| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg | |||
| Other Sizes |
| Targets |
5-HT1D receptor (Kis = 6 nM)
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|---|---|
| ln Vitro |
Sumatriptan's intrinsic activity was found to be 84%, while PNU-142633's at the human 5-HT1D receptor was shown to be 70% intrinsic activity in a cell sensor cell-based test [1].
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| ln Vivo |
Neurogenic plasma protein extravasation was stopped in male Hartley guinea pigs treated intravenously with PNU-142633 (0.03-1 mg/kg). It is not possible for PNU-142633 to alter these vascular beds' resistance [1].
In this randomized, double-blind, placebo-controlled, parallel-group study, patients received a single 50-mg oral dose of a 5-HT(1D) agonist, PNU-142633 (n = 34), or matching placebo (n = 35) during an acute migraine attack. No statistically significant treatment effects were observed at 1 and 2 h after dosing, even after stratifying by baseline headache intensity. At 1 and 2 h post-dose, 8.8% and 29.4% of the PNU-142633 group, respectively, and 8.6% and 40.0% of the placebo group, respectively, experienced headache relief; 2.9% and 8.8% of the PNU-142633 group and 0% and 5.7% of the placebo group were free of headache pain. Adverse events associated with PNU-142633 treatment included chest pain (two patients) and QTc prolongation (three patients). Results from this study suggest that anti-migraine efficacy is not mediated solely through the 5-HT(1D) receptor subtype, although this receptor may contribute, at least in part, to the adverse cardiovascular effects observed with 5-HT agonist medications[2]. |
| Enzyme Assay |
The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study [1].
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| Animal Protocol |
Animal/Disease Models: Male Hartley guinea pig (250-300 g) stimulated with bipolar electrodes [1]
Doses: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg Route of Administration: intravenous (iv) (iv)injection Experimental Results: External Significant reduction in osmosis was effective at doses of 0.1 and 0.3 mg/kg, but not at doses of 0.03 and 1.0 mg/kg. |
| References |
[1]. McCall RB, et al. Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633. Cephalalgia. 2002 Dec;22(10):799-806.
[2]. Gomez-Mancilla B, et al. Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine. Cephalalgia. 2001 Sep;21(7):727-32. |
| Additional Infomation |
These studies investigated the pharmacological mechanisms of neurogenic dural vasodilation in anesthetized guinea pigs. After establishing a closed cranial window, meningeal (dural) vessels were observed using a live microscope, and their diameters were continuously measured using a video sizing analyzer. Before dilating dural vessels with calcitonin gene-related peptide (CGRP; 1 μg kg⁻¹, intravenously) or local electrical stimulation of the dura mater (up to 300 μA), endothelin-1 (3 μg kg⁻¹, intravenously) was administered to constrict the dural vessels. In guinea pigs pretreated with the CGRP receptor antagonist CGRP((8-37)) (0.3 mg kg⁻¹, intravenously), the vasodilatory response induced by electrical stimulation was inhibited by 85%, indicating that CGRP plays an important role in neurogenic dural vasodilation in this species. Neurogenic dural vasodilation can also be blocked by the 5-HT(1B/1D) receptor agonist rizatriptan (100 μg/kg), with plasma concentrations estimated to be comparable to those required for efficacy in treating migraines. Rizatriptan does not reverse CGRP-induced dural vasodilation, suggesting it acts on presynaptic receptors on the sensory fibers of the trigeminal nerve innervating the dural vessels. Furthermore, the selective 5-HT(1D) receptor agonist PNU-142633 (100 μg kg⁻¹) also blocks neurogenic dural vasodilation, while the 5-HT(1F) receptor agonist LY334370 (3 mg kg⁻¹) does not, suggesting that rizatriptan may block neurogenic vasodilation by inhibiting CGRP release through action on 5-HT(1D) receptors located on the perivascular trigeminal nerve. This mechanism may be one of the mechanisms of action of triptan drugs such as rizatriptan in treating migraines, and suggests that guinea pigs are a suitable animal model for studying the pharmacology of neurogenic dural vasodilatory disorders. Br J Pharmacol. 2001 Aug;133(7):1029-34.
|
| Molecular Formula |
C24H30N4O3
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|---|---|
| Molecular Weight |
422.53
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| Exact Mass |
422.232
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| Elemental Analysis |
C, 68.22; H, 7.16; N, 13.26; O, 11.36
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| CAS # |
187665-65-2
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| PubChem CID |
9845148
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| Appearance |
White to off-white solid powder
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| LogP |
3.065
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
|
| Heavy Atom Count |
31
|
| Complexity |
614
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CNC(C1=CC2CCO[C@](CCN3CCN(C4=CC=C(C(=O)N)C=C4)CC3)([H])C=2C=C1)=O
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| InChi Key |
PNTVCCRNJOGKGA-QFIPXVFZSA-N
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| InChi Code |
InChI=1S/C24H30N4O3/c1-26-24(30)19-4-7-21-18(16-19)9-15-31-22(21)8-10-27-11-13-28(14-12-27)20-5-2-17(3-6-20)23(25)29/h2-7,16,22H,8-15H2,1H3,(H2,25,29)(H,26,30)/t22-/m0/s1
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| Chemical Name |
1H-2-Benzopyran-6-carboxamide, 1-(2-(4-(4-(aminocarbonyl)phenyl)-1-piperazinyl)ethyl)-3,4-dihydro-N-methyl-, (1S)-
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| Synonyms |
PNU 142633; PNU142633; PNU-142633; 187665-65-2; PNU 142633; 1H-2-Benzopyran-6-carboxamide, 1-(2-(4-(4-(aminocarbonyl)phenyl)-1-piperazinyl)ethyl)-3,4-dihydro-N-methyl-, (1S)-; B54P1BQ73L; CHEMBL441095; (1S)-1-[2-[4-(4-carbamoylphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-isochromene-6-carboxamide; UNII-B54P1BQ73L; PNU-142633
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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) |
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 | 2.3667 mL | 11.8335 mL | 23.6670 mL | |
| 5 mM | 0.4733 mL | 2.3667 mL | 4.7334 mL | |
| 10 mM | 0.2367 mL | 1.1833 mL | 2.3667 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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