ABSTRACT
HP-236 (3-[4-[4-(6-Fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5- trimethyl-4-thiazolidinone maleate; P-9236) (54) displayed a pharmacological profile indicative of potential atypical antipsychotic activity. A series of piperazinyl butyl thiazolidinones structurally related to this compound were prepared and evaluated in vitro for dopamine D2 and serotonin 5HT2 and 5HT1A receptor affinity. The compounds were examined in vivo in animal models of potential antipsychotic activity and screened in models predictive of extrapyramidal side effect (EPS) liability. The synthesis of these compounds, details of their structure-activity relationships, and discovery of a new lead, compound 50, as well as further development of the profiles of compounds 50 and 54 are described.
Subject(s)
Antipsychotic Agents/chemical synthesis , Spiro Compounds/chemical synthesis , Thiazoles/chemical synthesis , Animals , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Apomorphine/pharmacology , Behavior, Animal/drug effects , Binding, Competitive , CHO Cells , Cell Line , Cricetinae , Humans , Male , Molecular Structure , Motor Activity/drug effects , Rats , Rats, Wistar , Receptors, Dopamine D2/drug effects , Receptors, Dopamine D2/physiology , Receptors, Dopamine D4 , Receptors, Serotonin/metabolism , Spiperone/metabolism , Spiro Compounds/metabolism , Spiro Compounds/pharmacology , Stereotyped Behavior/drug effects , Structure-Activity Relationship , Thiazoles/metabolism , Thiazoles/pharmacology , ThiazolidinesABSTRACT
A series of benzisoxazole- and benzisothiazole-3-carboxamides has been prepared and tested for potential antipsychotic activity. In general, the compounds showed an affinity for dopamine D2 and serotonin 5HT2A and 5HT1A receptors. Several members of this series have demonstrated activity in animal models predictive of potential antipsychotic activity. In addition, compounds 18, 19, 22, 27, 28, 43, and 44 have also shown a potential for reduced EPS liability as suggested by the ratio of activity seen in mesolimbic-mediated vs nigrostriatal-mediated behavioral assays.
Subject(s)
Antipsychotic Agents/pharmacology , Isoxazoles/pharmacology , Thiazoles/pharmacology , Animals , Apomorphine/pharmacology , Behavior, Animal/drug effects , Male , Mice , Rats , Rats, Wistar , Stereotyped Behavior/drug effects , Structure-Activity RelationshipSubject(s)
Antipsychotic Agents/therapeutic use , Schizophrenia/drug therapy , Thiazoles/therapeutic use , 8-Hydroxy-2-(di-n-propylamino)tetralin , Animals , Antipsychotic Agents/metabolism , Mice , Rats , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Substrate Specificity , Tetrahydronaphthalenes/pharmacology , Thiazoles/metabolism , ThiazolidinesABSTRACT
4-Amino-3-pyridyl carbamates (2a-c) were synthesized as potential acetylcholinesterase inhibitors and acetylcholine releasers on the basis of the reported activity of the analogous N-(4-amino-3-pyridyl)-N',N'-dimethylurea (1). Although 4-amino-3-pyridyl N,N-dimethylcarbamate (2b) showed good cholinesterase inhibition [concentration that elicited a 50% reduction in the maximal enzyme response (IC50) was 13.4 microM], it had no effect on the stimulated release of [3H]acetylcholine from rat striatal slices. 4-[[(Dimethylamino)methylene]amino]-3-pyridyl N,N-dimethylcarbamate (7a), an intermediate in the synthesis of 2b, demonstrated surprisingly good cholinesterase inhibition (IC50 was 9.4 microM) but showed no activity as a release. A precursor to 7a, N-(3-hydroxy-4-pyridyl)-N',N'-dimethylformamidine (6a), showed some activity in release but was not an esterase inhibitor, whereas the precursor to 6a, 4-amino-3-pyridinol (5a), was a potent releaser. A new synthesis of 5a, based on an ortho-directed lithiation strategy, is also reported.
Subject(s)
Acetylcholine/metabolism , Aminopyridines/chemical synthesis , Carbamates/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Aminopyridines/pharmacology , Animals , Carbamates/pharmacology , Cholinesterase Inhibitors/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Male , Rats , Rats, Inbred StrainsABSTRACT
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.
