N-[反式-2-(3,4-~3H-吡咯基)-环己基]-N-甲基-3,4-二氯-苯乙酰胺盐酸盐的合成

N-[反式-2-(1-吡咯基)环己基]-N-甲基-3,4-二氯-苯乙酰胺盐酸盐(简称U-50488H(K-I))是近年来报道的高选择性的K-阿片受体激动剂,动物实验结果表明:该化合物具有较强的镇痛活性,且成瘾性较低,呼吸抑制较弱,无吗啡样副作用的新型麻醉镇痛剂。为研究它的药理作用,我们用氚标记了U-50488(K-I)。合成该化合物开始原料是N-甲基-反式-2-(1-△~3-吡咯啉基)环己基胺,按一般还原法以氧化铂为催化剂,通氚进行氚化反应,未经分离与3,4一二氯苯乙酸在二环己基碳二亚胺(DCC)存在下进行缩合脱水反应,生成N-[反式-2-(3,4-~3H-吡咯基)环己基]-N-甲基-3,4-二氯-苯乙酰胺,再用氯化氢乙醚处理,制得了氚化的U-50488(K-I)。合成途径如下:     

Acetone effects on N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity

Acetone has been shown to potentiate the toxicity of many halogenated hydrocarbons. The purpose of this study was to determine if acetone could alter the acute nephrotoxicity produced by the experimental fungicide N-(3,5-dichlorophenyl)succinimide (NDPS). Male Fischer 344 rats were administered acetone (1, 5 or 10 mmol/kg) or acetone vehicle (corn oil, 10 mg/kg) orally followed 16 h later by a single intraperitoneal injection of NDPS (0.2 or 0.4 mmol/kg) or NDPS vehicle (sesame oil, 2.5 ml/kg) and renal function was monitored at 24 and 48 h. Acetone (1 or 5 mmol/kg) did not alter NDPS (0.2 mmol/kg)-induced renal effects while acetone (10 mmol/kg) pretreatment attenuated NDPS (0.4 mmol/kg)-induced increases in blood urea nitrogen (BUN) concentration and kidney weight but had no effect on NDPS (0.4 mol/kg)-induced changes in urine volume or content, organic ion accumulation by renal cortical slices or renal morphology. These results suggest that acetone weakly attenuates NDPS-induced nephrotoxicity.     

Comparative acute renal effects of three N-(3,5-dichlorophenyl)carboximide fungicides: N-(3,5-dichlorophenyl)succinimide, vinclozolin and iprodione

A large number of carboximides have been synthesized, tested and, in some cases, marketed as agricultural fungicidal agents. One carboximide fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) proved to be both highly efficacious as a fungicide and a nephrotoxin. The purpose of this study was to compare the acute nephrotoxic potential of three N-(3,5-dichlorophenyl)carboximide fungicides [NDPS, vinclozolin (VCLZ) and iprodione (IPDO)] to determine if nephrotoxic potential correlated with fungicidal efficacy among this class of structurally-related agricultural agents. Male Fischer 344 rats (4 rats/group) received a single intraperitoneal injection of a fungicide (0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg), and renal function was monitored at 24 and 48 h. NDPS (0.4 or 1.0 mmol/kg)-induced renal effects were characterized by marked diuresis, increased proteinuria, elevated blood urea nitrogen (BUN) concentration and kidney weights, decreased organic ion accumulation by renal cortical slices and proximal tubular necrosis. In contrast, IPDO and VCLZ (0.4 or 1.0 mmol/kg) administration resulted in only minor or no alterations in the renal function parameters studied and renal morphology. These results suggest that fungicidal efficacy does not correlate with acute nephrotoxic potential among the N-(3,5-dichlorophenyl)carboximide fungicides.     

