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At least 19 recordsLinked to original sources
PubMed1988

Highly selective kappa opioid analgesics. Synthesis and structure-activity relationships of novel N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy]acetamide derivatives.

This paper describes the synthesis, structure-activity relationships (SAR) of mu and kappa opioid binding affinities, and analgesic properties of a series of novel highly selective kappa opioid N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy] acetamide derivatives. Ten compounds, 14, 15, 31-37, and 39 (Tables I and II), show a marked kappa selectivity of greater than 100:1 over mu binding, with high affinity for the kappa opioid receptor (approximately 10(-8) - 10(-9) M). Compound 39, (S,S-trans)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-4-benzo[b] furanacetamide hydrobromide, has the highest mu/kappa selectivity, 780:1 (kappa Ki = 4.2 nM), reported to date. Four of these compounds, 14, 15, and their S,S-trans enantiomers, 37 and 39, respectively, produce effective analgesia by oral administration, as assayed by a rat-paw pressure test (RPP) (MPE50 = 24, 26, 8.3, and 12 mg/kg, respectively). The R,R-trans isomer, 38, was inactive in binding and RPP. The analgesic effect was reversed by administration of naloxone, confirming these effects are opioid in character. Optimal activity is produced when the basic nitrogen atom is in a pyrrolidine ring, the aryl group is a 10-pi-electron-rich aromatic system, such as 4-benzo[b]thiophene, 4-benzo[b]furan, or 4-chlorophenoxy, and overall lipophilicity lies within the range log P = 3.5-5.0.

Acetamides↗
PubMed1993

Enhancement of Y-maze learning by piracetam, 2-thio-1-pyrrolidine-acetamide and 2-thio-1-pyrrolidine-thio-acetamide in rats.

Learning of rats given either piracetam, 2-thio-1-pyrrolidine-acetamide (thioacet) or 2-thio-1-pyrrolidine-thio-acetamide (thiothio) was studied in order to investigate nootropic effects of the compounds. Learning ability was measured using a Y-maze with water reward for the correct choice in a black-white discrimination task. Thioacet and thiothio enhanced learning ability of the rats at doses that were 2.5-10 times lower than those required for obtaining nootropic effects of piracetam. Thus the thio-derivatives of piracetam might be of value for studying mechanisms of action of nootropic drugs.

Animals↗
PubMed1987

Studies on the mechanism of acetamide hepatocarcinogenicity.

The hepatocarcinogen acetamide, in single doses of 100 and 400 mg/kg b.wt., was shown to act as an initiator in a dose-dependent fashion in rat liver using the Solt-Farber method. Acetamide and its putative metabolite N-hydroxy-acetamide did not cause liver necrosis in single dose experiments. Acetamide showed no evidence for genotoxicity in tests for mutations in Salmonella typhimurium, for DNA damage in rat hepatoma cells or for DNA repair in isolated rat hepatocytes. In contrast, N-hydroxy-acetamide displayed genotoxic activity in all 3 test systems. Neither acetamide nor N-hydroxy-acetamide induced transformation of primary Syrian hamster embryo cells or gave evidence of inhibition of metabolic cooperation in V79 cells. Radiolabelled acetamide and N-hydroxy-acetamide were not bound covalently to proteins in the presence of various metabolic activation systems (microsomes plus NADPH or xanthine/xanthine oxidase, cytosol or cytosol plus acetyl CoA or proline plus ATP). N-Hydroxy-acetamide was cytotoxic to monolayers of isolated hepatocytes at concentrations above 2.5 mM. This cytotoxicity was increased after diethyl maleate treatment, but N-hydroxy-acetamide did not deplete cellular glutathione. A HPLC system was developed for the separation and quantification of acetamide, N-hydroxy-acetamide and acetic acid. No significant excretion of N-hydroxy-acetamide or acetic acid in the urine could be demonstrated after treatment of rats with 100 or 1,000 mg/kg b.wt. of acetamide. The underlying mechanism for the observed initiating effect of acetamide is obscure.

Acetamides↗
PubMed2006

Remaining acetamide in acetonitrile degradation using nitrile hydratase- and amidase-producing microorganisms.

