PIPERIDINYLTETRALIN SIGMA-LIGANDS

sigma receptor ligands have been proposed to be potential antipsychoti c drugs based on their activity profile in animal behavioral models an d their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT(2) recepto rs, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whet her restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses a nd the structure-activity relationships of these compounds are reporte d herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT(2) receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po).