Abstract
A new class of potent dopamine D(4) antagonists was discovered with selectivity over dopamine D(2) and the alpha-1 adrenoceptor. The lead compound was discovered by screening our compound collection. The structure-activity relationships of substituted isoindoline rings and the chirality about the hydroxymethyl side chain were explored. The isoindoline analogues showed modest differences in potency and selectivity. The S enantiomer proved to be the more potent enantiomer at the D(4) receptor. Several analogues with greater than 100-fold selectivity for D(4) over D(2) and the alpha-1 adrenoreceptor were discovered. Several selective analogues were active in vivo upon oral or intraperitoneal administration. A chiral synthesis starting from either D- or L-O-benzylserine is also described.
MeSH terms
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Administration, Oral
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Animals
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Apomorphine / pharmacology
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Benzyl Compounds / chemical synthesis
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Benzyl Compounds / chemistry
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Benzyl Compounds / pharmacology
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Dizocilpine Maleate / metabolism
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Dopamine D2 Receptor Antagonists*
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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / metabolism
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Indoles / pharmacology*
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Infusions, Parenteral
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Isoxazoles / chemical synthesis
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Isoxazoles / chemistry*
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Isoxazoles / pharmacology*
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacology*
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Prazosin / metabolism
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Prazosin / pharmacology
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Rats
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Receptors, Dopamine D4
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Serine / analogs & derivatives
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Serine / chemistry
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Spiperone / metabolism
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Spiperone / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Substrate Specificity
Substances
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Benzyl Compounds
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Dopamine D2 Receptor Antagonists
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Drd4 protein, rat
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Indoles
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Isoxazoles
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Piperidines
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Receptors, Dopamine D4
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Serine
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Spiperone
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Dizocilpine Maleate
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Apomorphine
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Prazosin