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PubMed2005

Synthesis and evaluation of N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide: a deuterium-substituted radioligand for peripheral benzodiazepine receptor.

N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]2) is a potent ligand (IC(50): 1.71 nM) for peripheral benzodiazepine receptor (PBR). However, in vivo evaluation on rodents and primates showed that this ligand was unstable and rapidly metabolized to [(18)F]F(-) by defluorination of the [(18)F]fluoromethyl moiety. In this study, we designed a deuterium-substituted analogue, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[(18)F]fluoromethoxy-d(2)-5-methoxybenzyl)acetamide ([(18)F]5) as a radioligand for PBR to reduce the in vivo metabolic rate of the non-deuterated [(18)F]2. The design principle was based on the hypothesis that the deuterium substitution may reduce the rate of defluorination initiated by cleavage of the C-H bond without altering the binding affinity for PBR. The non-radioactive 5 was prepared by reacting diiodomethane-d(2) (CD(2)I(2), 6) with a phenol precursor 7, followed by treatment with tetrabutylammonium fluoride. The ligand [(18)F]5 was synthesized by the alkylation of 7 with [(18)F]fluoromethyl iodide-d(2) ([(18)F]FCD(2)I, [(18)F]9). Compound 5 displayed a similar in vitro affinity to PBR (IC(50): 1.90 nM) with 2. In vivo evaluation demonstrated that [(18)F]5 was metabolized by defluorination to [(18)F]F(-) as a main radioactive component, but its metabolic rate was slower than that of [(18)F]2 in the brain of mice. The deuterium substitution decreased the radioactivity level of [(18)F]5 in the bone of mouse, augmented by the percentage of specific binding to PBR in the rat brain determined by ex vivo autoradiography. However, the PET image of [(18)F]5 for monkey brain showed high radioactivity in the brain and skull, suggesting a possible species difference between rodents and primates.

Acetamides↗

PubMed2005

Insight into 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as peripheral benzodiazepine receptor ligands: synthesis, biological evaluation and 3D-QSAR investigation.

The present paper reports the synthesis and binding studies of new 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as selective Peripheral Benzodiazepine Receptor (PBR) ligands. The variability of substituents at the 3-position was investigated and a 3D-QSAR model was proposed to evaluate the effect of different substitutions on the acetamide moiety. In addition, a subset of the novel compounds showing high affinity for PBR was tested for their ability to modulate the steroid biosynthesis in C6 glioma cells.

Acetamides↗

PubMed1978

A theoretical study of Na+ and Mg+2 binding to the carbonyl oxygen of N-methyl acetamide.

Molecular orbital calculations (CNDO/2) are reported for the interaction of Na+ and Mg+2 with the carbonyl of a model peptide moiety (N-methyl acetamide) as a function of the C--O ... Me distance and angle and with variation in the number of ligands for the purpose of determining the steepness of the distance dependence of the binding energy and for the purpose of determining the reduction of charge on the ion with increasing numbers of ligands. The greater energy derived on divalent ion binding and the steeper distance dependence indicate that selective, divalent over monovalent, ion binding will occur whenever the liganding system can provide a coordination shell of appropriate dimension. The calculations indicate that the preferred C--O ... Me angle is not 180 degrees. Of particular note is the decrease of charge on the cation on binding to N-methyl acetamide. One ligand bound to Na+ reduces the charge from 1.0 to 0.7 electron units and four ligands bound to Mg+2 reduces the charge from 2.0 to 0.7 electron units. This is of primary significance in carrier and channel mechanisms for cation permeation of lipid membranes; and although the numerical values are qualitative, the implication is for allowance of multiple occupancy of channels by monovalent cations.

Acetamides↗

PubMed2001

Quinoline-4-acetamides as sPLA(2) inhibitors.