Effect of buthionine sulfoximine on N-(3,5-dichlorophenyl)-2-hydroxysuccinimide and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid nephrotoxicity

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an agricultural fungicide which induces acute tubular necrosis as its primary toxicity. Two NDPS metabolites, N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (NDHSA) previously have been shown to be more potent nephrotoxicants than NDPS. In addition, buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, was found to attenuate NDPS-induced nephrotoxicity. The purpose of this study was to examine the effects of BSO pretreatment on NDHS- and NDHSA-induced nephrotoxicity. Male Fischer-344 rats (4 rats/group) were administered intraperitoneally (i.p.) BSO (890 mg/kg) 2 h before NDHS or NDHSA (0.1 or 0.2 mmol/kg, i.p.) or vehicle (sesame oil, 2.5 ml/kg), and renal function monitored at 24-h intervals for 48 h. BSO pretreatment markedly attenuated NDHSA (0.1 or 0.2 mmol/kg)-induced effects on the renal functional parameters monitored. BSO pretreatment also markedly reduced NDHS (0.1 mmol/kg)-induced renal effects. However, NDHS (0.2 mmol/kg) nephrotoxicity was attenuated to a lesser extent than NDHS (0.1 mmol/kg) nephropathy. These results indicate that glutathione is an important mediator of NDPS metabolite nephrotoxicity and suggests that BSO did not attenuate NDPS nephropathy by inhibiting NDPS biotransformation to NDHS or NDHSA.     

Effects of Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] on the urinary bladder of male Wistar rats

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide widely used on agricultural crops such as soy, cotton and sugar cane. In a previous long-term study this herbicide exerted carcinogenic activity on the urinary bladder mucosa of male Wistar rats. In general, the genotoxic and mutagenic potentials of Diuron are considered to be negative. The present study aimed to evaluate the mode of action of Diuron on the urinary bladder mucosa of male Wistar rats. Six-week old male Wistar rats were fed pelleted Nuvilab diet mixed with Diuron at 125, 500 and 2500 ppm. As a positive control, 8.3% sodium saccharin (NaS) was fed in the diet. Preceding the sacrifice of the animals at the 20th week, urinary pH was measured and the genotoxic potential of Diuron was evaluated by the comet assay. Histological urothelial lesions in the urinary bladder and in the renal pelvis mucosa, cell proliferation/apoptosis evaluations, and scanning electron microscopy (SEM) of the urinary bladder mucosa were also performed. No DNA changes were found in urothelial or peripheral blood cells, and urinary pH was comparable to controls in all Diuron groups. In the urinary bladder urothelium, the incidence of simple hyperplasia (SH) by light microscopy was significantly increased (7/10; p<0.005) in the 2500 ppm Diuron group but not at the lower doses. By SEM, three of five animals treated with 2500 ppm Diuron showed urothelial cell necrosis and hyperplasia. In the renal pelvis, the incidence of SH was significantly increased in the Diuron 500 and 2500 ppm and in the NaS 8.3% groups. Cell proliferation was significantly increased in the Diuron 2500 ppm (p<0.05) and NaS 8.3% (p<0.05) groups. The results indicate that a high dietary concentration of Diuron is associated with urothelial necrosis and continuous regenerative cell proliferation that leads to urothelial hyperplasia.     

N-(3,5-dichlorophenyl)succinimide nephrotoxicity in streptozotocin-induced diabetic rats

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an experimental fungicide which induces renal toxicity. The following study examined the nephrotoxicity induced by NDPS in streptozotocin (STZ) diabetic rats. Male Fischer 344 (F344) rats were injected with 35 mg/kg STZ (i.p.) or citrate buffer. Fourteen days after STZ or citrate buffer injection, the rats (4-6 rats/group) were injected with (0.4 or 1.0 mmol/kg) NDPS or vehicle (sesame oil, 2.5 ml/kg). Kidney weight, blood urea nitrogen (BUN) levels, morphology and renal cortical slice uptake of organic ions was quantitated 48 h after NDPS administration. A 0.4 mmol/kg dose of NDPS induced diuresis, increased kidney weight and a moderate elevation in BUN levels in the normoglycemic group. The 1.0 mmol/kg dose of NDPS produced diuresis, proteinuria, increased kidney weight and a marked increase in BUN levels in the normoglycemic group. The renal cortical slice uptake of p-aminohippurate (PAH) and tetraethylammonium (TEA) was also decreased 48 h after NDPS injection in the normoglycemic group. No alterations in kidney weight, BUN levels, morphology or renal cortical slice uptake of organic ions was observed in the diabetic animals treated with (0.4 or 1.0 mmol/kg) NDPS. The results of this study indicate that the renal toxicity of NDPS was reduced in the diabetic rat.     

