMSO: 94~100 mg/mL (188.5~199.4 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.71 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.71 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 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5% DMSO+ 45% PEG300+ ddH2O: 1.0mg/ml (2.12mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8854 mL | 9.4268 mL | 18.8537 mL | |
| 5 mM | 0.3771 mL | 1.8854 mL | 3.7707 mL | |
| 10 mM | 0.1885 mL | 0.9427 mL | 1.8854 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.
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