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BRL-15572 dihydrochloride

Alias: BRL15572; BRL 15572 HCl; BRL-15,572; BRL-15572; BRL 15,572; 3-(4-(3-chlorophenyl)piperazin-1-yl)-1,1-diphenylpropan-2-ol dihydrochloride; BRL-15572 (dihydrochloride); BRL-15572 2HCl; BRL 15572; 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol;dihydrochloride; 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol dihydrochloride;BRL15,572
Cat No.:V0978 Purity: ≥98%
BRL-15572 (BRL-15,572; BRL-15572; BRL 15,572; BRL15,572) dihydrochloride salt is a potent and selective 5-HT1D receptor antagonist with important biological activity.
BRL-15572 dihydrochloride
BRL-15572 dihydrochloride Chemical Structure CAS No.: 1173022-77-9
Product category: 5-HT Receptor
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of BRL-15572 dihydrochloride:

  • BRL-15572 HCl
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

BRL-15572 (BRL-15,572; BRL-15572; BRL 15,572; BRL15,572) dihydrochloride salt is a potent and selective 5-HT1D receptor antagonist with important biological activity. It suppresses 5-HT1D with a pKi of 7.9.

Biological Activity I Assay Protocols (From Reference)
Targets
5-HT1D ( pKi = 7.9 ); 5-HT1A ( pKi = 7.7 ); 5-HT2B ( pKi = 7.4 ); 5-HT2A ( pKi = 6.6 ); 5-HT7 ( pKi = 6.3 )
ln Vitro

In vitro activity: BRL-15572 exhibits positive h5-HT1D receptor affinity and selectivity. Compared to 5-HT1B receptors, BRL-15572 exhibits a 60-fold greater affinity for h5-HT1D. BRL-15572 binds to h5-HT1B and h5-HT1D receptors with pKB of less than 6 and 7.1, respectively. In both the h5-HT1B and h5-HT1D receptor-expressing cell lines, BRL-15572 stimulates [35S]GTP γ S binding with potencies that correspond with their receptor binding affinities. 5-HT1A, 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 have receptor binding affinities for BRL-15572, with pKi values of 7.7, 6.1, 5.2, 6.0, 6.6, 7.4, 6.2, 5.9, and 6.3, respectively. Both BRL-15572 (1 µM) and pKB of 7.1 shift the 5-HT concentration response curve in the h5-HT1D cell line. The affinity of BRL-15572 for human 5-HT1A and 5-HT2B receptors is moderately high.[1] The electrically evoked tritium overflow in human atrial appendages is inhibited by 5-HT in a way that is amenable to BRL-15572 (300 nM; 23 times Ki at h5-HT1D receptors).[2] BRL-15572 is a h5-HT1D receptor ligand that counteracts the inhibitory effect of 5-HT on the K+-evoked glutamate overflow induction. At the autoreceptor controlling [3H]5-HT release, BRL-15572 (1 μM) cannot change the impact of 5-HT.[3] The selective 5-HT1D/1B receptor antagonist BRL 15572 inhibits the effect of the agonist L-694 247. [4]