Synthesis of N-[3,4-dimethoxyphenyl)propanoyl]pyrrole, a metabolite of Piper brachystachyum

N-[3-(3,4-Dimethoxyphenyl)propanoyl]pyrrole (1) has been synthesized in three steps starting from veratraldehyde (2) with an overall yield of 66%.     

Interactions among nephrotoxicants: N-(3,5-dichlorophenyl)succinimide and cephaloridine

Numerous studies have demonstrated the interactive potential between nephrotoxicants. The purpose of this study was to examine the interactive potential between two model nephrotoxicants, N-(3,5-dichlorophenyl)succinimide (NDPS) and cephaloridine (CPH). Male Fischer 344 rats (4 rats per group) were administered an intraperitoneal (i.p.) injection of CPH (500 mg/kg), NDPS (0.2 mmol/kg) or the appropriate vehicle 1 h prior to administration of an i.p. injection of NDPS (0.2, 0.4, or 1.0 mmol/kg), CPH (500, 750 or 1000 mg/kg) or the appropriate vehicle. Renal function was monitored at 24 and 48 h. Combination of non-nephrotoxic doses of CPH (500 mg/kg) and NDPS (0.2 mmol/kg) did not result in nephrotoxicity, regardless of which compound was administered first. NDPS (0.2 mmol/kg) weakly enhanced the nephrotoxicity observed following CPH (1000 mg/kg) injection but had little effect on CPH (750 mg/kg)-induced renal effects. However, CPH (500 mg/kg) markedly attenuated NDPS (0.4 or 1.0 mmol/kg)-induced nephrotoxicity. These results demonstrate that prior NDPS exposure has little effect on the outcome of CPH-induced renal effects, but prior CPH exposure can markedly alter the renal response to NDPS administration.     

Role of chloride groups in the nephrotoxic potential of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide,an oxidative metabolite of N-(3,5-dichlorophenyl)succinimide

Although the addition of chloride groups to the phenyl ring of N-phenylsuccinimide (NPS) is known to enhance the nephrotoxic potential of NPS, the mechanism of this enhancement is unknown. One chlorinated NPS derivative, N-(3,5-dichlorophenyl)succinimide (NDPS), is a potent nephrotoxicant which induces marked proximal tubular necrosis at i.p. doses of 0.4 mmol/kg or greater. The purpose of this study was to compare the nephrotoxic potential of 2-hydroxy-N-phenylsuccinimide (HNPS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS), an oxidative and nephrotoxicant metabolite of NDPS, to determine the importance of the chloride groups for the nephrotoxic potential of NDHS. Male Fischer 344 rats (4/group) were administered a single i.p. injection of HNPS (1.0 or 1.5 mmol/kg), NDHS (0.1 mmol/kg) or vehicle (25% dimethyl sulfoxide in sesame oil), and renal function measured at 24 and 48 h. HNPS was a nonnephrotoxicant at both doses tested, while NDHS induced marked nephrotoxicity characterized by diuresis, increased proteinuria, glucosuria, elevated blood urea nitrogen (BUN) concentration a kidney weight, decreased organic ion accumulation by renal cortical slices and proximal tubular necrosis. In vitro, HNPS reduced p-aminohippurate (PAH) and tetraethylammonium (TEA) accumulation beginning at HNPS bath concentrations of 0.05 and 0.5 ?M, respectively. The results of this study indicate that although HNPS has direct effects on renal function in vitro, HNPS is not a nephrotoxicant in vivo at doses up to 15 times the minimal nephrotoxicant dose of NDHS. Therefore, the chloro groups present on NDHS play an essential role in the nephrotoxic potential NDHS and contribute to aspects of the nephrotoxic mechanism of NDPS beyond NDPS oxidation to form NDHS.     

