Bivalent 5,8,9,13b-tetrahydro-6H-isoquino[1,2-a]isoquinolines and -isoquinolinium salts: novel heterocyclic templates for butyrylcholinesterase inhibitors.
Three different types of homobivalent compounds, 5,8,9,13b-tetrahydro-6H-isoqino[1,2-a]isoquinolines bearing tertiary N-atoms, their quaternary ammonium salts and their dibenzazecine analogues, connected by alkylene spacers of various lengths were synthesized. Compared to the therapeutically used inhibitor galanthamine, some of the bivalent compounds showed much higher inhibitory activities at both cholinesterases in the Ellman test. Surprisingly, not only the quaternary salts, but also the uncharged tertiary compounds exhibited IC(50) values at butyrylcholinesterase in the nanomolar range. Selectivity toward BChE of up to 76-fold was observed.
Schulze
Maria
M
Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, D-07743 Jena, Germany.
Siol
Oliver
O
Decker
Michael
M
Lehmann
Jochen
J
D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*
D002800:Cholinesterase Inhibitors; D006571:Heterocyclic Compounds; D007546:Isoquinolines; D000644:Quaternary Ammonium Compounds; D002091:Butyrylcholinesterase