Eight halogenated N,N'-diphenethylethylenediamines were synthesized, characterized and evaluated for σ1 receptor 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 (Ki values 6.35 - 15.82 nM) than the corresponding substitutions at the 2-position (Ki values 12.08 - 43.15 nM). Second, derivatives containing either a bromo or fluoro substituent at a given position showed higher σ1 receptor binding affinities than derivatives with a corresponding iodo substituent. The data indicate that σ1 receptor affinity for this structural series is sensitive to steric bulk at the 2-position. Log k'w measurements for the halogenated N,N'-diphenethylethylenediamines were determined by high performance liquid chromatography, and varied from 2.54 - 3.71. In particular, the 3-fluoro analog exhibited a log k'w = 2.54 accompanied by a σ1 receptor Ki = 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 σ1 receptors.
Keywords: Binding studies; Sigma receptor; Structure activity relationships; lipophilicity.