Free 2-phenylethylamine excretion was ... significantly elevated ... in phenylketonuric adults and children receiving a normal or a slightly restricted intake of phenylalanine. Urinary 2-phenylethylamine was also significantly increased in phenylketonuric children receiving low phenylalaine dietary therapy. Conjugated 2-phenylethylamine excretion was ... not ... increased above normal.
2-Phenylethylamine is an endogenous constituent of human brain and is implicated in cerebral transmission. It is also found in certain foodstuffs and may cause toxic side-effects in susceptible individuals. Metabolism of 2-phenylethylamine to phenylacetaldehyde is catalyzed by monoamine oxidase and the oxidation of the reactive aldehyde to its acid derivative is catalyzed mainly by aldehyde dehydrogenase and perhaps aldehyde oxidase, with xanthine oxidase having minimal transformation. The present investigation examines the metabolism of 2-phenylethylamine to phenylacetaldehyde in liver slices and compares the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase activity in the oxidation of phenylacetaldehyde with precision-cut fresh liver slices in the presence/absence of specific inhibitors of each enzyme. In liver slices, phenylacetaldehyde was rapidly converted to phenylacetic acid. Phenylacetic acid was the main metabolite of 2-phenylethylamine, via the intermediate phenylacetaldehyde. Phenylacetic acid formation was completely inhibited by disulfiram (specific inhibitor of aldehyde dehydrogenase), whereas isovanillin (specific inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent and allopurinol (specific inhibitor of xanthine oxidase) had little or no effect. Therefore, in liver slices, phenylacetaldehyde is rapidly oxidized by aldehyde dehydrogenase and aldehyde oxidase with little or no contribution from xanthine oxidase.
We report here very high urinary phenylethylamine level in a phenylketonuric newborn and variable phenylethylamine levels in phenylketonuric patients with similar phenylalanine levels. As phenylethylamine, a very toxic metabolite of phenylalanine, is rapidly degraded by monoamine oxydase type B, an enzyme that has a very low activity in neonates, these results are consistent with those of the hypothesis of MAO-B acting as a modifying gene in phenylketonuria.
Incubation of phenylethylamine with rabbit liver microsomes, divalent MN and NADPH generating system leads to formation of azoxy-2-phenylethane (a mutagen). 38 nmol of azoxy-2-phenylethane is formed from 10 umol of phenylethylamine during 30 min incubation. Metabolism to azoxy-2-phenylamine appears completely dependent on the presence of divalent MN.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
毒性总结
识别与用途：2-苯乙胺（PEA）是一种无色至微黄色液体，具有鱼腥味。它用于有机合成、作为实验室试剂，以及在闪烁计数器（CO2吸收剂）中使用。人类研究：PEA中毒在年轻健康个体中可能非常严重。最常报告的症状包括焦虑和幻觉（49%）、瞳孔扩大和头痛（41%）、心动过速（40%）和高血压（15%）。还观察到诸如癫痫发作（7%）、心脏骤停（5%）、毒性心肌炎（1%）和出血性中风（1%）等并发症。在苯丙酮尿症（PKU）患者中观察到的浓度下，PEA具有致畸性。动物研究：PEA作为一种被认为作用于5-HT和多巴胺能大脑机制的药物，其在Wistar、Sprague-Dawley和Long-Evans大鼠中的行为效应进行了研究。评估的行为成分包括：前爪拍打、头部摇摆和后肢张开，这些被认为是指示中枢5-HT刺激的迹象。在注射50 mg/kg后，Wistar大鼠比Long-Evans或Sprague-Dawley大鼠更活跃和反应灵敏。Wistar大鼠与Long-Evans和Sprague-Dawley品系大鼠对中枢单胺能机制刺激的反应存在显著差异。PEA每天给药6周的行为后果已经进行了研究。大鼠在单次注射PEA（50 mg/kg）或连续7天注射PEA（25 mg/kg）后表现出5-HT行为综合征的迹象。在3周治疗期间，综合征达到高峰强度。PEA在雄性大鼠单次注射后减少了24小时的食物摄入，并且在此4周治疗期间对此效果的耐受性没有发展。PEA在此期间导致了剂量依赖性的体重增加减少。PEA的厌食效应似乎在行为上特定于摄食，因为同时没有抑制饮水或利尿。PEA在麻醉大鼠的颌下肌中诱导了肌阵挛性收缩，并在电皮质记录中诱导了癫痫样肌阵挛尖波放电。PEA在啮齿动物中诱导的刻板行为被认为是对精神分裂症精神病症状的模拟。PEA被代谢为偶氮-2-苯乙烷（一种诱变剂）。将D9（神经胚形成）小鼠胚胎暴露于PEA水平，从0.01到1 mM不等，持续24小时的全胚胎培养，结果显示在0.01 mM时神经管闭合缺陷为0%，在0.1 mM时为67%，在1 mM时无法存活。组织学分析还显示，暴露于0.1和1 mM PEA的胚胎在神经上皮细胞中细胞死亡增加。D8（头部折叠）胚胎暴露于0.1 mM PEA表现出神经管闭合缺陷（89%）和颅面异常（67%），与D9相似，此外，28%的胚胎心脏绕行不正确。总之，苯丙氨酸的致畸潜力较低，而其代谢物PEA引起的畸形类似于PKU后代观察到的畸形。此外，头部折叠阶段似乎比神经胚形成时期更敏感。
