Enantiomeri kinuklidin-3-ol derivata: Razdvajanje enantiomera i interakcija s ljudskim kolinesterazama

The (R)- and (S)-enantiomers of quinuclidin-3-ol and quinuclidin-3-yl acetate as well as their quaternary N-methyl and N-benzyl derivatives were synthesized in order to study the stereoselectivity of human erythrocyte acetylcholinesterase (EC 3.1.1.7) and plasma butyrylcholinesterase (EC 3.1.1.8). The compounds were tested as substrates and inhibitors of cholinesterases. Both cholinesterases hydrolyze the derivatives of quinuclidin-3-yl acetate with a preference for the (R)- over (S)-enantiomers. In contrast to the hydrolysis of the enantiomers of acetates, the inhibition of acetylcholinesterase and butyrylcholinesterase by the (R)- and (S)-enantiomers of quinuclidin-3-ol derivatives does not reveal enantiomeric preference of the enzymes. The (R)- and (S)-acetates also act as nonstereoselective inhibitors of the enzyme-induced hydrolysis of acetylthiocholine. The best substrate is (R)-N-methyl-3-acetoxyquinuclidinium iodide with kcat = 1.5 x 106 min–1 and kcat = 5.5 x 104 min–1 for acetylcholinesterase and butyrylcholinesterase, respectively. The (R)- and (S)-N-benzylquinuclidinium derivatives are the most potent inhibitors of both enzymes.Priređeni su (R)- i (S)-enantiomeri kinuklidin-3-ola i kinuklidin-3-il-acetata te odgovarajući kvaterni N-metilni i N-benzilni derivati kako bi se proučila njihova interakcija s ljudskom eritrocitnom acetilkolinesterazom (EC 3.1.1.7) i butirilkolinesterazom iz plazme (EC 3.1.1.8). Spojevi su studirani kao supstrati i inhibitori tih enzima. Obje kolinesteraze pokazuju visoku stereoselektivnost pri hidrolizi kinuklidin-3-il acetata preferirajući (R)- u odnosu na (S)-enantiomere. Nasuprot hidrolizi enantiomera acetatnih derivata, inhibicija acetilkolinesteraze i butirilkolinesteraze s (R)- i (S)-enantiomerima kinuklidin-3-ola i kinuklidin-3-il-acetata te njihovih N-metilnih i N-benzilnih derivata, ne pokazuje stereoselektivnost tih enzima. Kao najbolji supstrat za oba enzima pokazao se (R)-N-metilkinuklidinijev acetat, s kcat = 1,5 x 106 min–1 za acetilkolinesterazu, odnosno kcat = 5,5 x 104 min–1 za butirilkolinesterazu. (R)- i (S)-N-benzilkinuklidinijevi derivati bili su najjači inhibitori za te enzime