CB-64D and CB-184: ligands with high σ2 receptor affinity and subtype selectivity

Abstract

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