Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists

James A Hendrix; Stephen J Shimshock; Gregory M Shutske; John D Tomer 4th; Kevin J Kapples; Mark G Palermo; Thomas J Roy Corbett; Hugo M Vargas; Sharon Kafka; Karen M Brooks; Lynn Laws-Ricker; David K H Lee; Inez de Lannoy; Michel Bordeleau; Geihan Rizkalla; Joshua Owolabi; Rajender K Kamboj

doi:10.1002/1439-7633(20021004)3:10<999::AID-CBIC999>3.0.CO;2-A

Synthesis and structure-activity relationship of the isoindolinyl benzisoxazolpiperidines as potent, selective, and orally active human dopamine D4 receptor antagonists

Chembiochem. 2002 Oct 4;3(10):999-1009. doi: 10.1002/1439-7633(20021004)3:10<999::AID-CBIC999>3.0.CO;2-A.

Authors

James A Hendrix¹, Stephen J Shimshock, Gregory M Shutske, John D Tomer 4th, Kevin J Kapples, Mark G Palermo, Thomas J Roy Corbett, Hugo M Vargas, Sharon Kafka, Karen M Brooks, Lynn Laws-Ricker, David K H Lee, Inez de Lannoy, Michel Bordeleau, Geihan Rizkalla, Joshua Owolabi, Rajender K Kamboj

Affiliation

¹ Aventis Pharmaceuticals Route, 202-206, PO Box 6800, Bridgewater, NJ 08807-0800, USA. james.hendrix@aventis.com

PMID: 12362366
DOI: 10.1002/1439-7633(20021004)3:10<999::AID-CBIC999>3.0.CO;2-A

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

Administration, Oral
Animals
Apomorphine / pharmacology
Benzyl Compounds / chemical synthesis
Benzyl Compounds / chemistry
Benzyl Compounds / pharmacology
Dizocilpine Maleate / metabolism
Dopamine D2 Receptor Antagonists*
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / metabolism
Indoles / pharmacology*
Infusions, Parenteral
Isoxazoles / chemical synthesis
Isoxazoles / chemistry*
Isoxazoles / pharmacology*
Piperidines / chemical synthesis
Piperidines / chemistry*
Piperidines / pharmacology*
Prazosin / metabolism
Prazosin / pharmacology
Rats
Receptors, Dopamine D4
Serine / analogs & derivatives
Serine / chemistry
Spiperone / metabolism
Spiperone / pharmacology
Stereoisomerism
Structure-Activity Relationship
Substrate Specificity

Substances

Benzyl Compounds
Dopamine D2 Receptor Antagonists
Drd4 protein, rat
Indoles
Isoxazoles
Piperidines
Receptors, Dopamine D4
Serine
Spiperone
Dizocilpine Maleate
Apomorphine
Prazosin