Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes.
9-Amino-1,2,3,4-tetrahydroacridine (THA) has been reported to cause improvement in patients with senile dementia of the Alzheimer's type. We have examined some effects of THA in vitro and in vivo to define its mechanism of action. In vitro, THA inhibits acetylcholinesterase (AChE) (IC50 = 223 nM) and blocks [3H]AFDX-116 (M2) and [3H]telenzepine (M1) binding (IC50 s of 1.5 and 9.1 microM respectively). In vivo levels of THA were 10-fold higher in brain than plasma following 3.2 mg/kg i.p., a dose which was found to be active in reversing amnesia induced by scopolamine assessed in T-maze tests in rats and passive avoidance tests in mice. Additionally, these brain concentrations were above the IC50 of THA for AChE inhibition. THA (5.6-17.8 mg/kg i.p.) also elevated acetylcholine levels in the rat CNS. THA-induced side effects were blocked by the central muscarinic antagonist, scopolamine, but not by the peripheral antagonists methscopolamine and glycopyrrolate, nor by nicotinic antagonists. We conclude that brain AChE inhibition by THA is sufficient to explain its purported therapeutic activity in Alzheimer's disease and that its favorable brain/plasma distribution in vivo may account for its central cholinergic action without inducing the severe peripheral cholinergic effects typically seen with other AChE inhibitors.
Nielsen
J A
JA
Central Research Division, Pfizer Inc., Groton, CT 06430.
Mena
E E
EE
Williams
I H
IH
Nocerini
M R
MR
Liston
D
D
D000110:Acetylcholinesterase / Q000378:metabolism; D000609:Aminoacridines / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D002800:Cholinesterase Inhibitors; D002851:Chromatography, High Pressure Liquid; D004435:Eating / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D010146:Pain / Q000503:physiopathology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet; D013619:Tacrine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
D000609:Aminoacridines; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase