1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Grand : Ohjelma = Program : 1.6. – 30.6.1938

Ravintolan viihdeohjelma

Folkförsörjningsministeriets beslut om prisförteckning för förplägningsrörelser gäller fr.o.m. den 1.6.1944

14 x 21 cm

Luettelo 1/6 1948 voimassa olleista, kansanhuoltoa koskevista säännöksistä, jotka on julkaistu asetuskokoelmassa

21 x 30 cm

Förteckning över den 1/6 1948 ikraftvarande och i författningssamlingen publicerade stadganden rörande folkförsörjningen

21 x 30 cm

Valoa kansalle Jes. 9:1-6

22 x 28 cm

Specimen tours in Finland 1/6 - 31/8 1930

kuv., 10 x 15 cm

Vorschläge für Sommerreisen in Finnland 1/6 - 31/8 1930

kuv., 11 x 15 cm

Seiberling hinnasto N:o 6 - 1.6.31

kuv., 10 x 14 cm

Huoltokirja ja varaosaluettelo : Volvo puuhiilikaasulaitteet, tyypit G-1 ja G-2

kuv., 15 x 22 cm

Seiberling Prislista N:o 6 - 1.6.31

kuv., 10 x 14 cm

Elevers läs- och skrivförmåga över tid : en longitudinell kohortstudie av läsförståelse och stavning i årskurs 1-6 i en finlandssvensk skola

Reports have shown that a growing number of students are leaving school without adequate reading and writing skills. At the same time, finnish children have improved in reading lit-eracy over the past decade. The school´s primary mission is to support student´s reading and writing development and follow it over time. Not only individual students´development has to be followd over time, as seen in this study, to be able to plan interventions. The purpose of this licentiate thesis is to study how the results in grades 1–6 exhibit in reading compre-hension and spelling over time in a school for the Swedish-speaking minority in Finland. Even gender differences in reading comprehension and spelling are being examined, as well as students with low performance. The data collection has been done during a period of twelwe years, 1997–2009, where data from practically every two years has been used for this study. Results are reported for the years 1997, 2000, 2001, 2003, 2007 and 2009. The measuring instruments are standardized and normative tests in reading comprehension and spelling. The same instruments were used all of the years. The number of students was 1 037 and when possible, students partici-pated more than once. There was a minimal loss of data. The groups of students mostly came from urban districts, and a smaller number came from rural districts. Students with special needs were included in the group, but none of the students in special units participat-ed. The results show that the skills in reading comprehension and spelling haven´t changed appreciably over time. The trend shows slightly positive or unchanged direction except in spelling in grade 1 and reading comprehension in grade 5 where the trend is slightly nega-tive. The most obvious change can be noticed over time in reading comprehension in grade 2, where performance has improved significantly. Significant differences between boys´and girls´performances occur some years and in favor of the girls, but more often in spelling than in reading comprehension. In grade 4, there are no differences in results between boys and girls in any year, neither in reading comprehension nor in spelling, nor in grade 2 in reading comprehension. When the results shows gender differences, there are always differ-ences in both reading comprehension and spelling. Poor performances are also analyzed over time. Isolated reading comprehension difficulties were common for those who was performing poorly. In grade 2, as the only grade, most common was a double deficit in both reading comprehension and spelling, and in grade 4, most students who performed poorly had isolated difficulties in spelling. The amount of poor results varies over time, and no particular trend can be discerned. In grade 2, however, the poor results decreased over time, especially for the boys. Even in reading comprehension for grade 6 the amount of poor results, especially for the boys (10th percentile), has decreased over time, at least in the later years, while the poor results in-creased in spelling generally. In grade 4 the amount of poor results in spelling (10th perc.) seems to be reduced for the girls.

Anthologium epigrammatum Graecorum 1:6

Painovuosi nimekkeestä. - S. [2] tyhjä.

Insecta Fennica enumerans 1:6

Painovuosi nimekkeestä.

Suomen taloudellinen kartta 1:100000: (kihlakunnankartta) = Finlands ekonomiska karta 1:100000 : (häradskarta) - Lehti = Blad 1:6, 2:6, Helsinki = Helsingfors

0-meridiaani : Helsinki.