| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
protein kinase G Iα; cGMP-PKG
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|---|---|
| ln Vitro |
Researchers investigated the inhibitory role of the nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway on receptor-activated TRPC6 channels in both a heterologous expression system (HEK293 cells) and A7r5 vascular myocytes. Cationic currents due to TRPC6 expression were strongly suppressed (by approximately 70%) by a NO donor SNAP (100 microm) whether it was applied prior to muscarinic receptor stimulation with carbachol (CCh; 100 microm) or after G-protein activation with intracellular perfusion of GTPgammaS (100 microm). A similar extent of suppression was also observed with a membrane-permeable analogue of cGMP, 8Br-cGMP (100 microm). The inhibitory effects of SNAP and 8Br-cGMP on TRPC6 channel currents were strongly attenuated by the presence of inhibitors for guanylyl cyclase and PKG such as ODQ, KT5823 and DT3. Alanine substitution for the PKG phosphorylation candidate site at T69 but not at other sites (T14A, S28A, T193A, S321A) of TRPC6 similarly attenuated the inhibitory effects of SNAP and 8Br-cGMP. SNAP also significantly reduced single TRPC6 channel activity recorded in the inside-out configuration in a PKG-dependent manner. SNAP-induced PKG activation stimulated the incorporation of (32)P into wild-type and S321A-mutant TRPC6 proteins immunoprecipitated by TRPC6-specific antibody, but this was greatly attenuated in the T69A mutant. SNAP or 8Br-cGMP strongly suppressed TRPC6-like cation currents and membrane depolarization evoked by Arg(8)-vasopressin in A7r5 myocytes. These results strongly suggest that TRPC6 channels can be negatively regulated by the NO-cGMP-PKG pathway, probably via T69 phosphorylation of the N-terminal. This mechanism may be physiologically important in vascular tissues where NO is constantly released from vascular endothelial cells or nitrergic nerves. [1]
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| ln Vivo |
DT-3 is an inhibitor of protein kinase G (PKG). 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-1 (ODQ) inhibits nitric oxide-sensitive guanylyl cyclase (GC) to reduce cGMP generation. A PKA inhibitor fragment 5–24 amide trifluoroacetate salt (IP-20) binds to the catalytic subunit of protein kinase A (PKA), mimicking the protein substrate (Chen et al., 2014). These inhibitors reduce the level of cGMP or inhibit the binding of PKA/PKG to the downstream substrate. Our previous study reported that ODQ, DT-3 or IP-20 alone did not influence stroke-induced injury (Chen et al., 2014). To explore whether a cGMP-dependent pathway is involved in yonkenafil-induced neuroprotection, rats were simultaneously treated with yonkenafil and ODQ, IP-20 or DT-3. The reduction in brain water content and the increase in surviving neurons induced by yonkenafil were significantly reversed by ODQ, DT-3 or IP-20 (brain water content: IP-20 79.9 ± 0.5%, ODQ 80.3 ± 0.5%, DT-3 79.4 ± 0.7% vs 78.3 ± 0.4%; surviving neurons: cortex IP-20 116.6 ± 4.8, ODQ 117.4 ± 5.5, DT-3 133.0 ± 5.4 vs 156.7 ± 3.8; striatum IP-20 72.4 ± 4.4, ODQ 73.7 ± 4.1, DT-3 104.7 ± 4.1 vs 151.9 ± 4.3, Fig. 1, Fig. 4). The yonkenafil-induced reductions in neurological deficit scores and infarct volume were significantly reversed by ODQ or IP-20 (Neurological scores: IP-20 1.9 ± 0.2, ODQ 1.9 ± 0.2, DT-3 1.2 ± 0.3 vs 1.1 ± 0.1; Infarct volume: IP-20 22.1 ± 3.9%, ODQ 24.1 ± 6.0%, DT-3 16.4 ± 5.0% vs 10.8 ± 3.0%, Fig. 1, Fig. 4). [2]
|
| References |
|
| Additional Infomation |
DT-3 is a specific PKG inhibitor (Chen et al., 2014, Ramchandran et al., 2012). PKA promotes glutamate uptake and inhibits Ca2 + release to prevent neuronal injury (Ballestas and Benveniste, 1997, Pisano et al., 1996). IP-20 is a specific PKA inhibitor. It has been reported that DT-3 or IP-20 alone cannot influence stroke-induced injury (Chen et al., 2014). The present study could not distinguish between the relative contributions of PKA and PKG to neuronal survival and reduced edema. However, the yonkenafil-induced reductions in neurological deficits, infarct volume and Nogo-R expression were significantly reversed by the PKA inhibitor IP-20 but not the PKG inhibitor DT-3. These results show that yonkenafil reduces neurological deficits, infarction and Nogo-R expression mainly through the cGMP/PKA pathway. [2]
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| Molecular Formula |
C152H258N52O28S
|
|---|---|
| Molecular Weight |
3294.072
|
| Exact Mass |
3293.011
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| CAS # |
329306-46-9
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| PubChem CID |
146158608
|
| Sequence |
Arg-Gln-Ile-Lys-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Met-Lys-Trp-Lys-Lys-Leu-Arg-Lys-Lys-Lys-Lys-Lys-His; H-DL-Arg-DL-Gln-DL-xiIle-DL-Lys-DL-xiIle-DL-Trp-DL-Phe-DL-Gln-DL-Asn-DL-Arg-DL-Arg-DL-Met-DL-Lys-DL-Trp-DL-Lys-DL-Lys-DL-Leu-DL-Arg-DL-Lys-DL-Lys-DL-Lys-DL-Lys-DL-Lys-DL-His-OH; DL-arginyl-DL-glutaminyl-DL-isoleucyl-DL-lysyl-DL-isoleucyl-DL-tryptophyl-DL-phenylalanyl-DL-glutaminyl-DL-asparagyl-DL-arginyl-DL-arginyl-DL-methionyl-DL-lysyl-DL-tryptophyl-DL-lysyl-DL-lysyl-DL-leucyl-DL-arginyl-DL-lysyl-DL-lysyl-DL-lysyl-DL-lysyl-DL-lysyl-DL-histidine
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| SequenceShortening |
RQIKIWFQNRRMKWKKLRKKKKKH
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| Appearance |
Typically exists as solid at room temperature
|
| LogP |
-8.7
|
| Hydrogen Bond Donor Count |
52
|
| Hydrogen Bond Acceptor Count |
44
|
| Rotatable Bond Count |
128
|
| Heavy Atom Count |
233
|
| Complexity |
7120
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
C(C1=CNC2=CC=CC=C12)[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)O)CC1NC=NC=1)CC1=CNC2=CC=CC=C12)CC1C=CC=CC=1
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| InChi Key |
QXCWYQJRASXXJG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C152H258N52O28S/c1-8-88(5)123(204-140(223)112(59-61-121(164)206)182-125(208)96(162)43-35-72-175-149(166)167)146(229)196-107(54-25-34-71-161)139(222)203-124(89(6)9-2)147(230)201-117(80-92-84-180-98-45-16-14-42-95(92)98)144(227)198-115(78-90-39-11-10-12-40-90)142(225)194-111(58-60-120(163)205)137(220)200-118(82-122(165)207)145(228)193-110(57-38-75-178-152(172)173)132(215)190-108(55-36-73-176-150(168)169)133(216)195-113(62-76-233-7)138(221)189-105(52-23-32-69-159)135(218)199-116(79-91-83-179-97-44-15-13-41-94(91)97)143(226)191-103(50-21-30-67-157)130(213)187-104(51-22-31-68-158)134(217)197-114(77-87(3)4)141(224)192-109(56-37-74-177-151(170)171)131(214)186-102(49-20-29-66-156)128(211)184-100(47-18-27-64-154)126(209)183-99(46-17-26-63-153)127(210)185-101(48-19-28-65-155)129(212)188-106(53-24-33-70-160)136(219)202-119(148(231)232)81-93-85-174-86-181-93/h10-16,39-42,44-45,83-89,96,99-119,123-124,179-180H,8-9,17-38,43,46-82,153-162H2,1-7H3,(H2,163,205)(H2,164,206)(H2,165,207)(H,174,181)(H,182,208)(H,183,209)(H,184,211)(H,185,210)(H,186,214)(H,187,213)(H,188,212)(H,189,221)(H,190,215)(H,191,226)(H,192,224)(H,193,228)(H,194,225)(H,195,216)(H,196,229)(H,197,217)(H,198,227)(H,199,218)(H,200,220)(H,201,230)(H,202,219)(H,203,222)(H,204,223)(H,231,232)(H4,166,167,175)(H4,168,169,176)(H4,170,171,177)(H4,172,173,178)
|
| Chemical Name |
2-[[6-amino-2-[[6-amino-2-[[6-amino-2-[[6-amino-2-[[6-amino-2-[[2-[[2-[[6-amino-2-[[6-amino-2-[[2-[[6-amino-2-[[2-[[2-[[2-[[4-amino-2-[[5-amino-2-[[2-[[2-[[2-[[6-amino-2-[[2-[[5-amino-2-[(2-amino-5-carbamimidamidopentanoyl)amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylsulfanylbutanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoyl]amino]-3-(1H-imidazol-4-yl)propanoic acid
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| Synonyms |
329306-46-9; L-Histidine, L-arginyl-L-glutaminyl-L-isoleucyl-L-lysyl-L-isoleucyl-L-tryptophyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-arginyl-L-arginyl-L-methionyl-L-lysyl-L-tryptophyl-L-lysyl-L-lysyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-; DA-77556; H-DL-Arg-DL-Gln-DL-xiIle-DL-Lys-DL-xiIle-DL-Trp-DL-Phe-DL-Gln-DL-Asn-DL-Arg-DL-Arg-DL-Met-DL-Lys-DL-Trp-DL-Lys-DL-Lys-DL-Leu-DL-Arg-DL-Lys-DL-Lys-DL-Lys-DL-Lys-DL-Lys-DL-His-OH
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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) |
Typically soluble in DMSO (e.g. 10 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 | 0.3036 mL | 1.5179 mL | 3.0358 mL | |
| 5 mM | 0.0607 mL | 0.3036 mL | 0.6072 mL | |
| 10 mM | 0.0304 mL | 0.1518 mL | 0.3036 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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