Sodium sulfate potentiates N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) nephrotoxicity in the Fischer 344 rat

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity as its major toxicity in rats. Previous studies have shown that NDPS induces nephrotoxicity following oxidation of the succinimide ring to form N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and the hydrolysis product of NDHS, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). Our recent work found that sodium sulfate potentiated NDPS nephrotoxicity, suggesting that sulfate conjugation of NDPS metabolites might be a bioactivation step mediating NDPS nephrotoxicity. The purpose of this study was to determine if sodium sulfate also potentiated the nephrotoxicity of the two nephrotoxic metabolites of NDPS and further to see if sodium sulfate potentiated NDHS and 2-NDHSA nephrotoxicity to the same degree. Male Fischer 344 rats (4-16 rats/group) received an intraperitoneal (ip) injection of sodium sulfate (10 mg/kg) 20 min before a non-nephrotoxic dose (0.05 mmol/kg, ip) of NDHS or 2-NDHSA, or vehicle (12.5% dimethyl sulfoxide in sesame oil). Renal function was then monitored over 48 h. Sodium sulfate pretreatment potentiated the renal effects of a non-nephrotoxic dose of NDHS and 2-NDHSA to induce nephrotoxicity. Nephrotoxicity was characterized by diuresis, increased proteinuria, elevated blood urea nitrogen (BUN) concentration, increased kidney weight and proximal tubular necrosis. Differences in the potentiation of NDHS and 2-NDHSA nephrotoxicity by sodium sulfate were also observed as NDHS nephrotoxicity was potentiated to a lesser degree than 2-NDHSA-induced nephrotoxicity. These results support the likelihood that one or more sulfate conjugate(s) of NDPS metabolites contribute to NDPS nephrotoxicity.     

Stimulatory effect of N-[4-[2-(dimethylamino)-ethoxy] benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) on normal and delayed gastrointestinal propulsion

To estimate the effect of a new gastroprokinetic agent, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803), on non-ulcer dyspepsia, the influence of HSR-803 on gastrointestinal propulsion was assayed in dogs, rats and mice in comparison with some gastroprokinetic agents. HSR-803 (30 mg/kg, p.o.) significantly enhanced gastric emptying in dogs, and it significantly improved the delayed gastric emptying induced by dopamine (0.4 mg/kg, i.p.) and morphine (1 mg/kg, s.c.) in rats. Metoclopramide (30 mg/kg, p.o.) also significantly restored the dopamine-induced delay, but at a dose of 10 mg/kg, p.o., it enhanced the morphine-induced delay in gastric emptying in rats. HSR-803 (10-100 mg/kg, p.o.) increased small intestinal transit in mice in a dose-dependent manner, and the effect was abolished by atropine (0.3 mg/kg, i.p.). Metoclopramide also increased small intestinal transit, but domperidone and cisapride had no effect. In delayed small intestinal transit in mice, HSR-803 (10-100 mg/kg, p.o.) improved the morphine (0.3 mg/kg, s.c.)-induced delay in a dose-dependent manner. In conclusion, because of the promotion of normal and delayed gastrointestinal propulsion, HSR-803 seems to be a promising gastroprokinetic agent for the treatment of non-ulcer dyspepsia. The action of HSR-803 is likely to be exerted through cholinergic stimulation.     

Note: Synthesis of N-[3-(3,4-Dimethoxyphenyl)Propanoyl]Pyrrole,a Metabolite of Piper brachystachyum

Abstract

N-[3-(3,4-Dimethoxyphenyl)propanoyl]pyrrole (1) has been synthesized in three steps starting from veratraldehyde (2) with an overall yield of 66%.     

Nephrotoxicity following acute administration of N-(3,5-dichlorophenyl)succinimide in rats

The acute renal effects of the fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) were studied in male Sprague-Dawley rats. NDPS (50 mg/ kg, i.p.) increased urine volume and decreased food intake and body weight at 24 h but not 48 h. No change in urine content of the accumulation by renal cortical slices of the organic anion p-aminohippurate (PAH) or the organic cation tetraethylammonium (TEA) was observed with 50 mg/kg NDPS when compared to control animals. Rats receiving 100 or 200 mg/kg NDPS (i.p.) exhibited increased urine volume, proteinuria, glucosuria, decreased food intake and body weight, increased BUN and decreased accumulation of PAH and TEA at both 24 h and 48 h. These effects were generally more pronounced at the 200 mg/kg dose level. Pair-fed control experiments demonstrated that renal effects were NDPS-induced and not related to daily food consumption. No change in water intake was observed with any dose of NDPS used. The results demonstrate that NDPS alters renal function in a dose-dependent manner. In addition, NDPS (50 mg/kg) is capable of producing diuresis without apparent nephrotoxicity while doses of 100 mg/kg or more produce diuresis and nephrotoxicity.