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.

Keywords: S1R agonist; S1R antagonist; SR ligands; drug discovery; mechanical hypersensitivity; molecular modeling; sigma receptors.

Figure 1

Chemical structures of SR ligands evaluated in clinical trials.

Figure 2

General structure of designed SR ligands and sites of structure–activity relationship (SAR) exploration.

Scheme 1. Synthetic Strategy for the Preparation of Target Compounds 4a–f and 5a,b

Reagents and conditions: (i) iodobenzene, Pd₂(dba)₃, SPhos, t-BuOK, toluene, 100 °C, on; (ii) alkyl bromide, K₂CO₃, ACN, 50 °C, on; (iii) acyl chloride, triethylamine (TEA), CH₂Cl₂, rt, 2 h; (iv) TFA, CH₂Cl₂, rt, 4 h; (iv) Boc₂O, CH₂Cl₂, rt, on.

Scheme 2. Synthetic Strategy for the Preparation of Target Compounds 8a–g

Reagents and conditions: (i) Boc₂O, CH₂Cl₂, rt, on; (ii) iodobenzene, Pd₂(dba)₃, SPhos, t-BuOK, toluene, 100 °C, on; (iii) alkyl bromide, K₂CO₃, ACN, 50 °C, on; (iv) TFA, CH₂Cl₂, rt, 4 h.

Figure 3

3D representation of (A, B) compound 4b (salmon carbon sticks), (C, D) compound 5b (green carbon sticks) and (E, F) compound 8f (yellow carbon sticks) in complex with S1R (A, C, E) and S2R (B, D, F), respectively. The S1R and S2R are represented as blue and violet cartoons, respectively. The receptor residues involved in crucial contacts with the compounds are reported as blue and violet carbon sticks. Hydrogen bonds, salt bridges, π–π stacking, and π-cation interactions are represented by yellow, magenta, azure, and green dashed lines, respectively.

Figure 4

Effects of the systemic administration of standard S1R drugs (BD-1063 and PRE-084) and several experimental compounds in capsaicin-induced mechanical hypersensitivity in mice. (A) Effects of the subcutaneous (s.c.) administration of BD-1063, 8f and 5b on mechanical allodynia induced by the intraplantar (i.pl.) administration of capsaicin (1 μg), and absence of antiallodynic effects induced by 4b. (B) Effects of BD-1063, 8f and 5b administered alone and associated with the S1R agonist PRE-084. (C) Effect of BD-1063 alone and associated with 4b. Values are the mean ± standard error of the mean (SEM) obtained from six to nine animals per group: * p < 0.05, **p < 0.01 vs nonsensitized animals treated with the solvent of the drugs (black bar); ^#p < 0.05, ^##p < 0.01 vs capsaicin-injected mice treated with the solvent of the drugs (white bar); ⁺p < 0.05,⁺⁺p < 0.01 selected doses of antiallodynic compounds associated with PRE-084 (B) or 4b (C), or their solvent (one-way analysis of variance (ANOVA) followed by Bonferroni test).