The tandem conversion process involving nitrile hydratase- and amidase-producing microorganisms has potential for use in the treatment of acetonitrile-containing wastes. In that process, the acetamide hydrolysis step catalyzed by amidase is very slow compared with the acetonitrile hydration step catalyzed by nitrile hydratase, and a small amount of acetamide remains in the resulting solution. This study aimed to improve the efficiency of the acetamide hydrolysis step. An amidase-producing microorganism, Rhodococcus sp. S13-4, was newly obtained, whose use enabled rapid acetamide degradation. Though residual acetamide was still detected, it was successfully reduced by the addition of cation/anion mixed ion exchange resin or calcium hydroxide after the acetamide hydrolysis reaction using Rhodococcus sp. S13-4 cells. This result implies that acetamide hydrolysis and acetamide formation are in equilibrium. The incubation of Rhodococcus sp. S13-4 cells with high concentrations of ammonium acetate produced acetamide. The purified amidase from Rhodococcus sp. S13-4 revealed the acetamide formation activity (specific activity of 30.6 U/mg protein). This suggests that the amidase-catalyzed amide formation may cause the remaining of acetamide in the acetonitrile conversion process.

Acetamides↗
PubMed2005

Inhibitory effect of acetamide-45 on airway inflammation and phosphodiesterase 4 in allergic rats.

AIM: To determine the effects of acetamide-45 on respiratory function, airway inflammation, and the activity of phosphodiesterase 4 (PDE4) in allergic rats. METHODS: Rats were sensitized by a single intramuscular injection with ovalbumin (OVA) and were challenged with ovalbumin applied by using an aerosol repeatedly for 7 d after 2 weeks. Acetamide-45 at concentrations of 5, 10, or 30 mg/kg was then administered by intraperitoneal injection. Changes in dynamic lung compliance and lung resistance, the accumulation of inflammatory cells in bronchoalveolar lavage, PDE4 activity, and the concentration of interleukin-4 in rat lung tissue were determined. RESULTS: Seven days of treatment with acetamide-45 prevented eosinophil accumulation in allergic rats. At doses of 5, 10, and 30 mg/kg, acetamide-45 decreased lung resistance to 0.20+/-0.04, 0.25+/-0.07, and 0.22+/-0.05 cmH2O.s(-1).mL(-1), respectively (P<0.05 vs OVA), and it also increased dynamic lung compliance to 0.41+/-0.07, 0.39+/-0.06, and 0.42+/-0.09 mL/cmH2O (P<0.05 vs OVA). After being treated with different doses of acetamide-45, the PDE4 activities in lung tissue were 281+/-55, 273+/-57, and 238+/-36 nmol.g(-1).min( -1) (P<0.05 vs OVA), and the concentrations of interleukin-4 in lung tissue were 6.22+/-1.13, 5.95+/-1.20, and 5.68+/-2.20 microg/protein (P<0.05 vs OVA). CONCLUSIONS: Acetamide-45 was found to improve respiratory function and inhibit airway inflammation in this animal model, and the PDE4 activity of lung tissue was obviously inhibited. Acetamide-45 was an effective anti-inflammatory agent in respiratory inflammation, and the mechanism of its action might depend on inhibition of PDE4.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Acetamide-45 inhibits histamine-and methacholine-induced contraction of isolated guinea pig trachea.

AIM: To investigate the effects of the new antiallergic agent N-(pyridin-4-yl)-(indol-3-yl) acetamide-45 (acetamide-45) on histamine- and methacholine-induced contraction of the isolated guinea pig trachea. METHODS: Cumulative histamine or methacholine concentration-contraction studies were carried out in the absence or presence of acetamide-45. Changes in isometric force were measured by force transducers and recorded on a multi-channel polygraph recorder. RESULTS: Acetamide-45 (1 - 30 micromol/L) concentration-dependently inhibited histamine- or methacholine-induced contractile response of isolated guinea pig trachea. At concentrations of 3, 10, 30 mumol/L, acetamide-45 significantly decreased maximum contractile response to histamine by 21 % - 51 %, and EC50 values (95 % confidence limits) were 31.1 (24.4 - 39.8), 34.7(26.8 - 45.0), and 134.4 (82.2 - 220.0) micromol/L, respectively. Similarly, acetamide-45 also inhibited the contraction induced by methacholine in isolated guinea pig trachea. CONCLUSION: Acetamide-45 inhibited histamine- or methacholine-induced contraction of isolated guinea pig trachea, and these effects might be non-specific for either histamine receptor or cholinoceptor.

