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 D4 antagonists was discovered with selectivity over dopamine D2 and the α‐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 D4 receptor. Several analogues with greater than 100‐fold selectivity for D4 over D2 and the α‐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. Antipsycotic drugs without side effects may eventually result from further research on a new class of potent and selective D4 antagonists with oral activity. A series of isoindolinyl compounds (see scheme) was synthesized. The structure–activity relationships of the substituted isoindoline rings and the importance of the chirality about the hydroxymethyl side chain were explored by measurement of inhibition constants for binding of the compounds to dopamine D4 and D2 receptors and the α‐1 adrenoreceptor.