PF-592379
目录号 : GC31225
PF-592379是一种有效的多巴胺D3受体激动剂，EC50为21nM。
Cas No.:710655-15-5
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | The binding affinities of PF-592379 (PF-592,379) and 7-OH-DPAT are characterized at each the five dopamine receptor subtypes using the following radioligands: [3H]SCH23390 (D1 and D5, 70 Ci mmol, 1 nM), [3H]U-86170 (D2, 62 Ci/mmol, 2 nM), and [3H]spiperone (D3 and D4, 96 Ci/mmol, 0.2 nM). CHO cells expressing recombinant human D1, D2, D3, D4, and D5 receptors are rinsed with, and harvested in, ice-cold Ca2+/Mg2+-free phosphate-buffered saline prior to pelleting (500g, 5 min), resuspension in 25 mM Tris, 5 mM EDTA, and 5 mM EGTA, pH 7.5, and freezing the cells in liquid nitrogen. Upon thawing, the cells are homogenized and centrifuged at 1,000g to remove nuclei and unbroken cells, with the supernatant subsequently centrifuged at 47,000g. The membrane pellet is then washed with Tris, EGTA, EDTA, resuspended in 20 mM HEPES, pH 7.5, 150 mM NaCl, 10 mM MgCl2, and 1 mM EDTA, and frozen in liquid nitrogen prior to storage of membrane aliquots at -70°C. Membranes are then thawed and diluted into 20 mM HEPES, pH 7.4, 150 mM NaCl, 10 mM MgCl2, or 1 mM EDTA, 10 mM MgSO4, with binding reactions carried out in a total volume of 0.9 ml for 1 h at room temperature, and stopped by vacuum filtration. Nonspecific binding is assessed with 3 µM SCH23390 (D1-like antagonist) or 3 µM haloperidol (D2-like antagonist). Competition binding experiments employ 11 concentrations of PF-592379 or 7-OH-DPAT run in duplicate. IC50 values are determined by fitting the data to a one-site model by nonlinear least-squares minimization, and Ki values are calculated with the Cheng-Prusoff equation[3]. |
Animal experiment: | Rats[1]Male Sprague-Dawley rats (~8-10 weeks and 250 g) are surgically prepared with an indwelling jugular vein cannula at least 2 days before administration of dose. Rats had free access to food (rat diet pellets) and water throughout the duration of the study. Four rats receive PF-592379 either by IV dosing via the caudal vein (n=2) or via oral dosing (n=2) (both routes 2 mg/kg, 1 mL/kg). Blood samples (175 μL) are collected into heparinised tubes before dosing and at time points over a 24 h period from the jugular vein cannula, which is flushed with heparinised saline (100 μL, 10 units/mL), and plasma is prepared by centrifugation and stored at -20°C until analysis[1]. |
References: [1]. Attkins N, et al. Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog, and human. Xenobiotica. 2010 Nov;40(11):730-42. | |
PF-592379 is a potent dopamine D3 receptor agonist with an EC50 of 21 nM.
PF-592379 appears to be a full agonist (Emax=95%) when compared with the standard Pramipexole, a D2/D3 receptor agonist for the treatment of Parkinson's disease[1]. PF-592379 is a potent and selective dopamine 3 agonist with EC50 and Ki of 21 nM and 322 nM, respectively[2]. In vitro binding assays show that PF-592379 (PF-592,379) selectively binds human D3 receptors with a high affinity (Ki=215 nM). Although PF-592379 also binds to human D4 receptors (Ki=4165 nM), it displays a 19-fold binding selectivity for human D3 over D4 receptors. PF-592379 fails to bind human D2 (Ki≥10 μM), D1 (Ki≥10 μM), or D5 (Ki≥10 μM) receptors at concentrations of up to 10 µM, and thus is at least 46-fold selective for D3 over D2, D1, and D5 receptors[3].
PF-592379 is an oral dopamine 3 agonist in rat, and dog. PF-592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 mL/min/kg in dog and 44.8 and 58.2 mL/min/kg in rat. It has high permeability in Caco-2 cells and is completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs[1].
