Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists.
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.
D000284:Administration, Oral; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007263:Infusions, Parenteral; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D050638:Receptors, Dopamine D4; D012694:Serine / Q000031:analogs & derivatives / Q000737:chemistry; D013134:Spiperone / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001593:Benzyl Compounds; D065127:Dopamine D2 Receptor Antagonists; C493601:Drd4 protein, rat; D007211:Indoles; D007555:Isoxazoles; D010880:Piperidines; D050638:Receptors, Dopamine D4; D012694:Serine; D013134:Spiperone; D016291:Dizocilpine Maleate; D001058:Apomorphine; D011224:Prazosin