Abstract
The development of a synthetic approach to the novel pyrrolo[2, 1-b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (+/-)-3b was resolved into its enantiomers by using HPLC techniques. In vitro testing confirmed that (-)-3b is a more potent D2 receptor ligand, maintaining high affinity for 5-HT2 receptors. In contrast, the (+)-3b enantiomer presents a 35 times higher affinity for 5-HT2 than for dopamine D2 receptors with a similar dopamine D1 receptor affinity to that of (-)-3b. Overall, (+)-3b shows an "atypical" neuroleptic binding profile, while (-)-3b has a more "classical" profile. Furthermore pharmacological and biochemical testing displayed that the novel benzothiazepine (+/-)-3b is able to increase the extracellular levels of dopamine in the rat striatum and causes a dose-related suppression of apomorphine-induced locomotor activity. At low doses (+/-)-3b does not induce catalepsy, showing atypical antipsychotic properties similar to those of olanzapine. These heterocyclic compouds represent new leads for the development of novel antipsychotic drugs with atypical properties.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3,4-Dihydroxyphenylacetic Acid / metabolism
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Animals
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Antipsychotic Agents / chemical synthesis*
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Antipsychotic Agents / chemistry
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Antipsychotic Agents / metabolism
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Antipsychotic Agents / pharmacology
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Brain / drug effects
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Brain / metabolism
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Catalepsy / chemically induced
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Dopamine / metabolism
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Dopamine Antagonists / chemical synthesis*
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Dopamine Antagonists / chemistry
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Dopamine Antagonists / metabolism
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Dopamine Antagonists / pharmacology
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Dose-Response Relationship, Drug
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Male
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Motor Activity / drug effects
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / metabolism
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Pyrroles / pharmacology
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Rats
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Receptors, Dopamine D1 / metabolism
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Receptors, Dopamine D2 / metabolism
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Receptors, Dopamine D3
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Receptors, Serotonin / metabolism
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / metabolism
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Serotonin Antagonists / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thiazepines / chemical synthesis*
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Thiazepines / chemistry
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Thiazepines / metabolism
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Thiazepines / pharmacology
Substances
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7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo(2,1-b)(1,3)benzothiazepine
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Antipsychotic Agents
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Dopamine Antagonists
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Drd3 protein, rat
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Pyrroles
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Receptors, Dopamine D3
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Receptors, Serotonin
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Serotonin Antagonists
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Thiazepines
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3,4-Dihydroxyphenylacetic Acid
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Dopamine