Quinoline-4-acetamides were designed as potential phospholipase A(2) inhibitors by structural based method and synthesized. The chemical structures of the obtained compounds were confirmed by elemental analyses, 1H NMR and MS. Preliminary bioassay study shows that quinoline-4-acetamides display certain inhibition to sPLA(2).

Acetamides↗

PubMed2004

Reactivity of a (mu-oxo)(mu-hydroxo)diiron(III) diamond core with water, urea, substituted ureas, and acetamide.

A series of iron(III) complexes of the tetradentate ligand BPMEN (N,N'-dimethyl-N,N'-bis(2-pyridylmethyl)ethane-1,2-diamine) were prepared and structurally characterized. Complex [Fe(2)(mu-O)(mu-OH)(BPMEN)(2)](ClO(4))(3) (1) contains a (mu-oxo)(mu-hydroxo)diiron(III) diamond core. Complex [Fe(BPMEN)(urea)(OEt)](ClO(4))(2) (2) is a rare example of a mononuclear non-heme iron(III) alkoxide complex. Complexes [Fe(2)(mu-O)(mu-OC(NH(2))NH)(BPMEN)(2)](ClO(4))(3) (3) and [Fe(2)(mu-O)(mu-OC(NHMe)NH)(BPMEN)(2)](ClO(4))(3) (4) feature N,O-bridging deprotonated urea ligands. The kinetics and equilibrium of the reactions of 1 with ligands L (L = water, urea, 1-methylurea, 1,1-dimethylurea, 1,3-dimethylurea, 1,1,3,3-tetramethylurea, and acetamide) in acetonitrile solutions were studied by stopped-flow UV-vis spectrophotometry, NMR, and mass spectrometry. All these ligands react with 1 in a rapid equilibrium, opening the four-membered Fe(III)(mu-O)(mu-OH)Fe(III) core and forming intermediates with a (HO)Fe(III)(mu-O)Fe(III)(L) core. The entropy and enthalpy for urea binding through oxygen are DeltaH degrees = -25 kJ mol(-1) and DeltaS degrees = -53.4 J mol(-1) K(-1) with an equilibrium constant of K(1) = 37 L mol(-1) at 25 degrees C. Addition of methyl groups on one of the urea nitrogen did not affect this reaction, but the addition of methyl groups on both nitrogens considerably decreased the value of K(1). An opening of the hydroxo bridge in the diamond core complex [Fe(2)(mu-O)(mu-OH)(BPMEN)(2)] is a rapid associative process, with activation enthalpy of about 60 kJ mol(-1) and activation entropies ranging from -25 to -43 J mol(-1) K(-1). For the incoming ligands with the -CONH(2) functionality (urea, 1-methylurea, 1,1-dimethylurea, and acetamide), a second, slow step occurs, leading to the formation of stable N,O-coordinated amidate diiron(III) species such as 3 and 4. The rate of this ring-closure reaction is controlled by the steric bulk of the incoming ligand and by the acidity of the amide group.

Acetamides↗

PubMed2006

[2-11C]isopropyl-, [1-11C]ethyl-, and [11C]methyl-labeled phenoxyphenyl acetamide derivatives as positron emission tomography ligands for the peripheral benzodiazepine receptor: radiosynthesis, uptake, and in vivo binding in brain.

The peripheral benzodiazepine receptor (PBR) is widely expressed in peripheral tissues, blood cells, and in glia cells in the brain. We have previously developed two positron emission tomography (PET) ligands, N-(2-[(11)C],5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([(11)C]2) and its [(18)F]fluoroethyl analogue ([(18)F]6), for the current investigation of PBR in the human brain. The aim of this study was to label the potent PBR agonist N-(4-chloro-2-phenoxyphenyl)-N-(isopropoxybenzyl)acetamide (3) and its ethyl (7) and methyl (8) homologues with (11)C and to evaluate them as PET ligands for PBR with mice, rats, and monkeys. Ligands [(11)C]3, [(11)C]7, and [(11)C]8 were synthesized by alkylation of phenol precursor 9 with 2-[2-(11)C]iodopropane ([(11)C]10), [1-(11)C]iodoethane ([(11)C]11), and [(11)C]iodomethane ([(11)C]12), respectively. The alkylating agent [(11)C]10 or [(11)C]11 was prepared by reacting CH(3)MgBr with [(11)C]CO(2), followed by reduction with LiAlH(4) and iodination with HI. In vitro quantitative autoradiography determined that 3, 7, and 8 had potent binding affinities (K(i) = 0.07-0.19 nM) for PBR in the rat brain. These [(11)C]ligands could pass across the blood-brain barrier and enter the rat brain (0.17-0.32% of injected dose per gram wet tissue). Ex vivo autoradiography showed that the [(11)C]ligands preferably distributed in the olfactory bulb and cerebellum, two regions with richer PBR density in the rat brain. The co-injection of PBR-selective 2 reduced the [(11)C]ligand binding in the two regions, suggesting that binding in the rat brain was specific to PBR. PET study determined that the [(11)C]ligands preferably accumulate in the occipital cortex of the monkey brain, a region with a high density of PBR in the primate brain. Moreover, in vivo binding of the methyl homologue [(11)C]8 in the monkey brain could be inhibited by PBR-selective 2 or 1, indicating that some of the [(11)C]8 binding was due to PBR. Metabolite analysis demonstrated that these [(11)C]ligands were metabolized by debenzylation to polar products mainly in the plasma.

Acetamides↗

PubMed2006

Conformation of N(alpha)-substituted hydrazino acetamides in CDCl3, the precious help of the analysis of Deltadelta between amidic hydrogens, and correlation to the conformation of aza-beta3-peptides.

[structures: see text] We studied the conformation of a series of primary amides in a solution of chloroform. Classical NMR tools such as dilution experiments, influence of DMSO, and 2D-NOESY, together with X-ray diffraction, were combined with an analysis of the difference of the chemical shift Deltadelta between the geminal amidic protons. This study was addressed in order to understand the conformation adopted by hydrazino acetamides 1a and 1b as model compounds for aza-beta3-peptides. In this manner, it was possible to show that the amidic group of these compounds acts as a H-bond donor and interacts with two different H-bond acceptors. We concluded that the hydrazinoturn, a specific bifurcated H-bond system observed in the solid state, is also the preferred conformation of hydrazino acetamides 1a and 1b in solution. Our results show that the short-range interaction with the N(alpha)-nitrogen lone pair not only stabilizes the C8 pseudocycle but could also contribute to the folding process of aza-beta3-peptides. In light of this, it could explain why aza-beta3-peptides develop a different H-bond network in comparison to their isosteric beta3-peptides analogues. Our work is in keeping with the recent interest of hydrazino peptides as an extension of the beta-peptide concept.

Acetamides↗

PubMed1995

Synthesis and characterization of adducts of alachlor and 2-chloro-N-(2,6-diethylphenyl)acetamide with 2'-deoxyguanosine, thymidine, and their 3'-monophosphates.

Adducts of the preemergence herbicide 2-chloro-N-(methoxymethyl)-N-(2,6-diethylphenyl)-acetamide (alachlor) and 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) with 2'-deoxyguanosine, thymidine, 2'-deoxyguanosine 3'-monophosphate, and thymidine 3'-monophosphate have been synthesized and characterized. Under mildly basic conditions alachlor and CDEPA form N-1 adducts with 2'-deoxyguanosine and N-3 adducts with thymidine as a result of chlorine displacement. In addition, alachlor formed an N-7 adduct with 2'-deoxyguanosine, 7-[[(N-(methoxymethyl)-N-(2,6-diethylphenyl)carbamoyl]methyl]guani ne. N-1 adducts of alachlor and CDEPA with 2'-deoxyguanosine 3'-monophosphate and N-3 adducts with thymidine 3'-monophosphate are also described. In addition to spectroscopic data, structural proof included the dephosphorylation of each nucleotide adduct to its corresponding nucleoside adduct by nuclease P1. Alachlor and alachlor adducts but not CDEPA and CDEPA adducts exhibited rotational isomerism as evidenced by proton and 13C NMR studies. These rotamers were attributed to hindered rotation about the shortened N-carbonyl bond. Computational methods employing molecular mechanics and quantum mechanics were used to characterize the structures and energies of these rotamers to account for the patterns of duplicate NMR resonances observed.

