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| Targets |
L-745870 HCl primarily targets the dopamine D4 receptor, a G protein-coupled receptor involved in cognitive function, attention, and emotional regulation. It acts as a potent antagonist with a Ki of 0.43 nM for the human D4 receptor. The compound exhibits high selectivity for D4 over D2 (Ki = 960 nM) and D3 (Ki = 2300 nM) receptors, making it a valuable tool for studying D4 receptor-specific functions. L-745870 HCl also shows moderate affinity for 5-HT2 receptors, sigma sites, and α-adrenoceptors, indicating some off-target interactions.
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| ln Vitro |
In transfected human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells, L-745870 inhibits the capacity of D4 receptors to suppress agonist-induced stimulation of [35S]-GTPgS binding. It also prevents forskolin-stimulated glandular stimulation. Glycolate cyclase activity inhibition, blocking dopamine-induced suppression of the Ca2+ current in transfected GH4C1 pituitary cells, blocking D4 activation of clonal G protein-coupled inward rectifier K+ channels, and counteracting the stimulation of extracellular acidification of transfected cells caused by dopamine[1].
In vitro, L-745870 HCl functions as a potent and selective dopamine D4 receptor antagonist with a Ki of 0.43 nM. It demonstrates considerably weaker affinity for D2 (Ki = 960 nM) and D3 (Ki = 2300 nM) receptors. The compound exhibits moderate affinity for 5-HT2 receptors, sigma sites, and α-adrenoceptors. Binding affinity is typically measured using radioligand displacement assays in membrane preparations expressing recombinant human receptors. The high selectivity of L-745870 HCl for D4 receptors makes it useful for studying D4 receptor-mediated signaling pathways without significant off-target effects. |
| ln Vivo |
L-745870 has outstanding pharmacokinetic features in both rats and monkeys (oral bioavailability 20-60%, plasma t1/2 2.1-2.8 hours) and great brain penetration in rats and high brain-to-plasma ratio[1]. Oral treatment of L745870 (10 mg/kg p.o.) to squirrel monkeys elicited mild sedation and extrapyramidal motor symptoms, mainly bradykinesia, which became obvious at the 30 mg/kg dose. Lower doses of L-745870 exhibited no observable behavioral effects in monkeys [1].
In vivo, L-745870 HCl is orally active and brain-penetrant, making it suitable for studying central nervous system effects. It has been investigated in animal models of schizophrenia and other neuropsychiatric disorders. The compound's ability to cross the blood-brain barrier allows for direct assessment of D4 receptor antagonism in the brain. Behavioral studies in rodents have been used to evaluate the functional consequences of D4 receptor blockade. L-745870 HCl has been characterized in various preclinical models to understand the role of D4 receptors in cognition, attention, and emotional processing. |
| Enzyme Assay |
The cell-free receptor binding assay for L-745870 HCl involves incubating the compound with membrane preparations from cells expressing recombinant human dopamine D4 receptors. Radioligand displacement studies are performed using [3H]-labeled D4 receptor ligands to determine binding affinity (Ki values). The assay typically uses varying concentrations of L-745870 HCl (ranging from pM to μM) to compete with the radioligand for receptor binding. IC50 values are determined from competition curves, and Ki values are calculated using the Cheng-Prusoff equation. Selectivity is assessed by testing the compound against D2, D3, and other related receptors.
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| Cell Assay |
For in vitro cellular assays, L-745870 HCl is typically dissolved in DMSO and diluted in cell culture medium to desired concentrations. Cells expressing recombinant dopamine D4 receptors are treated with the compound at various concentrations (ranging from nM to μM). Functional assays such as cAMP accumulation or calcium flux measurements are used to assess antagonist activity. Receptor binding assays are performed using membrane preparations and radioligand displacement techniques. Data analysis involves calculating IC50 and Ki values from dose-response curves, comparing the compound's potency across different receptor subtypes to determine selectivity.
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| Animal Protocol |
In vivo animal studies of L-745870 HCl typically involve oral administration or intraperitoneal injection in rodent models. The compound is formulated in appropriate vehicles such as saline or PEG-based solutions for administration. Behavioral assays including prepulse inhibition, open field test, and novel object recognition are used to evaluate the effects of D4 receptor antagonism. Brain penetration is confirmed by measuring drug concentrations in brain tissue using LC-MS/MS. Pharmacodynamic endpoints include assessment of D4 receptor occupancy in brain regions using radioligand binding techniques.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of L-745870 HCl include a molecular weight of 363.28 g/mol and molecular formula C18H20Cl2N4. The compound is orally active with good brain penetration, making it suitable for central nervous system studies. It has a purity of ≥98% and is soluble in DMSO. The compound's ability to cross the blood-brain barrier (BBB) is a key feature for its use in neuropharmacology research. Detailed ADME parameters such as half-life, bioavailability, and tissue distribution are available in published literature.
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| Toxicity/Toxicokinetics |
The toxicity profile of L-745870 HCl has been characterized in preclinical studies. As a selective D4 receptor antagonist, the compound is generally well-tolerated at research doses. Standard safety pharmacology studies would include assessment of cardiovascular, respiratory, and central nervous system effects. The compound is intended for research use only and not for therapeutic applications in humans. L-745870 HCl should be handled with appropriate safety precautions, including the use of personal protective equipment and proper disposal procedures.
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| References |
[1]. Bristow LJ, et al. Schizophrenia and L-745,870, a novel dopamine D4 receptor antagonist. Trends Pharmacol Sci. 1997 Jun;18(6):186-8.
[2]. Patel S, et al. Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J Pharmacol Exp Ther. 1997 Nov;283(2):636-47. [3]. Kulagowski JJ, et al. 3-((4-(4-Chlorophenyl)piperazin-1-yl)-methyl)-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J Med Chem. 1996 May 10;39(10):1941-2. |
| Additional Infomation |
L-745870 HCl is a potent, selective, brain-penetrant, and orally active dopamine D4 receptor antagonist (Ki = 0.43 nM). It shows weaker affinity for D2 (Ki = 960 nM) and D3 (Ki = 2300 nM) receptors and moderate affinity for 5-HT2 receptors, sigma sites, and α-adrenoceptors. The compound has been investigated in schizophrenia research and as a tool for understanding D4 receptor function. L-745870 HCl has not been approved for clinical use and is strictly for research purposes. Key references: Bristow LJ, et al. Trends Pharmacol Sci. 1997; Patel S, et al. J Pharmacol Exp Ther. 1997; Kulagowski JJ, et al. J Med Chem. 1996.
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| Molecular Formula |
C18H20CL2N4
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| Molecular Weight |
363.284201622009
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| Exact Mass |
362.106
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| CAS # |
1173023-36-3
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| Related CAS # |
L-745870;158985-00-3;L-745870 trihydrochloride;866021-03-6
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| PubChem CID |
11957618
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
24
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| Complexity |
377
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
GFFJYISJZJIKAF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H19ClN4.ClH/c19-15-3-5-16(6-4-15)23-10-8-22(9-11-23)13-14-12-21-18-17(14)2-1-7-20-18;/h1-7,12H,8-11,13H2,(H,20,21);1H
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| Chemical Name |
3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine;hydrochloride
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| Synonyms |
L745870 HCl; L 745870 HCl
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ~32.26 mg/mL (~88.80 mM)
0.1 M HCL : 25 mg/mL (~68.82 mM) |
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7527 mL | 13.7635 mL | 27.5270 mL | |
| 5 mM | 0.5505 mL | 2.7527 mL | 5.5054 mL | |
| 10 mM | 0.2753 mL | 1.3763 mL | 2.7527 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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