ln Vivo
BRL-15572 (2 mg/kg), a selective 5-HT1D receptor antagonist, does not alter the reduced heart rate caused by vagal electrical stimulation in diabetic pithed rats. The effects of pretreatment with BRL-15572 on vagally induced bradycardia are not evident for L-694,247 (50 μg/kg), a selective agonist for non-rodent 5-HT1B and 5-HT1D receptors.[5]
Enzyme Assay
Despite only modest homology between h5-HT1B and h5-HT1D receptor amino acid sequences, these receptors display a remarkably similar pharmacology. To date there are few compounds which discriminate between these receptor subtypes and those with some degree of selectivity, such as ketanserin, have greater affinity for other 5-HT receptor subtypes. We now report on two compounds, SB-216641 (N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide) and BRL-15572 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1-diphenyl-2-propanol), which display high affinity and selectivity for h5-HT1B and h5-HT1D receptors, respectively. In receptor binding studies on human receptors expressed in CHO cells, SB-216641 has high affinity (pKi = 9.0) for h5-HT1B receptors and has 25-fold lower affinity at h5-HT1D receptors. In contrast, BRL-15572 has 60-fold higher affinity for h5-HT1D (pKi = 7.9) than 5-HT1B receptors. Similar affinities for these compounds were determined on native tissue 5-HT1B receptors in guinea-pig striatum. Functional activities of SB-216641 and BRL-15572 were measured in a [35S]GTPgammaS binding assay and in a cAMP accumulation assay on recombinant h5-HT1B and h5-HT1D receptors. Both compounds were partial agonists in these high receptor expression systems, with potencies and selectivities which correlated with their receptor binding affinities. In the cAMP accumulation assay, results from pK(B) measurements on the compounds again correlated with receptor binding affinities (SB-216641, pK(B) = 9.3 and 7.3; BRL-15572, pK(B) = <6 and 7.1, for h5-HT1B and h5-HT1D receptors respectively). These compounds will be useful pharmacological agents to characterise 5-HT1B and 5-HT1D receptor mediated responses[1].
Cell Assay
[35S]GTPγS binding studies. Studies on the binding of [35S]GTPγS are conducted in CHO cells that express either the h5-HT1B or h5-HT1D receptors. In summary, 1 × 106 cell membranes are preincubated in HEPES buffer (HEPES [20 mM], MgCl2 [3 mM], NaCl [100 mM], ascorbate [0.2 mM]) containing GDP (10 µ M), with or without BRL-15572, for 30 minutes at 30°C. A 100 pM assay concentration of [35S]GTPγS is added in 10 µL increments to initiate the reaction, which is then incubated for an additional 30 minutes at 30°C. The determination of non-specific binding is achieved by first adding unlabelled GTPγS (10 µM) and then adding cells. Whatman GF/B grade filters are used to quickly filter the reaction out, and five ice-cold HEPES buffer washes are then performed. Liquid scintillation spectroscopy is used to measure radioactivity.
Animal Protocol
Human cerebral cortical slices and synaptosomes, guinea-pig cerebral cortical slices and human right atrial appendages were used to study the effects of SB-216641, a preferential h5-HT1B receptor ligand, and of BRL-15572, a preferential h5-HT1D receptor ligand, on the presynaptic h5-HT1B and h5-HT1B-like autoreceptors in the human and guinea-pig brain preparations, respectively, and on the presynaptic h5-HT1D heteroreceptors in the human atrium. The brain preparations, preincubated with [3H]serotonin ([3H]5-HT), and the segments of atrial appendages, preincubated with [3H]noradrenaline, were superfused with modified Krebs' solution and tritium overflow was evoked electrically (human and guinea-pig cerebral cortex slices and human atrial appendages) or by high K+ (human cerebral cortex synaptosomes). The electrically evoked tritium overflow from guinea-pig cerebral cortex slices was reduced by the 5-HT receptor agonist 5-carboxamidotryptamine (5-CT). This effect was not modified by BRL-15572 (2 microM; concentration 154 times higher than its Ki at h5-HT1D receptors) but was antagonized by SB-216641 (0.1 microM; concentration 100 times higher than its Ki at h5-HT1B receptors; apparent pA2 8.45). SB-216641 (0.1 microM) by itself facilitated, whereas BRL-15572 (2 microM) did not affect, the evoked overflow. In human cerebral cortex slices SB-216641 (0.1 microM) also facilitated, and BRL-15572 (2 microM) again failed to affect, the electrically evoked tritium overflow. In human cerebral cortical synaptosomes, 5-CT reduced the K+-evoked tritium overflow. This response was unaffected by BRL-15572 (300 nM) but antagonized by SB-216641 (15 nM; drug concentrations 23 and 15 times higher than their Ki at h5-HT1D and h5-HT1B receptors, respectively). Both drugs, given alone, did not modify the K+-evoked tritium overflow. In human atrial appendages, the electrically evoked tritium overflow was inhibited by 5-HT in a manner susceptible to antagonism by BRL-15572 (300 nM; 23 times Ki at h5-HT1D receptors) but not by SB-216641 (30 nM; 30 times Ki at h5-HT1B receptors). Both drugs by themselves did not change the electrically evoked tritium overflow. In conclusion, SB-216641 behaves as a preferential antagonist at native human 5-HT1B receptors and BRL-15572 as a preferential antagonist at native human 5-HT1D receptors. These compounds are clearly useful tools for the differentiation between human 5-HT1B and 5-HT1D receptors in functional studies.[2]
Dissolved in 20% propylene glycol; 1 mg/kg, 2 mg/kg; i.v. injection
Male Wistar rats with diabetes
References

[1]. Naunyn Schmiedebergs Arch Pharmacol. 1997 Sep;356(3):312-20.

