Four members of a novel class of sigma (sigma) ligands were investigated for sigma subtype selectivity. (-)-1S,5S- and (+)-1R,5R-(E)-8-Benzylidene-5-(3-hydroxyphenyl)-2-methylmorphan-7- one (CB-64L and CB-64D, respectively) exhibited sigma 1 Ki = 10.5 nM and 3063 nM; sigma 2 Ki = 154 nM and 16.5 nM, respectively. The corresponding 3,4-dichloro derivatives, (-)-1S,5S- and (+)-1R,5R-(E)-8-(3,4-dichlorobenzylidene)-5-(3-hydroxyphenyl)-2-++ +methylmorphan-7 - one (CB-182 and CB-184, respectively) were also examined. CB-182 ((-)-isomer) showed sigma 1 and sigma 2 Ki = 27.3 nM and 35.5 nM, respectively, whereas CB-184 ((+)-isomer) exhibited sigma 1 and sigma 2 Ki = 7436 nM and 13.4 nM, respectively. Thus, the two sigma subtypes showed opposite enantioselectivity for these compounds, with (-) > (+) at sigma 1 and (+) > (-) at sigma 2. Importantly, CB-64D and CB-184 showed high sigma 2 affinity and, respectively, 185-fold and 554-fold selectivity for sigma 2 receptors over sigma 1. While high sigma 2 selectivity relative to sigma 1 was achieved with these compounds, they both exhibited high affinity at mu (mu) opioid receptors (Ki = 37.6 nM and 4.5 nM, respectively). Despite this, CB-64D and CB-184 will be useful tools for further characterization of sigma 2 receptors.