LÄHDE:
http://www.ncbi.nlm.nih.gov/pubmed/22331903
Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3540-5. doi: 10.1073/pnas.1119201109. Epub 2012 Feb 13. Shen J1, Ghai K, Sompol P, Liu X, Cao X, Iuvone PM, Ye K. N-acetyl serotonin derivatives as potent neuroprotectants for retinas.
Normelatoniini eli N-asetyyliserotoniini (NAS) syntetisoituu entsymaattisesti serotoniinista ja tätä entsyymiä esiintyy pääasiassa käpylisäkkeessä ja verkkokalvossa. Normelatoniini aktivoi TrkB kirkadisesti ( vuorokausirytmstä riippuvalla tavalla) ja ilmentää antidepressiivisiä vaikutuksia TrkB.stä riippuvalla tavalla. Se myös lisää hippokampissa neurogeneesiä koe-eläimen unideprivaatiossa.
Tutkijat tunnistavat sellaisia NAS johdannaisia, joilla on vielä vahvempia neuroprotektiivisia vaikutuksia
Normelatoniinia voimakkaampi TrkB-reseptorin aktivoija esitetään. Se suojaa retinaa valon indusoimalta degeneraatiolta. Aine on farmakokineettisesti stabiili seerumissa ja maksan mikrosomeissa. Se pääse veriaivoesteen läpi ja veri-retina-esteen läpi. Tutkijoitten mielestä tästä (HIOC) yhdisteestä voitaisiin johtaa lääkeainetta verkkokalvodegeneraatiotauteihin.
Abstract
N-acetylserotonin
(NAS) is synthesized from serotonin by arylalkylamine
N-acetyltransferase (AANAT), which is predominantly expressed in the
pineal gland and retina. NAS activates TrkB in a circadian manner and
exhibits antidepressant effects in a TrkB-dependent manner. It also
enhances neurogenesis in hippocampus in sleep-deprived mice.
Here we report the identification of NAS derivatives that possess much more robust neurotrophic effects with improved pharmacokinetic profiles. The compound N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) selectively activates TrkB receptor with greater potency than NAS. It potently protects retinas from light-induced retinal degeneration (LIRD), which is tightly coupled with pronounced TrkB activation in retinas. Pharmacokinetic studies demonstrate that this compound is stable in serum and liver microsomes. It can pass the blood-brain barrier and blood-retinal barrier. Hence, HIOC is a good lead compound for further drug development for treating retinal degenerative diseases.
Here we report the identification of NAS derivatives that possess much more robust neurotrophic effects with improved pharmacokinetic profiles. The compound N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-2-oxopiperidine-3-carboxamide (HIOC) selectively activates TrkB receptor with greater potency than NAS. It potently protects retinas from light-induced retinal degeneration (LIRD), which is tightly coupled with pronounced TrkB activation in retinas. Pharmacokinetic studies demonstrate that this compound is stable in serum and liver microsomes. It can pass the blood-brain barrier and blood-retinal barrier. Hence, HIOC is a good lead compound for further drug development for treating retinal degenerative diseases.
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