Amides and hydrazides of oxalic acid XVI. Basic amides of alkoxyoxanilic acids

Conclusions Some basic amides of alkoxyoxanilic acids, their salts and their quaternary halide salts have been synthesized; and their properties and biological activity have been studied.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 12, pp, 7–12, December, 1967.     

Exercise-induced changes in branched chain amino acid/aromatic amino acid ratio in the rat brain and plasma

Central fatigue was induced by running rats on a treadmill. Amino acid and ammonia metabolism in the brain and blood were followed with time to correlate its changes with physical exhaustion. The blood ammonia level did not change during running, but was prominently increased at exhaustion. The brain level of ammonia was also prominently high at the end of exercise with a time course of change similar to that of the blood level. Plasma concentrations of branched chain amino acids (BCAA) and aromatic amino acids (AAA) increased as the animals continued to run; however, the plasma BCAA/AAA ratio was definitely depressed at exhaustion. This was also true with the brain BCAA/AAA ratio. A positive correlation was demonstrated between the plasma and brain BCAA/AAA ratios at r=0.5040 and P less than 0.05. These exercise-related changes suggest that physical exercise-induced central fatigue involves not only an increase in brain ammonia, but also a disturbance in brain amine metabolism accompanying plasma and brain BCAA/AAA ratio depression. Furthermore, the ammonia level and BCAA/AAA ratio in the brain correlated with those in the blood. It is reasonable to consider that the blood ammonia concentration and plasma BCAA/AAA ratio may serve as important indices of the clinical condition of exercise-induced central fatigue.     

Effects of dipropylacetic acid on late components of the photically evoked potential and afterdischarge in rat.

The effects of dipropylacetic acid (DPA) on primary, secondary and afterdischarge waves of the photically evoked potential were examined. It was observed that DPA selectively attenuated late wave components and afterdischarge. A thalamic locus of action for these effects is postulated.     

Acetals of acid amides and lactams. 81. Synthesis and some properties of nitriles of the pyrrole and indole series

Communication 80 [1]     

Prostaglandin isosteres. 1. (8-Aza-, 8,10-diaza-, and 8-aza-11-thia)-9-oxoprostanoic acids and their derivatives.

A series of novel (8-aza-, 8,10-diaza-, and 8-aza-11-thia)-9-oxoprostanoic acids has been synthesized and evaluated for their ability to mimic the E series prostaglandins in stimulating cAMP formation in the mouse ovary and in binding to the rat kidney plasma prostaglandin receptor. 7-[2-(3-Hydroxyoctyl)-1,1,4-trioxo-3-thiazolidinyl]heptanoic acid markedly stimulates cAMP formation at reasonable pharmacological concentrations and avidly binds to the rat kidney prostaglandin receptor.     

Pyrimidin-8-on[2,1-f]theophylline-9-alkylcarboxylic acids amides as A1 and A2A adenosine receptor ligands

Starting from the appropriate esters (1-3), pyrimidin-8-on[2,1-f]theophylline-9-alkylcarboxylic acids amides (4-10) were synthesized and evaluated as hydrochlorides (4a-10a) for their affinity at brain A(1) and A(2A) adenosine receptor subtypes. Radioligand binding assay showed that morpholine-ethyl(-propyl) amide of pyrimidin-8-on[2,1-f]theophylline-9-acetic acid (4a, 5a) exhibited greater affinity and selectivity for A(1) and A(2A) receptors than parent compounds (theophylline and caffeine), with K(i) values: 12.2 and 3.1 microM for A(1) and 1.11 and 5.89 microM for A(2A), respectively. Morpholine-ethyl amide of pyrimidin-8-on[2,1-f]theophylline-9-propanoic acid (6a) and the dimethyl-amino analog (10a) exhibited much lower affinity for A(1) and A(2A) adenosine receptors, with K(i) values, respectively: 53.9 and 72.6 microM for A(1) and 120 and 115 microM for A(2A). Morpholine-propyl amide of pyrimidin-8-on[2,1-f]theophylline-9-propanoic acid (7a) exhibited relatively higher affinity for A(1) adenosine receptor with K(i) value 32.8 microM, comparable to caffeine, but it showed weaker affinity to A(2A) receptor. The variation of affinity at A(1) and A(2A) adenosine receptors depends on the structure of substituent in N9-position of fused tricyclic theophylline derivatives. The most interesting were morpholino-ethyl(-propyl) amides of pyrimidin-8-on[2,1-f]theophylline-9-acetic acid (4a, 5a). The longer alkylene chain (propylene) between amide nitrogen and the basic center (5a) resulted in higher A(1) but lower A(2A) receptor affinity.     

Search for antialcoholic agents in the series of amides of substituted pyrazole-4-carboxylic and pyrazole-4-acetic acids

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 23, No. 8, pp. 966–971, August, 1989.     

Developmental toxicity assessment of C8 iso acid in CD rats: relevance to embryotoxic aliphatic carboxylic acids.

Cekanoic C8 acid (CAS RN 25103-52-0) is a complex isomeric substance containing several aliphatic carboxylic acids, primarily dimethyl hexanoic acid. Because Cekanoic C8 acid is a structural isomer of octanoic acid, its potential for developmental toxicity was investigated in CD (Sprague-Dawley) rats. Cekanoic C8 acid was administered by oral gavage to 25 confirmed-mated females at doses of 0, 200, 400, and 800 mg/kg/day on gestation days (GD) 6-15, based on a range-finding experiment. Maternal body weights, food consumption, and clinical observations were recorded throughout gestation. On GD 21, cesarean sections were performed and the uterine contents removed and subjected to conventional teratological evaluation. At 800 mg/kg/day, maternal body weight gain and food consumption were reduced during the exposure period, and clinical signs were evident. There were no significant differences in fetal weight, malformation incidence, or fetal viability in any of the experimental groups. There was a statistically significant increase in the incidence of total variations in the 800-mg/kg/day group, which was within the historical control range of this laboratory and not considered biologically significant. These results indicate that, unlike related compounds, Cekanoic C8 acid was not teratogenic or a selective developmental toxicant in rats. This is the first report of a dimethyl substituted aliphatic acid being evaluated for developmental toxicity in a definitive study. The results are consistent with a structure-teratogenicity relationship for aliphatic acids, indicating that side-chain branching larger than a methyl group is required to elicit teratogenic effects. This study established a maternal no-observable-adverse-effect level (NOAEL) for Cekanoic C8 acid at 400 mg/kg/day and a developmental NOAEL at 800 mg/kg/day.     

Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19.

Hybridomas were isolated that produce 13 monoclonal antibodies (mAbs) that are specific and highly inhibitory to members of the human P450 2C subfamily, 2C8, 2C9, 2C9*2, and 2C19. Many of the mAbs to P450 2C8, 2C9, and 2C19 are specific and exhibit potent inhibitory activity (85-95%). mAb 281-1-1 specifically binds, immunoblots, and strongly inhibits the activity of P450 2C8. mAb 763-15-5 specifically binds and strongly inhibits the activity of P450 2C9. mAb 1-7-4-8 specifically binds and strongly inhibits the activity of P450 2C19. The other mAbs bind and inhibit sets and subsets of the P450 2C family. The single and the combinatorial use of the mAbs can "reaction phenotype", i.e., determine the metabolic contribution and interindividual variation of a P450 isoform for the metabolism of a drug or nondrug xenobiotic in human liver microsomes. The utility of the mAb-based analytic system was examined with the model substrates Taxol (paclitaxel), diazepam, tolbutamide, diclofenac, mephenytoin, and imipramine. The mAb system can identify drugs metabolized by a common P450 or several P450s and polymorphic P450s. The mAb system identifies drugs or drug metabolic pathways that are catalyzed by a single P450 and thus may be used for in vivo phenotyping. The mAb system can identify whether a particular drug is metabolized by a single P450 that may exhibit polymorphic expression in humans. The mAb system offers large potential for studies of cytochrome P450 function useful in drug discovery and reduces the possibility of adverse drug reactions due to polymorphisms and drug interactions.