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N K Allen

Publications and source records attributed to N K Allen.

At least 19 recordsLinked to original sources
PubMed1996

Structure-activity studies of 6-(tetrazolylalkyl)-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 1. Effects of stereochemistry, chain length, and chain substitution.

A series of 6-substituted decahydroisoquinoline-3-carboxylic acids were prepared as excitatory amino acid (EAA) receptor antagonists. These compounds are antagonists at the N-methyl-D-aspartate (NMDA) and 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl) propanoic acid (AMPA) subclasses of ligand gated ion channel (ionotropic) EAA receptors. (3S,4aR, 6R,8aR)-6-(2-(1H-tetrazol-5-yl)ethyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (9) is a potent, selective and systemically active AMPA antagonist. Other analogs from this series, including (3S,4aR,6S,8aR)-6-((1H-tetrazol-5-yl)methyl)- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (32) and (3S,4aR,6S,8aR)-6- (phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-ca rboxylic acid (61) are potent, selective, and systemically active NMDA antagonists. This and the subsequent publication look at the AMPA antagonist aspects of this SAR. Herein we report the effects of varying stereochemistry around the hydroisoquinoline ring; of tetrahydro-versus decahydroisoquinoline; of having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon chain connecting a tetrazole to the bicyclic nucleus; and of holding the connecting chain constant at two atoms, the effect of heteroatom substitution in the position adjacent to the bicyclic nucleus and substitution with methyl or phenyl on the chain. Compounds were evaluated on rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]-kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). Our findings revealed that the optimal stereochemical array was the same for both NMDA (32 and 61) and AMPA (9) antagonists identified in this series and that the tetrahydroisoquinoline (25) and the C-1 carboxy (30) analogs of 9 are inactive. With a tetrazole in the distal acid position, an ethylene spacer (9) is optimal; substitution with oxygen or nitrogen on the chain in the position adjacent to the bicyclic nucleus significantly reduced activity, while substitution with a methyl or phenyl group on the chain was well tolerated.

Animals↗
PubMed1996

Structure-activity studies of 6-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 2. Effects of distal acid bioisosteric substitution, absolute stereochemical preferences, and in vivo activity.

We have explored the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.

Animals↗
PubMed1995

(3SR,4aRS,6SR,8aRS)-6-(1H-tetrazol-5-yl)decahydroisoquinoline-3-carboxylic acid, a novel, competitive, systemically active NMDA and AMPA receptor antagonist.

We report the synthesis and characterization of 6 (LY246492), which is a competitive N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptor antagonist. Tetrazole-substituted amino acid 6 was prepared in four steps from the recently described aldehyde 7. The optical isomers (-)-6 and (+)-6 were obtained from the same sequence of reactions using the corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of responses mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.

Animals↗
PubMed1983

Effects of fusarium cultures, T-2 toxin, and zearalenone on reproduction of turkey females.

Nicholas Large White turkey hens in egg production (10 per treatment) were individually fed cultures of Fusarium roseum 'Gibbosum' to provide 100 ppm zearalenone, Fusarium tricinctum at a level of .1% of the diet, Fusarium roseum Alaska at a level of 2% of the diet, 100 ppm purified zearalenone, and 5 ppm purified T-2 toxin for 8 weeks. The following 4 weeks the birds were fed a control diet. Hens were inseminated every 2 weeks with .05 ml of pooled semen from males fed a control diet. After 30 days of toxin feeding, hens were innoculated with a killed Newcastle disease virus preparation. Blood samples were obtained periodically. Egg fertility and titers to Newcastle disease virus were unaffected by treatment. Egg weight was reduced by F. roseum 'Gibbosum'. F. roseum 'Gibbosum' and F. tricinctum caused decreases in feed consumption, body weight, and egg production. Egg production was decreased by zearalenone and T-2 toxin. Hens fed F. roseum 'Gibbosum', F. tricinctum, and T-2 toxin exhibited mouth lesions that healed rapidly upon withdrawing toxic feed. Hatchability of fertile eggs was reduced by feeding F. roseum 'Gibbosum', F. tricinctum and F. roseum Alaska to 28, 78, and 49%, respectively, of control values by the end of the 8 week test period. Upon removal of toxic feed, hatchability rapidly returned to control levels. Embryo mortality occurred mainly in the first 10 days of incubation for F. roseum Alaska and the last 18 days for F. roseum 'Gibbosum' and F. tricinctum fed hens. It appears that mycotoxins other than zearalenone and T-2 toxin are responsible for reduced hatchability from feeding Fusarium cultures.

Animals↗
PubMed1982

Fusarium-induced osteochondrosis (tibial dyschondroplasia) in chickens.

Broiler chickens were started and maintained on rations containing 2%, 5%, and 10% grain contaminated with Fusarium roseum. There was mortality of 75% and 100%, respectively, in chicks fed 5% and 10% levels, and osteochondrosis was present in chicks which died at 12 to 17 days of age. Chicks on 2% or 3% F. roseum-contaminated grain survived the experimental period and osteochondrosis was well-developed in the proximal tibias of 85 or 99% of these chicks. The number of chondroclasts was reduced markedly in the affected bones. Defective chondroclasis may play a role in the pathogenesis of osteochondrosis associated with F. roseum.

Animals↗
PubMed1982

The effect of a Fusarium roseum culture and diacetoxyscirpenol on reproduction of White Leghorn females.

White Leghorn females in egg production (36 weeks old) were fed a culture of Fusarium roseum containing 15 ppm diacetoxyscirpenol (DAS) and other unidentified toxins at culture levels of 0, 1, and 2% of the diet for 8 weeks. Following this, all hens were placed on control (0% toxins) feed for 6 weeks. Birds were inseminated weekly with .05 ml of pooled semen from males given normal diets. The F. roseum had no significant effect on body weight change or egg weights. During the initial 8 weeks, egg production was significantly depressed by both the 1 and 2% levels whereas feed consumption, fertility, and hatchability of fertile eggs was reduced only by the 2% level of F. roseum. Moreover, the majority of embryo mortality occurred prior to the 7th day of incubation. All production levels returned to normal when the toxins were removed during the final 6 weeks. In a second experiment, control (0%), .5 ppm purified DAS, and 3% F. roseum culture were fed to White Leghorn females (50 weeks old) for 4 weeks followed by a 2-week withdrawal period when all birds were given control diets. In 4 weeks, hatchability of fertile eggs was reduced 24% by DAS and 99% by the culture of F. roseum but returned to normal after the toxins were removed. Other production indices were unaffected by dietary treatment. The DAS appears to be only partially responsible for the reduced hatchability; the major toxicant has not been identified.

Animals↗
PubMed1981

Effects of dietary zearalenone on finishing broiler chickens and young turkey poults.

A total of 168 broiler chickens (6 to 9 weeks of age) and 192 turkey poults (3-1/2 to 6-1/2 weeks of age) were fed purified zearalenone at levels of 0 (control), 10, 25 (turkeys only), 50, 100, 200, 400, and 800 mg/kg diet for a 3 week period to evaluate its toxicity. Dietary zearalenone had no effect on body weight gain, feed consumption, weights of liver, heart, spleen, and bursa of Fabricius, serum calcium, phosphorus, alkaline phosphatase, total protein and cholesterol, hematocrit, hemoglobin, red blood cell count, white blood cell count, and differential leukocyte count in both chickens and turkeys. Male broiler comb and testes weights were reduced by high levels of zearalenone. Female comb weight, broiler oviduct weight, and turkey testes and ovaries were unaffected by zearalenone. Histopathological examination of tissues revealed no change due to zearalenone. Male turkeys fed 400 and 800 mg/kg zearalenone had increased development of dewlaps and caruncles and exhibited considerable strutting behavior. Muscle and fat tissue from broilers fed 800 mg/kg zearalenone had no detectable estrogenic activity as measured by mouse uterine bioassay. These studies indicate that the effects of dietary zearalenone on finishing broilers and young growing turkey poults are minimal.

Animals↗
PubMed1981

Toxic effects of repeated ethanol intubations to chicks.

Dosages of 95% ethanol (0, .5, or 1 ml) with variable quantities of water were administered to mixed sex chicks (263 g initial weight) on each of 7 consecutive days. The 1 ml dosage of ethanol significantly reduced body weight gains and feed consumption and increased liver weight per 100 g of body weight. Gross crop lesions (accumulation of exudates and hemorrhage) were observed for both the .5 and 1 ml dosage level of ethanol. For birds given the .5 ml ethanol dosage, dilution with water tended to reduce the severity of crop lesions but not for birds given 1 ml ethanol. All levels of ethanol produced mild ataxia within 5 to 10 min of dosage. Mild or moderate hepatocellular fatty change was present in livers from 5 to 6 birds given 1 ml ethanol. Crop exudates were composed of necrotic cells, fibrin and bacteria. Crop walls of birds given 1 ml of undiluted ethanol were ulcerated and inflamed. Areas within the crop wall were hemorrhagic, edematous, and infiltrated by heterophils and mononuclear cells.

