title: Synthesis and σ1Receptor Binding of Halogenated N,N'-Diphenethylethylenediamines.
abstract: Eight halogenatedN,N'-diphenethylethylenediamines were synthesized, characterized and evaluated for σ1receptor binding affinity in vitro. Measurements of lipophilicity also were obtained. The substitution pattern on one of the aromatic rings remained constant as 3,4-dichloro, while the substituents on the other aromatic ring were varied to include fluorine, bromine or iodine in either the 2-, 3- or 4- positions. Two main structure activity relationships were observed. First, halogen substitution on the 3- or 4-positions of the aromatic ring conferred higher binding affinities (Kivalues 6.35 - 15.82 nM) than the corresponding substitutions at the 2-position (Kivalues 12.08 - 43.15 nM). Second, derivatives containing either a bromo or fluoro substituent at a given position showed higher σ1receptor binding affinities than derivatives with a corresponding iodo substituent. The data indicate that σ1receptor affinity for this structural series is sensitive to steric bulk at the 2-position. Logk'wmeasurements for the halogenatedN,N'-diphenethylethylenediamines were determined by high performance liquid chromatography, and varied from 2.54 - 3.71. In particular, the 3-fluoro analog exhibited a logk'w= 2.54 accompanied by a σ1receptorKi= 7.8 nM. These novel N,N'-diphenethylethylenediamines warrant further investigation in behavioral assays, and radiolabeled versions may prove suitable for in vivo studies of σ1receptors.
authors.affiliation: Departments of Chemistry, University of Missouri - Columbia, Columbia, MO, USA ; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Fitzsimmons
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Lever
keywords: Binding studies; Sigma receptor; Structure activity relationships; lipophilicity
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