ABSTRACT
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.
Subject(s)
Alzheimer Disease/drug therapy , Aminoacridines/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Tacrine/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Cholinesterase Inhibitors/toxicity , Drug Evaluation , Drug Evaluation, Preclinical , Humans , Male , Memory/drug effects , Mice , Rats , Rats, Inbred Strains , Scopolamine/antagonists & inhibitors , Structure-Activity Relationship , Tacrine/analogs & derivatives , Tacrine/therapeutic use , Tacrine/toxicityABSTRACT
Nomifensine has demonstrated efficacy in several animal models that have been found to be predictive of clinical antidepressant activity, and has also been found to have a low potential for both cardiovascular and anticholinergic side effects. A comparison of nomifensine's profile with those of standard antidepressant agents shows this drug to possess clear advantages which may make it an attractive choice for the treatment of endogenous depression.