HIGHLY SELECTIVE SIGMA(1) LIGANDS BASED ON DEXTROMETHORPHAN

A series of 17-substituted-3-hydroxy- or 3-alkoxy- analogs of dextrome thorphan [(+)-3-methoxy-17-methylmorphinan] was prepared and evaluated for their binding affinities at sigma(1), sigma(2), and PCP sites on the NMDA receptor channel, in rat brain. The most potent and sigma(1)- selective compound was 3-ethoxy-17-benzylmorphinan (3e; K-i = 8.0 nM) that was >130 fold selective over sigma(2) sites and >5000-fold less p otent at PCP sites. All of the compounds demonstrated low affinity at sigma(2) sites (K-i range of similar to 0.5 --> 10 mu M) and at PCP si tes (K-i range of similar to 0.5 - 98 mu M). These compounds may provi de useful tools for elucidation of the functional role of sigma(1) rec eptors in the central nervous system.