IDENTIFICATION AND USE: 2-Phenylethylamine (PEA) is a colorless to slightly yellow liquid with fishy odor. It is used in organic synthesis, as a laboratory reagent, and in scintillation counters (CO2 absorber). HUMAN STUDIES: PEA poisonings may be severe in young and healthy individuals. The most frequently reported symptoms included anxiety and hallucinations (49%), mydriasis and headache (41%), tachycardia (40%) and hypertension (15%). Complications such as seizures (7%), cardiac arrest (5%), toxic myocarditis (1%) and hemorrhagic stroke (1%) were also observed. PEA was teratogenic at concentrations observed in individuals with phenylketonuria (PKU). ANIMAL STUDIES: Behavioral effects of PEA an agent proposed to act on both 5-HT and dopaminergic brain mechanisms, was examined in Wistar, Sprague-Dawley, and Long-Evans rats. Behavioral components assessed included: forepaw padding, headweaving, and splayed hindlimbs, which are thought to be indicative of central 5-HT stimulation. Following injection of 50 mg/kg Wistar rats were more active and reactive than Long-Evans or Sprague-Dawley rats. There was a significant difference in response to stimulation of central monaminergic mechanisms between Wistar rats and rats of the Long-Evans and Sprague-Dawley strains. The behavioral consequences of daily PEA administration for a period of 6 weeks have been examined. Rats showed signs of the 5-HT behavioral syndrome after a single injection of PEA (50 mg/kg) or 7 daily injections of PEA (25 mg/kg). The syndrome reached peak intensity after 3 weeks treatment. PEA reduced 24-hr food intake after a single injection in male rats and tolerance to this effect did not develop during 4-wk treatment. PEA caused a dose-dependent reduction in body wt gain during this period. The anorectic effect of PEA appears to be behaviorally specific to feeding, since there was no concurrent inhibition of water intake or diuresis. PEA induced myoclonic contractions in the submandibular muscle and epileptiform myoclonic spike discharges in electrocortical recording in anesthetized rats. PEA-induced stereotypy in rodents is suggested to model psychotic symptoms of schizophrenia. PEA is metabolized to azoxy-2-phenylethane (a mutagen). Exposure of D9 (neurulating) mouse embryos to PEA levels ranging from 0.01 to 1 mM for 24 hours in whole embryo culture results in 0% with neural tube closure defects at 0.01 mM and 67% at 0.1 mM and failure to thrive at 1 mM. Histological analysis also shows an increase in cell death in the neuroepithelium of embryos exposed to 0.1 and 1 mM PEA. D8 (head fold) embryos exposed to 0.1 mM PEA exhibited neural tube closure defects (89%) and craniofacial abnormalities (67%) similar to D9's, and in addition 28% had improper looping of the heart. In conclusion, it appears that phenylalanine has a low teratogenic potential, whereas, its metabolites PEA causes malformations similar to those observed in PKU offspring. Also the head fold stage appears more sensitive than the period of neurulation.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
神经毒素 - 其他中枢神经系统神经毒素
Neurotoxin - Other CNS neurotoxin
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
The effects of chronic administration of antidepressant drugs and 2-phenylethylamine on beta-adrenoceptor function were assessed. Monoamine oxidase inhibitors [phenelzine sulfate, 5 or 10 mg/kg per day, and (-)-deprenyl HCl, 1 mg/kg per day] and 2-phenylethylamine HCl (10 mg/kg per day) were administered to male Sprague-Dawley rats via Alzet osmotic minipumps. On days 21 and 22, the motor-suppressant actions of the beta-adrenoceptor agonist salbutamol hemisulfate (3 mg/kg intraperitoneally after 15 min) were assessed as a measure of beta-adrenoceptor sensitivity. On day 28, the animals were killed, and their brains were used for the measurement of monoamine oxidase activity and concentrations of 2-phenylethylamine, an endogenous amine and a metabolite of phenelzine. Phenelzine sulfate at 10 mg/kg per day (but not 5 mg/kg per day) and the combination of (-)-deprenyl and 2-phenylethylamine resulted in a decrease in the response to salbutamol. These treatments also resulted in substantial increases in brain 2-phenylethylamine concentrations. The phenelzine treatments each resulted in an equivalent inhibition of brain monoamine oxidase activity. These results support the proposal that 2-phenylethylamine may, at least in part, mediate the effects of phenelzine on beta-adrenoceptor function.