Acetamides↗

PubMed2005

2-acetamido-N-benzyl-2-(methoxyamino)acetamides: functionalized amino acid anticonvulsants.

In the crystal structure of 2-acetamido-N-benzyl-2-(methoxyamino)acetamide (3L), C12H17N3O3, the 2-acetylaminoacetamide moiety has a linearly extended conformation, with an interplanar angle between the two amide groups of 157.3 (1) degrees . In 2-acetamido-N-benzyl-2-[methoxy(methyl)amino]acetamide (3N), C13H19N3O3, the planes of the two amide groups intersect at an angle of 126.4 (4) degrees , resulting in a chain that is slightly more bent. The replacement of the methoxyamino H atom of 3L with a methyl group to form 3N and concomitant loss of hydrogen bonding results in some positional/thermal disorder in the methoxy(methyl)amino group. In both structures, in addition to classical N-H...O hydrogen bonds, there are also weak non-standard C-H...O hydrogen bonds. The hydrogen bonds and packing interactions result in planar hydrophilic and hydrophobic areas perpendicular to the c axis in 3L and parallel to the ab plane in the N-methyl derivative. Stereochemical comparisons with phenytoin have identified two O atoms and a phenyl group as molecular features likely to be responsible for the anticonvulsant activities of these compounds.

Acetamides↗

PubMed1984

Muscarinic receptor occupation and receptor activation in the guinea-pig ileum by some acetamides related to oxotremorine.

The dissociation constants (KD values) and relative efficacies of seven acetamide analogues of oxotremorine, including two enantiomeric pairs, at muscarinic receptors in the guinea-pig isolated ileum were determined. The method used involved analysis of dose-response data before and after fractional inactivation of receptors with propylbenzilylcholine mustard. All of the compounds studied had lower affinities than oxotremorine, but some had substantially higher relative efficacies. Replacement of the pyrrolidine ring of N-methyl-N-(4- pyrrolidino -2- butynyl )acetamide(I), the parent compound in the series, by a dimethylamino or a trimethylammonium group decreased the affinity 32 and 4.5 fold, respectively, whereas the relative efficacy increased 5.7-8.3 times. There was no correlation between relative efficacies and affinities of the compounds. The structural requirements for high affinity and high efficacy appeared to be quite different.

Acetamides↗

PubMed1964

METHYLUREA AND ACETAMIDE: ACTIVE REABSORPTION BY ELASMOBRANCH RENAL TUBULES.

The renal tubules of the shark actively reabsorb urea. They also can reabsorb acetamide and methylurea, but there is no evidence for active reabsorption of thiourea. The specificity of the transport system thus appears to be different from the urea secretory system in the frog in which thiourea is secreted but acetamide and methylurea are not secreted.

Acetamides↗

PubMed1980

Jack bean urease (EC 3.5.1.5). V. On the mechanism of action of urease on urea, formamide, acetamide, N-methylurea, and related compounds.

Acetamide and N-methylurea have been shown for the first time to be substrates for jack bean urease. In the enzymatic hydrolysis of urea, formamide, acetamide, and N-methylurea at pH 7.0 and 38 degrees C, kcat has the values 5870, 85, 0.55, and 0.075 s-1, respectively. The urease-catalyzed hydrolysis of all these substrates involves the active-site nickel ion(s). Enzymatic hydrolysis of the following compounds could not be detected: phenyl formate, p-nitroformanilide, trifluoroacetamide, p-nitrophenyl carbamate, thiourea, and O-methylisouronium ion. In the enzymatic hydrolysis of urea, the pH dependence of kcat between pH 3.4 and 7.8 indicates that at least two prototropic forms are active. Enzymatic hydrolysis of urea in the presence of methanol gave no detectable methyl carbamate. A mechanism of action for urease is proposed which involves initially an O-bonded complex between urea and an active-site Ni2+ ion and subsequently an O-bonded carbamato-enzyme intermediate.

