Ether modifications to 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503): Effects on binding affinity and selectivity for sigma receptors and monoamine transporters

Two series of novel ether analogs of the sigma (sigma) receptor ligand 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) have been prepared. In one series, the alkyl portion of the 4-methoxy group was replaced with allyl, propyl, bromoethyl, benzyl, phenethyl, and phenylpropyl moieties. In the second series, the 3,4-dimethoxy was replaced with cyclic methylenedioxy, ethylenedioxy and propylenedioxy groups. These ligands, along with 4-O-des-methyl SA4503, were evaluated for sigma(1) and sigma(2) receptor affinity, and compared to SA4503 and several known ether analogs. SA4503 and a subset of ether analogs were also evaluated for dopamine transporter (DAT) and serotonin transporter (SERT) affinity. The highest sigma(1) receptor affinities, K-i values of 1.75-4.63 nM, were observed for 4-O-des-methyl SA4503, SA4503 and the methylenedioxy analog. As steric bulk increased, sigma(1) receptor affinity decreased, but only to a point. Allyl, propyl and bromoethyl substitutions gave sigma(1) receptor K-i values in the 20-30 nM range, while bulkier analogs having phenylalkyl, and Z- and E-iodoallyl, ether substitutions showed higher sigma(1) affinities, with K-i values in the 13-21 nM range. Most ligands studied exhibited comparable sigma(1) and sigma(2) affinities, resulting in little to no subtype selectivity. SA4503, the fluoroethyl analog and the methylenedioxy congener showed modest six- to fourteen-fold selectivity for sigma(1) sites. DAT and SERT interactions proved much more sensitive than sigma receptor interactions to these structural modifications. For example, the benzyl congener (sigma(1) K-i = 20.8 nM; sigma(2) K-i = 16.4 nM) showed over 100-fold higher DAT affinity (K-i = 121 nM) and 6-fold higher SERT affinity (K-i = 128 nM) than the parent SA4503 (DAT K-i = 12650 nM; SERT K-i = 760 nM). Thus, ether modifications to the SA4503 scaffold can provide polyfunctional ligands having a broader spectrum of possible pharmacological actions. (C) 2014 Elsevier Ltd. All rights reserved.