Animals↗
PubMedDate not supplied

Carcinogenesis bioassay of acetamide, hexanamide, adipamide, urea and P-tolylurea in mice and rats.

As a part of the National Cancer Institute's effort to screen environmental and occupational chemicals for chronic toxicity and carcinogenicity, the amides acetamide, hexanamide, adipamide, urea, and p-tolylurea were fed to male and female C57B1/6 mice and Fischer 344 rats from 12 months. Rats received the following concentrations of compounds in their diets: acetamide, 2.36%; hexanamide, 1.5%; adipamide, 2.4% and 5.8%; urea, 0.45%, 0.9%, and 4.5%; and p-tolylurea, 0.2%. Mice received acetamide, 1.18% and 2.36%; hexanamide, 1.0% and 1.5%; adipamide, 1.6% and 2.4%; urea, 0.45%, 0.9%, and 4.5%; and p-tolylurea, 0.2%. In acetamide treated rats, there was a compound-related occurrence of neoplastic nodules (1/47 male, 3/48 female) and hepatocellular carcinomas (41/47 male, 33/48 female). The incidence, speed of onset and frequency of metastases, were greater in males than in females. In male mice treated with acetamide (low dose, 7/50; high dose, 7/46); hexanamide (low dose, 6/35; high dose, 6/39); and p-tolylurea (10/43), there was a compound-related increase in hematopoietic tumors, namely malignant lymphomas. Therefore, under the conditions of these studies, acetamide was an hepatocarcinogen in rats. In male mice, acetamide, hexanamide, and p-tolylurea caused malignant lymphomas. Urea and adipamide were considered to be non-carcinogenic.

Amides↗
PubMed1975

[Studies on the 14C-15N-acetamide turnover in sheep. 1. Studies on the 14C turnover].

4 male sheep (average weight: 53.5 kgs) were fed a semisynthetic diet containing acetamide as sole source of nitrogen. At the beginning of the trial twin-labelled 15N-14C-acetamide was administered by way of a ruminal fistula. The curve pattern of 14C activity in the TCE-soluble fraction of the ruminal fluid showed a synchronous behaviour in all animals beginning at 3 hours after the beginning of the trial. A half-life of 2 1/2 hours for the rate of absorption of 14C acetamide and deaminated 14C acetate was established from the decline in 14C activity observed in the TCE-soluble fraction of the ruminal fluid. The peak level of 14C labelling in ruminal proteins was reached after 6 hrs. The specific 14CO2 activity in respiratory air reached its maximum level after 4 hrs, and was then found to decline continuously. 56% of the administered amount of 14C was excreted over a period of up to 50 hrs after beginning of the trial. The very fact that the peak level of 14C activity was observed to appear in the TCE-soluble fraction of the blood plasma as early as after 1 hr seems to indicate that acetamide is also absorbed through the ruminal wall. The half-life of decline in the 14C activity of this fraction was 5.7 hrs. Analysis by thin layer chromatography showed that 75% of this amount of activity is present in 14C acetamide. The rate of 14C incorporation into blood plasma proteins reached a plateau region after 21 hrs, which was also maintained on the 2nd day of the experiment. 6.5% of the administered amount of 14C activity was excreted in the urine until the 7th day of experiment. 76.6% of the amount of urinary 14C activity excreted within a period of 48 hrs were voided as 14C acetamide. 3.8% of the administered amount of 14C activity was excreted with the faeces within the first 6 days of experiment.

Acetamides↗
PubMed2000

Differential branchial and renal handling of urea, acetamide and thiourea in the gulf toadfish Opsanus beta: evidence for two transporters.

The possible presence of a urea transporter in the kidney of the gulf toadfish (Opsanus beta) and further characterization of the pulsatile facilitated transporter previously identified in its gills were investigated by comparing the extra-renal and renal handling of two urea analogues with the handling of urea. Toadfish were fitted with caudal artery and indwelling urinary ureteral catheters and injected with an iso-osmotic dose of (14)C-labelled urea analogue (acetamide or thiourea) calculated to bring plasma analogue concentrations close to plasma urea concentrations. Branchial permeabilities to urea, acetamide and thiourea were similar during non-pulsing periods and all increased during pulse events, although urea permeability was greater than analogue permeability during pulses. The incidence and magnitude of acetamide and urea pulses at the gills were significantly correlated, acetamide pulses being 35-50 % of the size of urea pulses. However, the thiourea and urea pulses at the gills were only weakly correlated, thiourea pulses being less than 16 % of the size of urea pulses. Thiourea inhibited branchial urea excretion by reducing the pulse frequency. The renal handling of thiourea and urea were similar in that both substances were more concentrated in the urine than in the plasma, whereas acetamide was found in equal concentrations in the urine and plasma. Urea and thiourea were secreted 2-3 times more effectively than Cl(-) and water, whereas acetamide was secreted at a similar relative rate. The differential handling of the urea analogues by the gills and kidney indicates the presence of a different, possibly unique, transporter in the kidney. The movement of thiourea and urea into the renal tubule against an apparent concentration gradient suggests the presence of an active transport mechanism.

Acetamides↗
PubMed2005

[Inhibition of acetamide-45 on airway smooth muscle contraction induced by electric field stimulation and methacholine in vitro].

OBJECTIVE: To investigate the effects of the new antiallergic agent N-(pyridin-4-yl)-(indol-3-yl) acetamide-45 (acetamide-45) on electric field stimulation (EFS)-and methacholine-induced contraction of airway smooth muscle in vitro. METHODS: Contractions were induced by EFS in isolated trachea and bronchus of rats or by cumulative methacholine concentrations in isolated trachea of guinea pigs. Changes in isometric force of isolated airway smooth muscle were measured by force transducers and recorded on a multi-channel polygraph recorder. RESULTS: Acetamide-45 inhibited the contraction induced by EFS in isolated rat airway. The IC50 was 10.74 (95% CI 8.87-13.00) micromol.L(-1) and 18.83 (95% CI 14.57-24.33) micromol.L(-1) in tracheae and bronchi, respectively. Acetamide-45 also inhibited methacholine-induced contractile response of isolated guinea pig trachea in a concentration-dependent manner. At concentrations of 3, 10, 30 micromol.L(-1) acetamide-45 significantly decreased maximal contractile response of methacholine by 24.6%-43.2% and increased EC50 of methacholine by 3.1-to 21.4-fold. CONCLUSION: Acetamide-45 inhibits EFS-or methacholine-induced contraction of isolated airway smooth muscle, and these effects might be non-specific inhibition on cholinergic receptor.

Acetamides↗
PubMed1989

Synergistic effect of allyl isopropyl acetamide with cadmium on hepatic heme synthesis in chick embryo.

The effect of cadmium along with a porphyrogenic drug, allyl isopropyl acetamide, on the induction of 5-amino levulinic acid (ALA) synthetase, ALA dehydratase and heme level was studied. The interaction of cadmium with allyl isopropyl acetamide indicated that the decrease in hepatic heme level by cadmium or allyl isopropyl acetamide may occur in a synergistic manner, whereas the induction of ALA synthetase by cadmium or allyl isopropyl acetamide may not take place in the same manner. Further, neither allyl isopropyl acetamide treatment alone nor allyl isopropyl acetamide-cadmium treatment had any effect on ALA dehydratase activity.

5-Aminolevulinate Synthetase↗
PubMed1982

[Comparative studies of the enrichment of Pseudomonas aeruginosa in asparagine, malachite green, and acetamide broths and the isolation on cetrimide and endo agar].

We studied the efficience of the following broths for the enrichment of Pseudomonas aeruginosa: asparagine broth, malachite green broth, acetamide broth I (1% acetamide) and II (0.2% acetamide). A total of 275 P. aeruginosa containing sewage water samples was investigated. We isolated 784 P. aeruginosa strains. 6.3% of them produced no pyocyane. Until now the acetamide broth was used only diagnosticly but it can be employed also for enrichment. The acetamide broths had yields of 85.1%, 78.0% respectively. The asparagine broth showed a yield of 73.8% and the malachite green broth of 62.9% (Table 1). The comparison of the two used agars showed isolation quotas of 77.1% on cetrimide agar and of 58.3% on endo agar (Table 1). Incubation at 36 degrees C during 48 hours yielded more strains in all broths, the most in malachite green broth. However, the acetamid broth I showed already a decay of some organisms (Table 2).

Acetamides↗