Systemic administration of beta-phenylethylamine caused behavioral syndrome in rats consistent with activation of 5-HT receptors in CNS. Redection of endogenous 5-HT levels did not prevent syndrome. 5-HT receptor antagonists, methysergide and mianserine, blocked effects of beta-phenylethylamine. Beta-phenylethylamine produces serotonergic effects by direct 5-ht agonist action.
In rats, beta-phenylethylamine (50-100 mg/gk, ip) induced stereotypic behavior and disrupted polyribosomes. Haloperidol and chlorpromazine antagonized these effects.
This study was performed to characterize the intestinal transport of beta-phenylethylamine (PEA). Uptake of [(14)C]PEA into Caco-2 cells was Na(+)-independent but strongly stimulated by an outside directed H(+) gradient. At extracellular pH 7.5, the concentration-dependent uptake of PEA was saturable with kinetic parameters of 2.6 mM (K(t)) and 96.2 nmol/min per mg of protein (V(max)). Several biogenic amines such as harmaline and N-methylphenylethylamine as well as cationic drugs such as phenelzine, tranylcypromine, d,l-amphetamine, methadone, chlorphenamine, diphenhydramine and promethazine strongly inhibited the [(14)C]PEA uptake with K(i) values around 1 mM. Tetraethylammonium, N-methyl-4-phenylpyridinium and choline had no effect. We also studied the bidirectional transepithelial transport of [(14)C]PEA at cell monolayers cultured on permeable filters. Net transepithelial flux of [(14)C]PEA from apical-to-basolateral side exceeded basolateral-to-apical flux 5-fold. We conclude that PEA is transported into Caco-2 cells by a highly active, saturable, H(+)-dependent (antiport) process. The transport characteristics do not correspond to those of the known carriers for organic cations of the SLC22, SLC44, SLC47 and other families.
Phenylethylamine was found in cervical spinal cord dorsal and ventral horns, zona intermedia, and lumbar cord dorsal and ventral horns of rats in concentrations of 114-238 pg/mg protein. Values found in caudate nucleus (218 pg/mg) and cerebellum (73 pg/mg). Repeated treatment with amphetamine for 10 days increased levels in both brain and spinal cord.
Specific binding of tritiated beta-phenylethylamine to rat forebrain membranes was saturable; the apparent dissociation constant was 55 nmol and the density of binding sites was approx 1078 pmol/mg protein. Highest binding was observed in hypothalamus and striatum.
The urinary excretion rate of the endogenous, amphetamine-like substance beta-phenethylamine was markedly elevated in human subjects in association with an initial parachuting experience. The increases were delayed in most subjects and were not correlated with changes in urinary pH or creatinine excretion. The data suggest a stress-related role for beta-phenethylamine.
seven novel NImNHP‐type pincer imidazolylphosphineruthenium complexes has been synthesized and fully characterized. The use of hydrogenation of benzonitrile as a benchmark test identified [RuHCl(CO)(NImNHPtBu)] as the most active catalyst. With its stable Ru−BH4 analogue, in which chloride is replaced by BH4, a broad range of (hetero)aromatic and aliphaticnitriles, including industrially interesting
已合成并充分表征了一系列七个新型的N Im N H P型钳型咪唑基膦膦钌配合物。使用苯甲腈加氢作为基准测试，确定了[RuHCl（CO）（N Im N H P t Bu）]是最具活性的催化剂。凭借其稳定的Ru-BH 4类似物（其中氯化物被BH 4替代），已在温和且无碱的条件下氢化了多种（杂）芳族和脂肪族腈，包括工业上有用的己二腈。
Divergent Approach for the Synthesis of Gombamide A and Derivatives
作者：Mohana Rao Vippila、Sameer Nikhar、Alan P. Gracia、Gregory D. Cuny
DOI：10.1021/acs.orglett.6b02379
日期：2016.9.16
A synthesis of gombamide A (1) using N-terminal peptide extension, oxidative disulfide bond formation, and late-stage 4-hydroxystyrylamide installation has been achieved. This divergent method was also utilized to synthesize several gombamide A derivatives with modification to the 4-hydroxystyrylamide via cyclic peptide 2. The natural product and four derivatives were found to be devoid of Na+/K+-ATPase
已经实现了使用N端肽段延伸，氧化二硫键形成和后期4-羟基苯乙烯基酰胺装置合成Gombamide A（1）的方法。这种发散的方法还用于通过环肽2合成几种对4-羟基苯乙烯基酰胺有修饰的邻苯二甲酰胺A衍生物。发现该天然产物和四种衍生物在10μM下没有Na + / K + -ATPase活性。此外，这些化合物在10μM的浓度下对一组癌细胞没有细胞毒性。
Novel compounds and compositions as protease inhibitors
申请人：——
公开号：US20020052378A1
公开（公告）日：2002-05-02
The present invention relates to novel cysteine protease inhibitors of Formula I:
1
the pharmaceutically acceptable salts and N-oxide derivatives thereof, their use as therapeutic agents and methods of making them.