Acetamides↗

PubMed2004

Electron-rich radicals by neutralizationreionization mass spectrometry. Generation, dissociations and energetics of the hydrogen atom adduct to acetamide.

Protonated acetamide exists as two planar conformers, the more stable anti-form (anti-1(+)) and the syn-form (syn-1(+)), DeltaG(degree) (298) (anti-->syn) = 10.8 kJ mol(-1). Collisional neutralization of 1(+) produces 1-hydroxy-1-amino-1-ethyl radicals (anti-1 and syn-1) which in part survive for 3.7 micros. The major dissociation of 1 is loss of the hydroxyl hydrogen atom (approximately 95%) which is accompanied by loss of one of the methyl hydrogen atoms (approximately 3%) and loss of the methyl group (approximately 2%). The most favorable dissociation of the OH bond is calculated to be only 34 kJ mol(1) endothermic but requires 88 kJ mol(-1) in the transition state. Other dissociations of 1, e.g., loss of one of the amide hydrogens, methyl hydrogens, and loss of ammonia are calculated to proceed through higher- energy transition states and are not kinetically competitive if proceeding from the ground doublet electronic state of 1. The unimolecular dissociation of 1 following collisional electron transfer is promoted by large Franck-Condon effects that result in 8090 kJ mol(-1) vibrational excitation in the radicals. Radicals 1 are calculated to exoergically abstract hydrogen atoms from acetamide in water, but not in the gas phase. The different reactivity is due to solvent effects that favor the products, (.)CH(2)CONH(2) and CH(3)CH(OH)NH(2), over the reactants.

Acetamides↗

PubMedDate not supplied

Accessory sperm as an indication of fertilizing ability of rabbit spermatozoa frozen in egg yolk-acetamide with detergent.

Many factors besides initial semen quality affect fertilization rates as sperm interact with the environment of the female reproductive tract. One of these factors is sperm transport, which can be evaluated by accessory sperm counts. Dutch rabbits were used to test the effects on sperm transport, fertilization, and production of young when sodium and triethanolamine lauryl sulfate (STLS) detergent was added to a medium for sperm cryopreservation. When STLS was added in 10 concentrations ranging from 0% to 2.0% (vol/vol) to an egg yolk-acetamide semen extender, optimal post-thaw motility of rabbit sperm occurred when 0.2% to 0.7% STLS was included. However, when 0%, 0.2%, and 0.7% STLS was included to cryopreserve sperm used for insemination, the fertilization rates were 95%, 68%, and 75%, and the corresponding mean numbers of accessory sperm per embryo were 13.1, 1.7, and 0.4 (P < .05). In another experiment, increasing the acetamide concentration from 0.75 M to 1.25 M decreased fertilization rates from 66% to 35%, and was associated with 4.5 and 0.6 accessory sperm per embryo (P < .05). In the final experiment, 48 does inseminated with sperm cryopreserved with 0%, 0.35%, and 0.70% STLS were allowed to produce young. Corresponding pregnancy rates were 56%, 56%, and 31% (P < .05), and litter sizes were 5.6, 4.1, and 4.2 (P > .05). In these studies, low concentrations of STLS improved motility of frozen-thawed sperm, but fertilization and pregnancy rates were reduced. Sperm transport was correspondingly reduced, and the accessory sperm count provided a reliable measure of the effect of STLS on fertility in contrast to the assessment of the percentage of motile sperm.

