title: 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.
abstract: Two series of novel ether analogs of the sigma (σ) 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 σ1 and σ2 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 σ1 receptor affinities, Ki values of 1.75-4.63 nM, were observed for 4-O-des-methyl SA4503, SA4503 and the methylenedioxy analog. As steric bulk increased, σ1 receptor affinity decreased, but only to a point. Allyl, propyl and bromoethyl substitutions gave σ1 receptor Ki values in the 20-30 nM range, while bulkier analogs having phenylalkyl, and Z- and E-iodoallyl, ether substitutions showed higher σ1 affinities, with Ki values in the 13-21 nM range. Most ligands studied exhibited comparable σ1 and σ2 affinities, resulting in little to no subtype selectivity. SA4503, the fluoroethyl analog and the methylenedioxy congener showed modest six- to fourteen-fold selectivity for σ1 sites. DAT and SERT interactions proved much more sensitive than σ receptor interactions to these structural modifications. For example, the benzyl congener (σ1Ki=20.8 nM; σ2Ki=16.4 nM) showed over 100-fold higher DAT affinity (Ki=121 nM) and 6-fold higher SERT affinity (Ki=128nM) than the parent SA4503 (DAT Ki=12650 nM; SERT Ki=760 nM). Thus, ether modifications to the SA4503 scaffold can provide polyfunctional ligands having a broader spectrum of possible pharmacological actions.
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Radiology, University of Missouri, Columbia, MO 65212, USA; Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Lord
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Peterson
authors.affiliation: Department of Radiology, University of Missouri, Columbia, MO 65212, USA; Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Fergason-Cantrell
authors.affiliation: Department of Radiology, University of Missouri, Columbia, MO 65212, USA; Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, USA. Electronic address: leverj@health.missouri.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Department of MU Research Reactor Center, University of Missouri, Columbia, MO 65211, USA. Electronic address: levers@missouri.edu.
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Lever
mesh_terms: D004986:Ether / Q000737:chemistry* / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017480:Receptors, sigma / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000097605:Sigma-1 Receptor
chemical_list: D004986:Ether; D010879:Piperazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C101789:SA 4503
keywords: Dopamine transporter; In vitro binding; Serotonin transporter; Sigma receptors