Animals↗
PubMed1981

Effect of dietary zearalenone on reproduction of chickens.

Variable quantities of zearalenone (0, 10, 25, 50, 100, 200, 400, or 800 mg/kg diet) were incorporated into a practical laying hen diet and fed to 30-week-old White Leghorn females in egg production. During the 3 week pretest and 8 week experimental periods hens were inseminated weekly with .05 ml of pooled semen from males fed normal diets. Zearalenone was without effect on egg production, egg size, feed consumption, change in body weight, fertility, hatchability of fertile eggs, growth of progeny to 3 weeks of age, comb, weight, oviduct weight, heart weight, liver weight, spleen weight, egg shell thickness, Haugh units, blood hematology, serum calcium, serum inorganic phosphorus, and serum alkaline phosphatase. Zearalenone above 50 mg/kg of diet caused reduced serum cholesterol. In a reciprocal study, adult male New Hampshire chickens were fed diets containing 0, 100, or 800 mg/kg zearalenone for an 8 week period. Semen was collected and inseminated into White Leghorn females fed normal diets. Zearalenone was without effect on fertility or hatch of fertile eggs resulting from matings of these males. Zearalenone resulted in reduced serum inorganic phosphorus, serum cholesterol, and serum alkaline phosphatase in males. Histological examination of a number of tissues in both males and females revealed no changes due to zearalenone feeding. It is concluded that zearalenone up to 800 mg/kg of diet is without effect on reproductive performance of mature chickens.

Animal Feed↗
PubMed1981

Toxicity of dietary and intravenously administered moniliformin to broiler chickens.

Moniliformin (1-hydroxy-cyclobut-1-ene-3,4-dione), either purified (0, 8, and 16 mg/kg of diet) or from culture of Fusarium moniliforme strain NRRL 6322 on corn grits (8, 16, and 64 mg/kg of diet) was fed to growing broiler chicks from 1 to 21 days of age. Up to 16 mg moniliformin/kg of diet from either source was without effect on chick weight gain, feed consumption, and mortality. Chicks fed 64 mg moniliformin/kg of diet from culture had reduced weight gain and feed consumption. Total daily moniliformin consumption by these chicks was nearly twice the reported single oral 50% lethal dose. Three of 10 chicks fed 64 mg/kg of moniliformin in the diet died. No lesions were found upon necropsy. The LD50 of purified moniliformin upon intravenous injection of 7-week-old female broiler chickens was 1.38 +/- .035 mg/kg body weight. Average time to death was 65 minutes. Progressive symptoms noted included lack of muscular coordination, tachypnea from moderate to severe followed by slow labored respiration, coma, terminal agonal struggle, and death.

Animal Feed↗
PubMed1980

Studies on the amino acid and protein requirements of laying Japanese quail (Coturnix coturnix japonica).

Six experiments were conducted to define the amino acid and protein requirements of laying Japanese quail. In the initial experiments the diets contained 12% protein from a mixture of casein and soybean meal and were supplemented with essential amino acids and glutamic acid to promote optimum egg production. Later studies were conducted with corn-soybean meal diets. Results from varying the levels of essential amino acids led to the following estimates of amino acid requirements (as percent of the diet): arginine, 1.13; histidine, .38; isoleucine, .81; leucine, 1.28; lysine, .86; methionine plus cystine, .68; phenylalanine plus tyrosine, 1.25; threonine, .67; tryptophan, .17; and valine, .83. These amino acid requirements are correlated with the amino acid composition of quail eggs (r = .74). The total protein requirement of laying Japanese quail was found to be slightly greater than 16% of the diet when quail were fed diets based on either casein and soybean meal alone or casein and soybean meal supplemented with essential amino acids and glutamic acid. Based on the consumption of from 18 to 19 g of this diet per day the daily protein requirement was 2.88 to 3.08 g. Quail fed a methionine supplemented corn-soybean meal diet consumed up to 22 g of feed per day resulting in an estimated protein requirement of 3.52 g per day.

Amino Acids↗