[1]. Attkins N, et al. Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog, and human. Xenobiotica. 2010 Nov;40(11):730-42. [2]. Wager TT, et al. Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects. ACS Chem Neurosci. 2017 Jan 18;8(1):165-177. [3]. Collins GT, et al. Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats. Behav Pharmacol. 2012 Jun;23(3):280-91.
| Cas No. | 710655-15-5 | SDF | |
| Canonical SMILES | NC1=NC=C([C@@H]2CN(CCC)[C@@H](C)CO2)C=C1 | ||
| 分子式 | C13H21N3O | 分子量 | 235.33 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 4.2494 mL | 21.2468 mL | 42.4935 mL |
| 5 mM | 0.8499 mL | 4.2494 mL | 8.4987 mL |
| 10 mM | 0.4249 mL | 2.1247 mL | 4.2494 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog, and human
PF-592379 is a potent, selective agonist of the dopamine 3 receptor, for the treatment of male erectile dysfunction and female sexual dysfunction. In vivo, PF-592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 ml/min/kg in dog and 44.8 and 58.2 ml/min/kg in rat. It has high permeability in Caco-2 cells and was completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs. These data are consistent with the physicochemical properties of PF-592379, which indicate complete absorption by the transcellular route. Elimination of PF-592379 was predominantly metabolic in nature. In vitro routes of metabolism studies indicate that metabolism in the rat is a combination of P450 mechanisms and N-glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates that N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N-glucuronidation were predicted to be low in humans compared with acyl or phenolic glucuronidation. PF-592379 was predicted to have complete absorption from the gastrointestinal tract and an oral bioavailability of >60% in the clinic. Clinical data verified that PF-592379 is a low clearance compound in human, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist, intended for on demand dosing.
Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival
In an effort to uncover systematic learnings that can be applied to improve compound survival, an analysis was performed on data from Phase II decisions for 44 programs at Pfizer. It was found that not only were the majority of failures caused by lack of efficacy but also that, in a large number of cases (43%), it was not possible to conclude whether the mechanism had been tested adequately. A key finding was that an integrated understanding of the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity (termed together as the 'three Pillars of survival') all determine the likelihood of candidate survival in Phase II trials and improve the chance of progression to Phase III.
Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats
Dopamine D3-preferring agonists are commonly used to treat Parkinson's disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly selective, full D3 agonist PF-592,379 to the less selective D3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naive rats failed to acquire responding when 7-OH-DPAT or PF-592,379 was made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under a FR5 or a progressive ratio (PR) schedule of reinforcement. Although 7-OH-DPAT maintained modest levels of responding when substituted under a FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D3 agonists, such as PF-592,379, will have low abuse potential in humans.
Chirality of Novel Bitopic Agonists Determines Unique Pharmacology at the Dopamine D3 Receptor
The dopamine D2/D3 receptor (D2R/D3R) agonists are used as therapeutics for Parkinson's disease (PD) and other motor disorders. Selective targeting of D3R over D2R is attractive because of D3R's restricted tissue distribution with potentially fewer side-effects and its putative neuroprotective effect. However, the high sequence homology between the D2R and D3R poses a challenge in the development of D3R selective agonists. To address the ligand selectivity, bitopic ligands were designed and synthesized previously based on a potent D3R-preferential agonist PF592,379 as the primary pharmacophore (PP). This PP was attached to various secondary pharmacophores (SPs) using chemically different linkers. Here, we characterize some of these novel bitopic ligands at both D3R and D2R using BRET-based functional assays. The bitopic ligands showed varying differences in potencies and efficacies. In addition, the chirality of the PP was key to conferring improved D3R potency, selectivity, and G protein signaling bias. In particular, compound AB04-88 exhibited significant D3R over D2R selectivity, and G protein bias at D3R. This bias was consistently observed at various time-points ranging from 8 to 46 min. Together, the structure-activity relationships derived from these functional studies reveal unique pharmacology at D3R and support further evaluation of functionally biased D3R agonists for their therapeutic potential.
Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats
Dopamine D3 receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D2- and D3-preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D2 agonist R-(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of R-(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D3 ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D3 agonist PF-592,379 [5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D3 antagonist PG01037 [N-[(E)-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D3 ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D2-and D3-preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment as a determinant of test drug effects. With the possible exception of the D3 antagonist PG01037, no ligand was promising in terms of cocaine addiction treatment.