Acetamides↗

PubMed1980

[Studies on acetamides and formamides for embryotoxic and teratogenic activities in the rabbit (author's transl)].

The acid amides acetamide, monomethylacetamide, dimethylacetamide, formamide, monoethylformamide and dimethylformamide were investigated for prenatal and teratogenic effects in rabbits. The compounds were administered by stomach tube to the animals as aqueous solutions from the 6th to the 18th day post insemination. In rabbits monomethylformamide caused the most serious teratogenic effect. A teratogenic effect was also caused by monomethylacetamide. Formamide showed an embryotoxic and weak teratogenic effect when it was given in a non-toxic maternal dosage whereas acetamide and dimethylacetamide had an embryolthal effect only in toxic maternal dosages. The rabbit seems to be more sensitive to dimethylformamide than are other animal species because foetuses with anomalies were already seen when the substance was given in non-toxic dosages.

Acetamides↗

PubMed1976

Changes in hepatic nuclei induced by acetamide and thioacetamide.

Rat liver nuclei were examined following intoxication with thioacetamide or acetamide. A prompt increase in nuclear size occurred with the administration of either agent. The acetamide-related change was evanescent and, by 16 hours, the nuclei did not differ from controls. Thioacetamide produced an acute enlargement during the first eight hours and a second, more prolonged increase during the next 24 hours. The enlargement noted by microscopy was also detectable in isolated nuclei by flow spectrometry. Chemical determinations on isolated nuclei appear to sample the same size population seen in situ. An increase in RNA content of thioacetamide-treated nuclei occurred during the late phase. The temporal sequence of physical and chemical change suggests that the initial increase in nuclear volume is not the result of retained macromolecular formation but may involve intracellular water and electrolyte shifts.

Acetamides↗

PubMed1976

Increased incidence of carcinoma of the breast in Buffalo strain rats with one kidney ingesting N-4-(4'-fluorobiphenyl)acetamide.

The role of the kidney in carcinogenesis of the breast was studied in inbred Buffalo strain female rats ingesting 0.04% N-4-(4'-fluorobiphenyl)acetamide. The experimental groups consisted of intact female rats 5 weeks of age with both kidneys intact and female rats with a uninephrectomy. The incidence of carcinomas of the breast and the number of rats with multiple carcinomas, poorly and undifferentiated carcinomas was greater in rats with a uninephrectomy. N-4-(4'-fluorobiphenyl)acetamide and its active metabolites apparently were not excreted as rapidly in the rats with one kidney as in the animals with both kidneys intact. The metabolites were then returned to the breast and/or other organs.

Aminobiphenyl Compounds↗

PubMed2004

Partial purification of an enzyme hydrolyzing indole-3-acetamide from rice cells.

The activity of indole-3-acetamide (IAM) hydrolase from rice cells was enriched ca. 628-fold by gel filtration and anion exchange column chromatography. The molecular masses of the IAM hydrolase estimated by gel filtration and sodium dodecyl sulfate polyacrylamide gel electrophoresis were approximately 50.5 kD and 50.0 kD, respectively. The enzyme exhibited maximum activity at pH 6.0-6.5. The enzyme was stable against heat treatments between 4 and 50 degrees C and works optimally at 52 degrees C. The activity remained constant at 4 degrees C for at least 143 days. The purified enzyme fraction hydrolyzed indoleacetic acid ethyl ester (Et-IAA) in addition to IAM and its homologue, 1-naphthalene-acetamide, but not indole-3-acetonitrile. Km values of the enzyme were 0.96 mM and 0.55 mM for IAM and Et-IAA, respectively. Although the molecular mass of the enzyme was very similar to that of IAM hydrolase of Agrobacterium tumefaciens involved in tumor formation, the biochemical properties of the enzyme including its high Km value were considerably different from those of the A. tumefaciens enzyme. Based on these enzyme properties, we will discuss whether the amidohydrolase is involved in auxin biosynthesis in rice cells.

Amidohydrolases↗