Article date: 1989/8/1
PubMed ID: 2754707
Journal name: Journal of medicinal chemistry (ISSN: 0022-2623)
The synthesis of a series of 9-amino-1,2,3,4-tetrahydroacridin-1-ols is reported. These compounds are related to 1,2,3,4-tetrahydro-9-acridinamine (THA, tacrine). They inhibit acetylcholinesterase in vitro and are active in a model that may be predictive of activity in Alzheimer's disease–the scopolamine-induced impairment of 24-h memory of a passive dark-avoidance paradigm in mice. Two compounds, (+/-)-9-amino-1,2,3,4-tetrahydroacridin-1-ol maleate (1a, HP-029) and (+/-)-9-(benzylamino)-1,2,3,4-tetrahydroacridin-1-ol maleate (1p, HP-128), were also active in reversing the deficit in 72-h retention of a one-trial dark-avoidance task in rats, induced by ibotenic acid lesions in the nucleus basalis magnocellularis. In addition, compound 1 p showed potent in vitro inhibition of the uptake of radiolabeled noradrenaline and dopamine (IC50 = 0.070 and 0.30 microM, respectively). Compounds 1a and 1p, which showed less acute toxicity in both rats and mice than THA, are in phase II and phase I clinical trials, respectively, for Alzheimer's disease.
Author List: Shutske G M, Pierrat F A, Kapples K J, Cornfeldt M L, Szewczak M R, Huger F P, Bores G M, Haroutunian V, Davis K L
Publication Types: Journal Article
Substances mentioned in the article: Aminoacridines; Cholinesterase Inhibitors; Scopolamine Hydrobromide; Tacrine;
Mesh terms: Alzheimer Disease/drug therapy; Aminoacridines/chemical synthesis; Animals; Chemical Phenomena; Chemistry; Cholinesterase Inhibitors/chemical synthesis; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Male; Memory/drug effects; Mice; Rats; Rats, Inbred Strains; Scopolamine Hydrobromide/antagonists & inhibitors; Structure-Activity Relationship; Tacrine/analogs & derivatives;