| Size | Price | |
|---|---|---|
| 1mg | ||
| Other Sizes |
| Targets |
Neuropeptide Y1 receptor
|
|---|---|
| ln Vitro |
Neuropeptide Y (NPY) is a potent vasoconstrictor released during sympathetic activation that may be involved in myocardial ischaemia. Researchers examined the effect of a Y1 receptor antagonist on haemodynamic and ischaemic responses to exercise in patients with coronary artery disease. [1]
Plasma NPY levels increased during exercise both during AR-H040922 and placebo. The increase in plasma concentrations of NPY was significantly greater during exercise with AR-H040922, regardless of dose, than with placebo [1]. |
| ln Vivo |
Eighty-two evaluable male patients were included in a randomized, double blind, two-way crossover study with a low dose (6.7 microg/kg/min; n=59)and a high dose (13.3 microg/kg/min; n=23) of the Y1 receptor antagonist AR-H040922 given as infusions for 2h or placebo. Myocardial ischaemia during a symptom-limited exercise test was monitored by conventional ST-segment analysis and heart rate (HR)-adjusted ST changes including the ST/HR slope and ST/HR recovery. Administration of the high dose AR-H040922 attenuated systolic blood pressure by 6-11 mmHg (p<0.05) during and after exercise without affecting HR. None of the two doses of AR-H040922 influenced any of the ischaemic parameters or duration of exercise, however. The maximal increase in NPY was higher during AR-H040922 (p<0.05) compared with placebo.
Conclusions: Selective NPY Y1 receptor blockade attenuates the increase in blood pressure during exercise indicating a role for endogenous NPY in blood pressure regulation. Despite this effect, the Y1 receptor antagonist did not influence exercise-induced ischaemic parameters in patients with coronary artery disease [1].
|
| Cell Assay |
Blood sampling [1]
Blood samples were drawn from an arm vein (contra-lateral to the arm in which the infusion was given) at rest before start of exercise, at 2 and 4min after start of exercise, at peak exercise, and after 4, 10 and 30min of recovery. Plasma was separated immediately and frozen at −70°C until analysed. NPY was assessed by radioimmunoassay.12The plasma concentration of AR-H040922 was measured by liquid chromatography with fluorescence detection.9The coefficients of intra-assay variation were 7.0% and 2.9% for NPY and AR-H040922, respectively. In addition routine biochemical analysis for safety reasons were performed at the pre-entry visit and at the follow-up visit 2–5 days after study day two. |
| Animal Protocol |
The study was performed as a randomized, double blind, two-way crossover, and placebo-controlled study in two separate groups of patients. One group of patients (n=64) received a low dose of the NPY antagonist AR-H040922 at a dose rate of 6.7μg/kg/min or and placebo (NaCl) on two occasions. The other group (n=24) received a high dose of AR-H040922 at a rate of 13.3μg/kg/min and placebo. AR-H040922 and placebo were given as i.v. infusions for 120min. The washout period between the two occasions was at least 1 week. Exercise started 45min after start of the infusion. [1]
|
| Toxicity/Toxicokinetics |
Eleven patients reported some side effects during infusion. Three patients (one in the low-dose group and two in the high-dose group) experienced hypotension during AR-H040922 infusion and required discontinuation of the infusion. One patient receiving low-dose treatment permanently discontinued the infusion during the post-exercise recovery period. The infusions of the other two patients were only temporarily stopped for 12 minutes and 13 minutes, respectively. Other side effects were nonspecific and were evenly distributed between the active drug group and the placebo group. [1]
|
| References |
[1]. The effect of a neuropeptide Y Y1 receptor antagonist in patients with angina pectoris. Eur Heart J. 2003 Jun;24(12):1120-7.
|
| Additional Infomation |
The limitation of this regimen is that AR-H040922 is administered via a single intravenous infusion. This regimen is based on the low oral bioavailability and short plasma half-life of AR-H040922. Despite this limitation, short-term administration of a high dose of AR-H040922 can still lower systolic blood pressure by 7 mmHg, and this effect can last for up to 30 minutes after exercise. However, the possibility of other effects from long-term or repeated oral administration of an effective Y1 receptor antagonist cannot be ruled out. It is currently unclear whether other medications being taken will interfere with the action of the NPY receptor antagonist. The patient did not take any morning medications on the day of the exercise test. Therefore, it can be inferred that the plasma concentrations of concomitant medications during the exercise test were low. Previous studies have shown that metoprolol can reduce the number and affinity of NPY binding sites in vascular smooth muscle cells of hypertensive rats. However, it is unclear whether β-blockers affect the binding of AR-H040922.
This study shows that high-dose AR-H040922 selectively blocks Y1 receptors, which can significantly inhibit the increase in blood pressure during and after exercise, suggesting that NPY plays a role in blood pressure regulation during and after sympathetic activation in patients with coronary artery disease. However, despite this effect, AR-H040922 does not affect the degree of myocardial ischemia during or after exercise. [1] |
| Molecular Formula |
C28H33N5O3
|
|---|---|
| Molecular Weight |
487.593326330185
|
| Exact Mass |
487.258
|
| CAS # |
221697-09-2
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| PubChem CID |
5311439
|
| Appearance |
White to off-white solid powder
|
| LogP |
2.9
|
| Hydrogen Bond Donor Count |
5
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
36
|
| Complexity |
688
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
O=C(N[C@@H](C(N[C@@H](C1=CC=C(O)C=C1)C)=O)CCCNC(N)=N)C(C2=CC=CC=C2)C3=CC=CC=C3
|
| InChi Key |
AOUQZUZEYSDMEZ-NTKDMRAZSA-N
|
| InChi Code |
InChI=1S/C28H33N5O3/c1-19(20-14-16-23(34)17-15-20)32-26(35)24(13-8-18-31-28(29)30)33-27(36)25(21-9-4-2-5-10-21)22-11-6-3-7-12-22/h2-7,9-12,14-17,19,24-25,34H,8,13,18H2,1H3,(H,32,35)(H,33,36)(H4,29,30,31)/t19-,24-/m1/s1
|
| Chemical Name |
(2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(1R)-1-(4-hydroxyphenyl)ethyl]pentanamide
|
| Synonyms |
Y1 receptor antagonist 1; 221697-09-2; H-409/22; Ar-H040922 freebase; 7NCK567YKQ; (2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(1R)-1-(4-hydroxyphenyl)ethyl]pentanamide; (2R)-2-((2,2-Diphenylacetyl)amino)-5-guanidino-N-((1R)-1-(4-hydroxyphenyl)ethyl)pentanamide; UNII-7NCK567YKQ;
|
| 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 |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.0509 mL | 10.2545 mL | 20.5090 mL | |
| 5 mM | 0.4102 mL | 2.0509 mL | 4.1018 mL | |
| 10 mM | 0.2051 mL | 1.0255 mL | 2.0509 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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