[2]. Naunyn Schmiedebergs Arch Pharmacol. 1997 Sep;356(3):321-7.

[3]. Br J Pharmacol. 1999 Feb;126(3):607-12.

[4]. Clin Exp Pharmacol Physiol. 2005 Oct;32(10):894-900.

[5]. Clin Exp Pharmacol Physiol. 2007 Nov;34(11):1199-206.

[6]. Naunyn Schmiedebergs Arch Pharmacol. 2004 Jul;370(1):46-53.

Additional Infomation
1. In the present study, we investigated how alloxan-induced diabetes affects the ability of 5-hydroxytryptamine (5-HT) to modulate bradycardia induced in vivo by electrical stimulation of the vagus nerve in pithed rats. We also analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats with a single injection of alloxan (150 mg/kg, s.c.). Four weeks later, rats were anaesthetized, pretreated with atenolol and pithed. Electrical stimulation (3, 6 and 9 Hz) of the vagus nerve resulted in frequency dependent decreases in heart rate (HR). 3. In diabetic rats, intravenous bolus administration of high doses of 5-HT (100 and 200 microg/kg) increased the bradycardia induced by vagal electrical stimulation. Similarly, low doses (10 microg/kg) of the 5-HT(1/7) receptor agonist 5-carboxamidotryptamine (5-CT), increased vagally induced bradycardia. However, at high doses (50, 100 and 150 microg/kg), 5-CT reduced the bradycardia. Attenuation of the vagally induced bradycardia evoked by the higher doses of 5-CT was reproduced by L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors. Enhancement of the vagally induced bradycardia elicited by low doses of 5-CT was reproduced by the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT; 50 microg/kg). These stimulatory and inhibitory actions on vagal stimulation-induced bradycardia in diabetic rats were also observed after administration of exogenous acetylcholine. 4. Vagally induced bradycardia in diabetic rats was not affected by administration of the selective 5-HT(2) receptor agonist alpha-methyl-5-HT (150 microg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 microg/kg) or the selective 5-HT(1B) receptor agonist CGS-12066B (50 microg/kg). 5. Enhancement of the electrical stimulation-induced bradycardia in diabetic rats caused by 5-CT (10 microg/kg) or 8-OH-DPAT (50 microg/kg) was abolished by the selective 5-HT(2/7) receptor antagonist mesulergine (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 microg/kg), respectively. Similarly, pretreatment with the non-selective 5-HT(1) receptor antagonist methiothepin (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 microg/kg) on the bradycardia induced by vagal electrical stimulation in diabetic rats. BRL-15572 (2 microg/kg), a selective 5-HT(1D) receptor antagonist, inhibited the action of L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors, on the vagally induced bradycardia. 6. In conclusion, in the present study, experimental diabetes evoked changes in both the nature and 5-HT receptor types/subtypes involved in vagally induced bradycardia.[5]
It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT1B/1D receptors and alpha2-adrenoceptors. The present study has reanalysed this suggestion by using more selective antagonists alone and in combination. Fifty-two anaesthetised dogs were prepared for ultrasonic measurements of external carotid blood flow. The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 ml/kg; control), or the antagonists SB224289 (300 microg/kg; 5-HT1B), BRL15572 (300 microg/kg; 5-HT1D), rauwolscine (300 microg/kg; alpha2), SB224289 + BRL15572 (300 microg/kg each), SB224289 + rauwolscine (300 microg/kg each), BRL15572 + rauwolscine (300 microg/kg each), rauwolscine (300 microg/kg) + prazosin (100 microg/kg; alpha1), SB224289 (300 microg/kg) + prazosin (100 microg/kg), SB224289 (300 microg/kg) + rauwolscine (300 microg/kg) + prazosin (100 microg/kg), SB224289 (300 microg/kg) + prazosin (100 microg/kg) + BRL44408 (1,000 microg/kg; alpha2A), SB224289 (300 microg/kg) + prazosin (100 microg/kg)+ imiloxan (1,000 microg/kg; alpha2B), or SB224289 (300 microg/kg) + prazosin (100 microg/kg) + MK912 (300 microg/kg; alpha2C). Each group received consecutive 1-min intracarotid infusions of ergotamine (0.56, 1, 1.8, 3.1, 5.6, 10 and 18 microg/min), following a cumulative schedule. In saline-pretreated animals, ergotamine induced dose-dependent decreases in external carotid blood flow without affecting arterial blood pressure or heart rate. These control responses were: unaffected by SB224289, BRL15572, rauwolscine or the combinations of SB224289 + BRL15572, BRL15572 + rauwolscine, rauwolscine + prazosin, SB224289 + prazosin, or SB224289 + prazosin + imiloxan; slightly blocked by SB224289 + rauwolscine; and markedly blocked by SB224289 + rauwolscine + prazosin, SB224289 + prazosin + BRL44408 or SB224289 + prazosin + MK912. Thus, the cranio-selective vasoconstriction elicited by ergotamine in dogs is predominantly mediated by 5-HT1B receptors as well as alpha2A/2C-adrenoceptor subtypes and, to a lesser extent, by alpha1-adrenoceptors.[6]
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C25H29CL3N2O
Molecular Weight
479.87
Exact Mass
478.13
CAS #
1173022-77-9
Related CAS #
BRL-15572 hydrochloride; 1173022-77-9
PubChem CID
9891303
Appearance
White to off-white solid powder
Boiling Point
580.7ºC at 760 mmHg
Flash Point
305ºC
Vapour Pressure
2.51E-14mmHg at 25°C
LogP
5.459
Hydrogen Bond Donor Count
3
Hydrogen Bond Acceptor Count
3
Rotatable Bond Count
6
Heavy Atom Count
31
Complexity
451
Defined Atom Stereocenter Count
0
SMILES
0
InChi Key
WPEXRXMQMPOHIO-UHFFFAOYSA-N
InChi Code
InChI=1S/C25H27ClN2O.2ClH/c26-22-12-7-13-23(18-22)28-16-14-27(15-17-28)19-24(29)25(20-8-3-1-4-9-20)21-10-5-2-6-11-21;;/h1-13,18,24-25,29H,14-17,19H2;2*1H
Chemical Name
3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol;dihydrochloride
Synonyms
BRL15572; BRL 15572 HCl; BRL-15,572; BRL-15572; BRL 15,572; 3-(4-(3-chlorophenyl)piperazin-1-yl)-1,1-diphenylpropan-2-ol dihydrochloride; BRL-15572 (dihydrochloride); BRL-15572 2HCl; BRL 15572; 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol;dihydrochloride; 3-[4-(3-chlorophenyl)piperazin-1-yl]-1,1-diphenylpropan-2-ol dihydrochloride;BRL15,572
HS Tariff Code
2934.99.9001
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)
Solubility Data
Solubility (In Vitro)
DMSO: 96~250 mg/mL (200.1~521 mM)
Water: <1 mg/mL
Ethanol: ~40 mg/mL (~83.4 mM)
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.33 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 20.8 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: ≥ 2.08 mg/mL (4.33 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 20.8 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: ≥ 2.08 mg/mL (4.33 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.


Solubility in Formulation 4: 30% Propylene glycol , 5% Tween 80 , 65% D5W: 20 mg/mL

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.0839 mL 10.4195 mL 20.8390 mL
5 mM 0.4168 mL 2.0839 mL 4.1678 mL
10 mM 0.2084 mL 1.0419 mL 2.0839 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.

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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.
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Biological Data
  • Antagonism by GR 127935, SB-224289, BRL-15572 or (+)-WAY 100135 of the inhibition by 5-HT of the K+-evoked [3H]-overflow from human cerebrocortical synaptosomes prelabelled with [3H]-5-HT. Br J Pharmacol . 1999 Feb;126(3):607-12.
  • Antagonism by BRL-15572 or SB-224289 of the inhibition by 5-HT of the K+-evoked glutamate overflow from human cerebrocortical synaptosomes. Br J Pharmacol . 1999 Feb;126(3):607-12.
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