Syntheses of benzoquinolizidine and benzoindolizidine derivatives as anti-amnesic agents.
Tacrine, one of the drugs available for Alzheimer's disease based on the cholinergic approach, suffers from considerable toxicity. Many analogues of tacrine have been prepared which retain the pharmacologically rich aminopyridine or aminoquinoline motifs. The current research was undertaken to produce an acetylcholinesterase inhibitor by employing 11-aminobenzoquinolizidines (4) and 10-aminobenzoindolizidines (5) as templates. Thus, we aimed to achieve three goals relative to tacrine: eliminate the pyridine and quinoline moieties and render the molecule less flat. Overall, the compounds we prepared were poorer inhibitors of acetylcholinesterase compared to tacrine. The 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, despite the poor acetylcholinesterase inhibition by 6b, this compound proved to be an effective anti-amnesic agent at 45 mg/kg dose.
Zhao
S
S
Department of Chemistry and Biochemistry, University of Notre Dame, IN 46556, USA.
Totleben
M J
MJ
Freeman
J P
JP
Bacon
C L
CL
Fox
G B
GB
O'Driscoll
E
E
Foley
A G
AG
Kelly
J
J
Farrell
U
U
Regan
C
C
Mizsak
S A
SA
Szmuszkovicz
J
J
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D013329:Structure-Activity Relationship
D018697:Nootropic Agents; D011807:Quinolizines