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 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.

Hazards of Using Masking Protocols When Performing Ligand Binding Assays: Lessons From the Sigma-1 and Sigma-2 Receptors

“…We have previously shown affinities of 7.7 nM (Spruce et al, 2004) and 17 nM (Brimson et al, 2011) (obtained from MDA-MB-468 membranes and permeabilised cells, respectively). A selection of data from other studies with a variety of tissues and conditions gives overlapping results: guinea pig liver microsomes (0.8 nM) (Hanner et al, 1996); mouse lung membranes (1.4 nM) ; guinea pig brain membranes (1.6 nM obtained by means of homologous competition) (Xu et al, 2015); mouse brain homogenates (5.1 nM) (Langa et al, 2003); bovine adrenal medullar membranes (18 nM) (Paul et al, 1993); and rat cerebral membranes (19.9 nM) (Shiba et al, 2005). It is recognised that 100 nM 2.5 ± 0.9 4.7 ± 1.6 8.6 ± 2.6 26.3 ± 9.9 37 ± 11 1 μM 2.9 ± 2.5 4.8 ± 3.9 7.6 ± 5.9 11.6 ± 8.2 17 ± 11 differences in the sigma-1 receptor sequences from different species may contribute to some variation in affinity.…”

N -phenylpropyl- N ′-substituted piperazines occupy sigma receptors and alter methamphetamine-induced hyperactivity in mice

“…In vitro binding affinities to the DAT are known to be very weak for SA4503 ( K i = 12650 nM; (Xu et al 2015)) and low for YZ-185 and YZ-067 ( K i ’s ca. 1400 nM; (Matsumoto et al 2004)).…”

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

“…SA4503 displays a 4.6 nM and a 63.09 nM binding affinity ( K i ) for σ 1 and σ 2 receptor in guinea pig (gp) brain tissue, respectively . At least four groups have reinvestigated the σ receptor binding activity of SA4503 reporting slight differences in affinity and selectivity ( K i : σ1 = 3.3–4.6 nM; σ 1/ σ 2 = 13.7–55). ,− In 2015, Lever et al . prepared two series of SA4503 ether analogues ( 1 – 5 ) with different patterns and types of substituents on the phenethyl fragment (Figure ).…”

“…These compounds typically display a broad spectrum of pharmacological action with relatively high σ 1 receptor binding affinity and low selectivity over the σ 2 receptor, as well as moderate to low DAT and SERT affinity ( e.g. , 1 – 5 ), suggesting that these polyfunctional ligands may be developed as potential medications for treatment of psychostimulant abuse, depression, and anxiety …”