TABLE 1

Binding affinities of SN79 derivatives at sigma-1 and sigma-2 receptors

Radioligand competition binding assays were performed using [³H](+)-pentazocine to measure sigma-1 receptors and [³H]DTG in the presence of unlabeled (+)-pentazocine to measure sigma-2 receptors as described in Materials and Methods. Single-position changes to the core structure of SN79 resulted in drastic changes in affinity and selectivity at sigma-1 and sigma-2 receptors. Generally, changes in the X position determined selectivity, with S substitutions resulting in reduced selectivity and O substitutions resulting in increased selectivity for the sigma-2 receptor. R-group substitutions did not demonstrate a discernably consistent pattern across the ligand series. An accurate K_i value could not be determined for CM572 (X = O, R = NCS) at sigma-1 receptors because of insolubility above 1 mM. However, ∼50% of total sigma-1 receptors were bound by 10,000 nM CM572 compared with total available sigma-1 receptor binding capacity, as measured by [³H](+)-pentazocine alone. The results are presented as the average ± S.D. of K_i values from at least three independent experiments for each ligand (except for CM572 at sigma-1 receptors). All experiments were performed in duplicate.