title: CB-64D and CB-184: ligands with high sigma 2 receptor affinity and subtype selectivity.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: W D
authors.initials: WD
authors.lastname: Bowen
authors.forename: C M
authors.initials: CM
authors.lastname: Bertha
authors.forename: B J
authors.initials: BJ
authors.lastname: Vilner
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000378:metabolism*; D006168:Guinea Pigs; D008024:Ligands; D009019:Morphinans / Q000378:metabolism*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism; D017480:Receptors, sigma / Q000145:classification / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
chemical_list: D001597:Benzylidene Compounds; C096583:CB 182; C096582:CB 64D; D008024:Ligands; D009019:Morphinans; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma