Membrane-altering effects of velnacrine and N-methylacridinium: relevance to tacrine and Alzheimer's disease.
The interaction of pharmacological agents potentially useful in Alzheimer's disease, 9-amino-1,2,3,4-tetrahydroacridine (THA or tacrine) and its major metabolite velnacrine (or HP-029), along with related compounds with cytoskeletal proteins in human erythrocyte membrane was investigated using electron paramagnetic resonance spin labeling techniques. The results suggest that: (1) the position of the positive charge of tacrine may be important in the mechanism of its interaction with the membrane cytoskeleton; (2) like tacrine, velnacrine also strengthens cytoskeletal protein-protein interactions in erythrocyte membranes, but appears to be only about half as potent as tacrine. These results are discussed with relevance to therapeutic use of these agents in Alzheimer's disease.
Butterfield
D A
DA
Department of Chemistry, University of Kentucky, Lexington 40506-0055.
Rangachari
A
A
D000166:Acridines / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000166:Acridines; D003598:Cytoskeletal Proteins; C028189:N-methylacridine; D013619:Tacrine; C056424:velnacrine