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
Examination of HP 184, [N-n-propyl)-N-(3-fluoro-4-pyridinyl) -1H-3-methylindodel-1-amine hydrochloride], in a variety of tests for serotonergic activity revealed some unique properties of this compound. We report here that 100 microM HP 184 enhanced spontaneous release of [3H]serotonin (5-HT) from rat hippocampal slices. This release was independent of the uptake carrier. In vivo assays confirmed that HP 184 (20 mg/kg, i.p.) lacked significant interactions at the norepinephrine (NE) or 5-HT uptake carrier itself. Notably, HP 184 (15 mg/kg, i.p.) reduced drinking behavior in schedule-induced polydipsic (SIP) rats. We previously reported that some selective 5-HT reuptake inhibitors decrease SIP 30-40% after a 14-21 day treatment. In the current study, HP 184 decreased SIP beginning with the first treatment, and this reduction (30%) was maintained for 28 days. We further investigated HP 184 and serotonin metabolite levels. One hour after i.p. administration of 30 mg/kg HP 184, the ratio of whole brain 5-hydroxyindolacetic acid (5-HIAA) to 5-HT was increased, suggesting serotonergic activation. Under these conditions, the brain:plasma ratio of HP 184 was approximately 2:1, with brain concentrations of 1.6 micrograms/gram. We speculate that the spontaneous release effects of HP 184 may be responsible for the behavioral effects observed.
Subject(s)
Biogenic Amines/metabolism , Brain/metabolism , Drinking Behavior/drug effects , Hippocampus/metabolism , Indoles/pharmacology , Pyridines/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , 5-Hydroxytryptophan/toxicity , Animals , Blepharoptosis/chemically induced , Blepharoptosis/prevention & control , Brain/drug effects , Drug Synergism , Fenfluramine/pharmacology , Hippocampus/drug effects , Hydroxyindoleacetic Acid/metabolism , In Vitro Techniques , Indoles/pharmacokinetics , Male , Mice , Norepinephrine/metabolism , Pyridines/pharmacokinetics , Rats , Rats, Wistar , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1 , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Synaptosomes/drug effects , Synaptosomes/metabolism , TetrabenazineABSTRACT
The aim of the present paper is to report on the adrenergic and serotonergic effects of besipirdine (HP 749) in vivo and to discuss its potential use in the treatment of obsessive compulsive disorder. Besipirdine inhibited biogenic amine uptake in vitro. It prevented tetrabenazine-induced ptosis in mice and potentiated the 5-hydroxytryptophan-induced serotonin syndrome in rats. Furthermore, it decreased schedule-induced polydipsic behavior in rats. Schedule-induced polydipsia may be a model for obsessive compulsive disorder. Previous results from our group have shown that certain selective serotonin reuptake inhibitors decrease schedule-induced polydipsia after 14-21 days of treatment. Besipirdine reduced schedule-induced polydipsic behavior immediately and this reduction lasted throughout the duration of the experiment (29 days).
