Syntheses of benzoquinolizidine and benzoindolizidine derivatives as anti-amnesic agents

Tacrine, one of the drugs available for Alzheimer's disease based on the ch olinergic approach, suffers from considerable toxicity. Many analogues of t acrine have been prepared which retain the pharmacologically rich aminopyri dine or aminoquinoline motifs. The current research was undertaken to produ ce an acetylcholinesterase inhibitor by employing 11-aminobenzoquinolizidin es (4) and 10-aminobenzoindolizidines (5) as templates. Thus, we aimed to a chieve three goals relative to tacrine: eliminate the pyridine and quinolin e moieties and render the molecule less flat. Overall, the compounds we pre pared were poorer inhibitors of acetylcholinesterase compared to tacrine. T he single exception was compound 6f which exhibited an effect comparable to that of tacrine, but only at a dose of the order of 10(-3) M. However, des pite the poor acetylcholinesterase inhibition by 6b, this compound proved t o be an effective anti-amnesic agent at 45 mg/kg dose. (C) 1999 Elsevier Sc ience Ltd. All rights reserved.