ABSTRACT
A series of 5-amino-5,6,7,8-tetrahydroquinolinones was designed and synthesized as acetylcholinesterase inhibitors. The compounds are related to hyperzine A, a naturally occurring cholinesterase inhibitor. They inhibit acetylcholinesterase in vitro, and many are active in vivo in reversing a scopolamine-induced impairment of 24 h memory in a passive avoidance paradigm. Although these compounds were designed as partial structures of huperzine A, it is unlikely that they bind to the enzyme in a similar fashion, since they lack the unsaturated three-carbon bridge of huperzine A and both the quinolinone nitrogen and the amino group must be substituted in order to obtain good enzyme affinity.
Subject(s)
Alzheimer Disease/drug therapy , Aminoquinolines/pharmacology , Cholinesterase Inhibitors/pharmacology , Acetylcholinesterase/drug effects , Alkaloids , Aminoquinolines/chemistry , Animals , Cholinesterase Inhibitors/chemistry , Dementia/chemically induced , Dementia/drug therapy , Drug Evaluation , Male , Mice , Rats , Scopolamine/pharmacology , Sesquiterpenes/chemistry , Structure-Activity RelationshipABSTRACT
In a continuing program to discover antipsychotic agents with a reduced propensity toward extrapyramidal side-effects, a series of N-alkoxyimides and -amides was prepared. Evaluation of these compounds in vitro revealed affinities for D2, 5HT2 and 5HT1A receptors. Several members of the series displayed a profile indicative of potential antipsychotic activity in preclinical assays. The most potent compound in these assays, 7, also displayed possible effectiveness for the negative symptoms of schizophrenia. The synthesis of these compounds and details of their structure-activity relationships are described.
Subject(s)
Amides/pharmacology , Antipsychotic Agents/pharmacology , Imides/pharmacology , Phthalimides/pharmacology , Spiro Compounds/pharmacology , Amides/chemical synthesis , Amides/metabolism , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/metabolism , Apomorphine/pharmacology , Avoidance Learning/drug effects , Catalepsy/chemically induced , Chemical Phenomena , Chemistry , Drug Evaluation, Preclinical , Imides/chemical synthesis , Imides/metabolism , Male , Mice , Molecular Structure , Motor Activity/drug effects , Phthalimides/chemical synthesis , Phthalimides/metabolism , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Rats , Rats, Inbred Strains , Receptors, Adrenergic, alpha/metabolism , Receptors, Dopamine/metabolism , Receptors, Dopamine D2 , Receptors, Serotonin/metabolism , Self Stimulation , Social Behavior , Spiro Compounds/chemical synthesis , Spiro Compounds/metabolism , Stereotyped Behavior/drug effects , Thiazoles/chemistry , Thiazoles/metabolism , Thiazoles/pharmacologyABSTRACT
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.