Discovery and computational studies of piperidine/piperazine-based compounds endowed with sigma receptor affinity

Abstract

Herein, we describe our efforts to identify sigma receptor 1 (S1R) ligands through a screening campaign on our in-house collection of piperidine/piperazine-based compounds. Our investigations led to the discovery of...

Exploring Structural Requirements for Sigma-1 Receptor Linear Ligands: Experimental and Computational Approaches

“…To achieve this purpose, we overlapped the pharmacophore model with our previously reported lead compound 2-[4-(benzyl)-1-piperidin-1-yl]-1−4-(4-phenylpiperazin-1-yl)ethanone (1) having high affinity toward S1R (K i value of 3.2 nM). 20 The pharmacophoric alignment (Table 3) revealed that the benzyl group matched well with the hydrophobic feature; moreover, the model suggested that smaller groups might replace the benzyl moiety. To further investigate the performance of our model, we examined the pharmacophoric alignment for the analog compound 3-[4-[(4-fluorophenyl)methyl]-1-piperidyl]-1-[4-(4-hydroxyphenyl)piperazin-1-yl]propan-1-one (2) having a poor S1R affinity (K i value of 434.5 nM) 20 when compared to the analog compound 1 (see Table 3).…”

“…Finally, we carried out in vitro assays to test the affinity of 3-6 against S1R following a previously reported procedure. 20 Compounds 3−6 showed K i values ranging from 4.38 to 25.4 nM (Table 3), thus demonstrating good affinity when compared to reference compound haloperidol (K i value of 2.6 nM). 20 Notably, experimental data confirmed previous in silico results in terms of pharmacophoric performance for the design of new potential S1R ligands.…”

“…20 Compounds 3−6 showed K i values ranging from 4.38 to 25.4 nM (Table 3), thus demonstrating good affinity when compared to reference compound haloperidol (K i value of 2.6 nM). 20 Notably, experimental data confirmed previous in silico results in terms of pharmacophoric performance for the design of new potential S1R ligands. By comparing binding affinities of lead-compound 1 and new ligands 3−5, we can observe that the substitution of the benzyl moiety with a smaller group did not significantly affect the binding to S1R.…”

“…Finally, we carried out in vitro assays to test the affinity of 3 - 6 against S1R following a previously reported procedure . Compounds 3 – 6 showed K i values ranging from 4.38 to 25.4 nM (Table ), thus demonstrating good affinity when compared to reference compound haloperidol ( K i value of 2.6 nM) .…”

“…After the positive assessment of our model in retrieving S1R ligands already reported in the literature, we further explored if our pharmacophore could help expand our library of S1R binders 20 bearing piperazine core (e.g., 1 and 2 displayed in Figure 6).…”