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Alzheimerjeva bolezen (AB) je večfunkcionalna nevrodegenerativna bolezen, kjer poleg upada holinergičnega prenosa pride tudi do motenj v delovanju noradrenergičnega sistema v možganih. Pri napredovani obliki AB se poveča aktivnost butirilholin esteraze (BChE), ki nadomesti acetilholin esterazo kot prevladujoča holin esteraza v holinergičnih sinapsah, večje aktivno mesto BChE pa omogoča racionalno načrtovanje selektivnih zaviralcev tega encima. Vezava oligomerov amiloida β na α2A adrenergične receptorje (α2AAR) aktivira kinazo GSK3β in vodi v hiperfosforilacijo proteina tau. Učinkovine, ki hkrati delujejo na oba nevrotransmitorska sistema, imajo večji potencial za učinkovitejše zdravljenje, ki bi lahko upočasnilo nevrodegenerativne procese v možganih. V magistrski nalogi smo načrtovali in sintetizirali 10 spojin, ki naj bi dosegle zaviranje človeške hBChE in delovale antagonistično na α2AAR. Izhodišče je predstavljal atipamezol (znan selektiven antagonist α2AR), na katerega smo z reakcijo N-aciliranja uvedli karbamatno skupino ključno za zaviranje holin esteraz. Zaviralno aktivnost zoper obe holin esterazi so izkazovali zgolj karbamati (7, 8, 11–13 in 16), ki so preko kovalentnega načina vezave zavirali hBChE. Vsi karbamati, razen spojine 11, so encim zavirali v nanomolarnih koncentracijah, izkazovali pa so tudi selektivnost napram acetilholin esterazi. Največji potencial za nadaljnjo optimizacijo ima spojina 16, ki selektivno zavira hBChE z IC50 vrednostjo 2,39 nM. Alzheimer's disease is a multifunctional neurodegenerative disease featuring a decline in cholinergic transmission, as well as dysfunction of the noradrenergic system activity in the brain. The disease is characterised by increased butyrylcholinesterase (BChE) activity, which becomes the predominant brain cholinesterase. Its enlarged active site allows the rational design of selective inhibitors. Oligomers of amyloid β bind to α2A adrenergic receptors (α2AAR), leading to GSK3β activation and tau hyperphosphorylation. Multifunctional compounds that act simultaneously on both neurotransmitter systems have a great potential for a more effective treatment that could even slow down the neurodegenerative processes in the brain. In the master's thesis, 10 compounds were designed and synthesized to achieve both human hBChE inhibition and α2AAR antagonism. The starting point was atipamezole (a known selective α2AR antagonist). Using N-acylation, we have introduced a carbamate group, which is crucial for the inhibition of cholinesterases, in its structure. Only the carbamates (7, 8, 11–13 and 16) covalently bound to and inhibited hBChE. All carbamates, except compound 11, inhibited the enzyme at nanomolar concentrations, and were more selective for hBChE over acetylcholinesterase. The compound with the highest potential for further optimisation is compound 16, which selectively inhibits hBChE with an IC50 value of 2.39 nM. |
