Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation

Dichiara, Maria; Artacho-Cordón, Antonia; Turnaturi, Rita; Santos-Caballero, Miriam; González‐Cano, Rafael; Pasquinucci, Lorella; Barbaraci, Carla; Rodríguez-Gómez, Isabel; Gómez-Guzmán, Manuel; Marrazzo, Agostino; Cobos, Enrique J.; Amata, Emanuele

doi:10.1016/j.ejmech.2021.114091

Cited by 10 publications

(19 citation statements)

References 51 publications

(70 reference statements)

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“…The increase in pain sensitivity in the area surrounding capsaicin injection results from central sensitization, and this process plays a pivotal role in chronic pain development and maintenance . Capsaicin-induced mechanical hypersensitivity has been used to study drug effects in central sensitization in both humans and rodents. , In particular, this behavioral model has been previously employed to evaluate the S1R functional profile of new compounds (including clinical candidates) since compounds that act as an antagonist at S1R can reduce sensory hypersensitivity, whereas compounds that act as agonists at S1R reverse the effects of the former. ,, …”

Section: Resultsmentioning

confidence: 99%

“…Non-sensitized mice showed a response latency to the mechanical stimulation of 44.19 ± 2.59 s. The response latency markedly decreased in mice intraplantarly treated with capsaicin up to 13.51 ± 1.93 s, denoting the development of tactile allodynia (Figure A). BD-1063 (10–40 mg/kg, s.c.), used as a control standard S1R antagonist, induced a dose-dependent and full reversal of capsaicin-induced allodynia, as previously described. , Compounds 8a and 14a (10–40 mg/kg, s.c.) also induced dose-dependent antiallodynic effects. However, the extent of their effects was limited in comparison to BD-1063, as they were unable to fully reverse capsaicin-induced hypersensitivity at 40 mg/kg, reaching latency values of just 30.28 ± 5.02 s for 8a and 26.55 ± 3.55 s for 14a (Figure A).…”

Section: Resultsmentioning

confidence: 99%

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Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity

et al. 2023

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The design and synthesis of a series of 2,7-diazaspiro [4.4]nonane derivatives as potent sigma receptor (SR) ligands, associated with analgesic activity, are the focus of this work. In this study, affinities at S1R and S2R were measured, and molecular modeling studies were performed to investigate the binding pose characteristics. The most promising compounds were subjected to in vitro toxicity testing and subsequently screened for in vivo analgesic properties. Compound 9d (AD258) exhibited negligible in vitro cellular toxicity and a high binding affinity to both SRs (K i S1R = 3.5 nM, K i S2R = 2.6 nM), but not for other pain-related targets, and exerted high potency in a model of capsaicininduced allodynia, reaching the maximum antiallodynic effect at very low doses (0.6−1.25 mg/kg). Functional activity experiments showed that S1R antagonism is needed for the effects of 9d and that it did not induce motor impairment. In addition, 9d exhibited a favorable pharmacokinetic profile.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity

et al. 2023

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“…Liver homogenates for S1R and S2R receptor binding assays were prepared from male Sprague-Dawley rats as previously reported. , In vitro S1R ligand binding assays were carried out in Tris buffer (50 mM, pH 8), using [ 3 H](+)-pentazocine (2 nM) in a final volume of 0.5 mL with increasing concentrations of test compounds. The K d value of [ 3 H](+)-pentazocine was 2.9 nM.…”

Section: Methodsmentioning

confidence: 99%

“…The K d value of [ 3 H]DTG was 17.9 nM. Nonspecific binding was evaluated with unlabeled DTG (10 μM) …”

Section: Methodsmentioning

confidence: 99%

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

Dichiara

Ambrosio

Barbaraci

et al. 2023

ACS Chem. Neurosci.

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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.

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“…Brain and liver homogenates for σ 1 R and σ 2 R binding assays were prepared from male Dunkin-Hartley guinea pigs and Sprague-Dawley rats, respectively (ENVIGO RMS S.R.L., Udine, Italy), as previously reported. ,, In vitro σ 1 R ligand binding assays were carried out in a Tris buffer (50 mM, pH 7.4) for 150 min at 37 °C. The thawed membrane preparation of the guinea pig brain cortex was incubated with increasing concentrations of test compounds and [ 3 H](+)-pentazocine (2 nM) in a final volume of 0.5 mL.…”

Section: Experimental Protocolsmentioning

confidence: 99%

Dual Piperidine-Based Histamine H₃ and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

et al. 2023

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In search of new dual-acting histamine H3/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active in vivo ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, KSK67 and KSK68, differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σ1Rs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (3, 7, and 12) for further biological evaluation. Compound 12 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.

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Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation

Cited by 10 publications

References 51 publications

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity

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

Dual Piperidine-Based Histamine H₃ and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

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Dual Sigma-1 receptor antagonists and hydrogen sulfide-releasing compounds for pain treatment: Design, synthesis, and pharmacological evaluation

Cited by 10 publications

References 51 publications

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity

Discovery of AD258 as a Sigma Receptor Ligand with Potent Antiallodynic Activity

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

Dual Piperidine-Based Histamine H3 and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain

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Product

Resources

About

Dual Piperidine-Based Histamine H₃ and Sigma-1 Receptor Ligands in the Treatment of Nociceptive and Neuropathic Pain