Synthesis, characterization and 11C radiolabeling of aminophenyl benzothiazoles:structural effects on the alkylation of amino group

Several aminophenyl benzothiazoles were prepared with a view to using them as amyloid binding agents for imaging β-amyloid in Alzheimer's disease. These precursors were radiolabeled with 11C-positron-emitting radioisotope using an automated synthesizer and selected radiolabeled compounds were further purified by HPLC. Our results demonstrate that changes in structure have a major influence on the radioactive yield and the ease with which the radiolabel can be introduced. Aminophenyl benzothiazoles with an attached isopropyl group resisted dialkylation perhaps due to steric hindrance caused by this group. Straight chain attachment of methyl, ethyl, butyl, and crotyl groups in the structure decreased the radiochemical yield. Notably, the o-aminophenyl benzothiazole derivatives were difficult to alkylate despite stringent experimental conditions. This reactivity difference is attributed to the hydrogen bonding characteristics of the o-amino group with the nitrogen atom of the thiazole ring

The declining representativeness of the British party system, and why it matters

In a recent article, Michael Laver has explained ‘Why Vote-Seeking Parties May Make Voters Miserable’. His model shows that, while ideological convergence may boost congruence between governments and the median voter, it can reduce congruence between the party system and the electorate as a whole. Specifically, convergence can increase the mean distance between voters and their nearest party. In this article we show that this captures the reality of today’s British party system. Policy scale placements in British Election Studies from 1987 to 2010 confirm that the pronounced convergence during the past decade has left the Conservatives and Labour closer together than would be optimal in terms of minimising the policy distance between the average voter and the nearest major party. We go on to demonstrate that this comes at a cost. Respondents who perceive themselves as further away from one of the major parties in the system tend to score lower on satisfaction with democracy. In short, vote-seeking parties have left the British party system less representative of the ideological diversity in the electorate, and thus made at least some British voters miserable

Effects of Proportions of Dietary Macronutrients on Glucocorticoid Metabolism in Diet-Induced Obesity in Rats

Tissue glucocorticoid levels in the liver and adipose tissue are regulated by regeneration of inactive glucocorticoid by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and inactivation by 5α- and 5β-reductases. A low carbohydrate diet increases hepatic 11β-HSD1 and reduces glucocorticoid metabolism during weight loss in obese humans. We hypothesized that similar variations in macronutrient proportions regulate glucocorticoid metabolism in obese rats. Male Lister Hooded rats were fed an obesity-inducing ad libitum ‘Western’ diet (37% fat, n = 36) for 22 weeks, then randomised to continue this diet (n = 12) or to switch to either a low carbohydrate (n = 12) or a moderate carbohydrate (n = 12) diet for the final 8 weeks. A parallel lean control group were fed an ad libitum control diet (10% fat, n = 12) throughout. The low and moderate carbohydrate diets decreased hepatic 11β-HSD1 mRNA compared with the Western diet (both 0.7±0.0 vs 0.9±0.1 AU; p<0.01), but did not alter 11β-HSD1 in adipose tissue. 5α-Reductase mRNA was increased on the low carbohydrate compared with the moderate carbohydrate diet. Compared with lean controls, the Western diet decreased 11β-HSD1 activity (1.6±0.1 vs 2.8±0.1 nmol/mcg protein/hr; p<0.001) and increased 5α-reductase and 5β-reductase mRNAs (1.9±0.3 vs 1.0±0.2 and 1.6±0.1 vs 1.0±0.1 AU respectively; p<0.01) in the liver, and reduced 11β-HSD1 mRNA and activity (both p<0.01) in adipose tissue. Although an obesity-inducing high fat diet in rats recapitulates the abnormal glucocorticoid metabolism associated with human obesity in liver (but not in adipose tissue), a low carbohydrate diet does not increase hepatic 11β-HSD1 in obese rats as occurs in humans

ABCC1 modulates negative feedback control of the hypothalamic-pituitary-adrenal axis in vivo in humans

BACKGROUND: Cortisol and corticosterone both circulate in human plasma and, due to differing export by ATP-binding cassette (ABC) transporters, may exert differential cellular effects. ABCB1 (expressed in brain) exports cortisol not corticosterone while ABCC1 (expressed in adipose and skeletal muscle) exports corticosterone not cortisol. We hypothesised that ABCC1 inhibition increases corticosteroid receptor occupancy by corticosterone but not cortisol in humans. METHODS: A randomised double-blind crossover study was conducted in 14 healthy men comparing placebo and ABCC1 inhibitor probenecid. Blood sampling, including from veins draining adipose and muscle, was undertaken before and after administration of mineralocorticoid receptor antagonist potassium canrenoate and glucocorticoid receptor antagonist mifepristone (RU486). RESULTS: During placebo, systemic plasma cortisol and corticosterone concentrations increased promptly after canrenoate. Cortisol uptake was detected from adipose but not muscle following canrenoate + RU486. Probenecid significantly increased systemic cortisol concentrations, and tended to increase corticosterone and ACTH concentrations, after combined receptor antagonism but had no effects on net glucocorticoid balance in either adipose or muscle. Using quantitative PCR in brain bank tissue, ABCC1 expression was 5-fold higher in human pituitary than hypothalamus and hippocampus. ABCB1 was more highly expressed in hypothalamus compared to pituitary. CONCLUSIONS: Although displacement of corticosterone and/or cortisol from receptors in adipose and skeletal muscle could not be measured with sufficient precision to detect effects of probenecid, ABCC1 inhibition induced a greater incremental activation of the hypothalamic-pituitary-adrenal axis after combined receptor blockade, consistent with ABCC1 exporting corticosterone from the pituitary and adding to the evidence that ABC transporters modulate tissue glucocorticoid sensitivity

Cortisol Release From Adipose Tissue by 11β-Hydroxysteroid Dehydrogenase Type 1 in Humans

OBJECTIVE—11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates cortisol from cortisone. 11β-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11β-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11β-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo