CB-64D AND CB-184 - LIGANDS WITH HIGH SIGMA(2) RECEPTOR AFFINITY AND SUBTYPE SELECTIVITY

Four members of a novel class of sigma (a) ligands were investigated for a 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) K-i=10.5 nM and 3063 nM; sigma(2) K-i=154 nM and 16.5 nM, respectively. The corresponding 3,4-dichloro derivatives, (-)-1S,5S- and (+)-1R,5R-(E)-8-(3,4-dichiorobenzylidene)-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) K-i=27.3 nM and 35.5 nM, respectively, whereas CB-184 ((+)-isomer) exhibited sigma(1) and sigma(2) K-i=7436 nM and 13.4 nM, respectively. Thus, the two a 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 (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 sigma(2) receptors.