Synthesis, Computational Insights, and Evaluation of Novel Sigma Receptors Ligands

Abstract

The development of diazabicyclo[4.3.0]nonane and 2,7-diazaspiro[3.5]nonane derivatives as sigma receptors (SRs) ligands is reported. The compounds were evaluated in S1R and S2R binding assays, and modeling studies were carried out to analyze the binding mode. The most notable compounds, 4b (AD186, K iS1R = 2.7 nM, K iS2R = 27 nM), 5b (AB21, K iS1R = 13 nM, K iS2R = 102 nM), and 8f (AB10, K iS1R = 10 nM, K iS2R = 165 nM), have been screened for analgesic effects in vivo, and their functional profile was determined through in vivo and in vitro models. Compounds 5b and 8f reached the maximum antiallodynic effect at 20 mg/kg. The selective S1R agonist PRE-084 completely reversed their action, indicating that the effects are entirely dependent on the S1R antagonism. Conversely, compound 4b sharing the 2,7-diazaspiro[3.5]nonane core as 5b was completely devoid of antiallodynic effect. Interestingly, compound 4b fully reversed the antiallodynic effect of BD-1063, indicating that 4b induces an S1R agonistic in vivo effect. The functional profiles were confirmed by the phenytoin assay. Our study might establish the importance of 2,7-diazaspiro[3.5]nonane core for the development of S1R compounds with specific agonist or antagonist profile and the role of the diazabicyclo[4.3.0]nonane in the development of novel SR ligands.

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

“…Phenytoin is an allosteric modulator for the S1R, and it differentially modulates the affinity of S1R ligands on the basis of their agonist or antagonist profile. 22,23 Indeed, phenytoin potentiates the receptor binding affinity of S1R agonists and produces no effects or slightly reduced receptor binding affinity for S1R antagonists. The functionality of compound 1 on S1R was determined by radioligand binding assay using rat liver in the presence of phenytoin, together with the known S1R agonist SKF-10 047 and antagonist BD-1063 ( Fig.…”

“…S1R and S2R radioligand binding assays involve the use of liver homogenates from male Sprague Dawley rats as previously reported. 21,22 In vitro S1R ligand binding assays were performed in Tris buffer (50 mM, pH 8), with [ 3 H](+)-pentazocine (2 nM) as radioligand. The final volume was 0.5 mL.…”

Design, Synthesis, and Cytotoxic Assessment of New Haloperidol Analogues as Potential Anticancer Compounds Targeting Sigma Receptors

“…In vitro S2R ligand binding assays were performed, using [ 3 H]-DTG (2 nM; K d = 17.9 nM) as a radioligand, (+)-pentazocine (5 μM) as S1R masking agent, and DTG (10 μM) for the measurement of non-specific binding. The final volume was 0.5 mL [ 54 ]. A millipore filter apparatus was employed to separate bound and free radioligands via filtration under conditions of reduced pressure through Whatman GF 6 glass fiber filters.…”

Novel object recognition test as an alternative approach to assessing the pharmacological profile of sigma-1 receptor ligands

“…in capsaicin and formalin models [ 2 , 3 ]. In order to unambiguously determine the functional profile of σ 1 R ligands, in vitro studies were also performed, including a well-established phenytoin-based functional assay [ 9 ]. Previous studies have shown that phenytoin, a low-potent allosteric modulator for the σ 1 R, differentially modulates the affinity of σ 1 R ligands depending on their agonist versus antagonist functionality.…”

“…Previous studies have shown that phenytoin, a low-potent allosteric modulator for the σ 1 R, differentially modulates the affinity of σ 1 R ligands depending on their agonist versus antagonist functionality. Phenytoin potentiates the receptor binding affinity of σ 1 R agonists, however, it produces no effects or slightly reduced receptor binding affinity for σ 1 R antagonists [ 9 ]. In fact, the results of phenytoin-based functional assay correlate with the in vivo activity of tested compounds, but the weak point is that the differences in binding affinities with the phenytoin are very small compared to the values obtained for compounds without an allosteric modulator [ 9 ].…”