A Comprehensive Ligand Based Mapping of the σ2 Receptor Binding Pocket.
ABSTRACT The sigma (σ) receptor system consists of at least two major receptor subtypes: σ1 and σ2. Several potential therapeutic applications would benefit from structural knowledge of the σ2 receptor but gaining this knowledge has been hampered by the difficulties associated with its isolation and, thus, characterization. Here, a ligand based approach has been adopted using the program PHASE® and a group of 41 potent and structurally diverse σ2 ligands to develop several pharmacophore models for different families of σ2 ligands. These pharmacophores were analyzed to identify the different binding modes to the receptor and were combined together to construct a comprehensive pharmacophore that was used to develop a structural model for the σ2 binding pocket. A total of six binding modes were identified and could be classified as neutral or charged modes. The results presented here also indicate the significance of hydrophobic interactions to σ2 binding and the requirement of hydrogen bonding interactions to increase the affinity for this receptor subtype. This work adds breadth to our knowledge of this receptor's binding site, and should contribute significantly to the development of novel selective σ2 ligands.
- [Show abstract] [Hide abstract]
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 nM - 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 nM - 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 nM - 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 (σ1 Ki = 20.8 nM; σ2 Ki = 16.4 nM) showed over 100-fold higher DAT affinity (Ki = 121 nM) and 6-fold higher SERT affinity (Ki = 128 nM) 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.Bioorganic & Medicinal Chemistry 11/2014; 23(1). DOI:10.1016/j.bmc.2014.11.007 · 2.95 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Sigma-2 receptor is a widely distributed protein, which can modulate cell proliferation and involved in the pathogenesis of tumor. Photo affinity labelling techniques testified that its molecular size is about 18 kDa. Recent studies indicated that sigma-2 receptor modulates the cytosolic Ca2+ concentration, dopaminergic transmission, and cocaine-induced addiction behavior. Some sigma-2 receptor ligands (ditolylguanidine, afobazole, etc) display the neuroprotective effect. Although sigma-2 receptor hasn't been cloned, tens of sigma-2 receptor ligands, which demonstrate high affinity and selectivity, have been identified in the past decade. In this review, we mainly focus onthese series of selective sigma-2 receptor ligands, their neuropsychological effects, and molecular probe for tracing sigma-2 receptors in central nervous system.Current Medicinal Chemistry 01/2015; 22(999). DOI:10.2174/0929867322666150114163607 · 3.85 Impact Factor