Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.
- MeSH
- aminochinoliny chemie farmakokinetika farmakologie MeSH
- Caco-2 buňky MeSH
- fenylethery chemie farmakokinetika farmakologie MeSH
- inhibitory enzymů chemie farmakokinetika farmakologie MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- molekulární modely MeSH
- synthasa oxidu dusnatého, typ I antagonisté a inhibitory metabolismus MeSH
- synthasa oxidu dusnatého, typ II antagonisté a inhibitory metabolismus MeSH
- synthasa oxidu dusnatého, typ III antagonisté a inhibitory metabolismus MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The reduction of nitroaromatic compound bifenox (methyl 5-(2,4-dichlorophenoxy)-2-nitrobenzoate) was studied in aprotic solvents in the absence or presence of cyclodextrin (CD) molecules of different cavity sizes. ßCD and ?CD form complexes with bifenox in DMSO with the complex formation constants (5 ± 2) × 102 M–1 [ßCD–bifenox] and (3 ± 1) × 102 M–1 [?CD–bifenox], respectively. Bifenox yields a relatively stable anion radical in dimethyl sulfoxide, which is further reduced at more negative potentials by an overall addition of three electrons and four protons to the corresponding phenylhydroxylamine. In the presence of ßCD the first reduction wave of bifenox becomes irreversible, it is shifted towards more positive potentials and the uptake of more than one electron is observed (up to four electrons during the exhaustive electrolysis). The first reduction wave of bifenox is not affected by the addition of glucose confirming that a simple availability of protons from the OH groups is not the main factor in further transformation of anion radical in the presence of ßCD. The complex formation with ßCD facilitates the protonation and additionally protects the molecule from disintegration into 2,4-dichlorophenol. A yield of 2,4-dichlorophenol decreases in the order ßCD, ?CD and ?CD, respectively.
Porucha pozornosti s hyperaktivitou (Attention Deficit Hyperactivity Disorder – ADHD) je psychiatrickou poruchou, která se vyskytuje u geneticky predisponovaných jedinců. Manifestuje se v dětství a je dobře popsána u dětí a adolescentů. ADHD postihuje v průměru 4–12 % dětí školního věku. Je provázena hyperaktivitou, impulsivitou a nesoustředivostí.
- MeSH
- atomoxetin MeSH
- dítě MeSH
- dospělí MeSH
- fenylethery farmakokinetika farmakologie MeSH
- hyperkinetická porucha farmakoterapie MeSH
- lidé MeSH
- mladiství MeSH
- noradrenalin antagonisté a inhibitory MeSH
- propylaminy farmakokinetika farmakologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- klinické zkoušky kontrolované MeSH
