RESUMO
Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest in recent years due to their involvement in a wide range of activities, including the modulation of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol (HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein, we describe the identification of novel SR ligands, obtained by a chemical hybridization approach. There wereendowed with pan-affinity for both SR subtypes and evaluated their potential anticancer activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach, we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism of action. The further exploration of their structure-activity relationships and their evaluation in additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the development of novel anticancer agents that target SRs.
Assuntos
Antineoplásicos , Desenho de Fármacos , Haloperidol , Receptores sigma , Receptores sigma/metabolismo , Receptores sigma/antagonistas & inibidores , Haloperidol/farmacologia , Haloperidol/análogos & derivados , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Estrutura Molecular , Sobrevivência Celular/efeitos dos fármacos , Ligantes , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Neurodegeneration is a slow and progressive loss of neuronal cells or their function in specific regions of the brain or in the peripheral system. Among several causes responsible for the most common neurodegenerative diseases (NDDs), cholinergic/dopaminergic pathways, but also some endogenous receptors, are often involved. In this context, sigma 1 receptor (S1R) modulators can be used as neuroprotective and antiamnesic agents. Herein, we describe the identification of novel S1R ligands endowed with antioxidant properties, potentially useful as neuroprotective agents. We also computationally assessed how the most promising compounds might interact with the S1R protein's binding sites. The in silico predicted ADME properties suggested that they could be able to cross the brain-blood-barrier (BBB), and to reach the targets. Finally, the observation that at least two novel ifenprodil analogues (5d and 5i) induce an increase of the mRNA levels of the antioxidant NRF2 and SOD1 genes in SH-SY5Y cells suggests that they might be effective agents for protecting neurons against oxidative damage.
Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Receptores sigma , Humanos , Antioxidantes/farmacologia , Antioxidantes/química , Ligantes , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Receptores sigma/metabolismoRESUMO
In our continuing effort to develop novel sigma receptor (SR) ligands, we present the design, synthesis and binding studies of a small library of aminopropylcarboxamide derivatives, obtained from a deconstruction of the piperidine ring of previously synthesized piperidine-based compounds. The best results were achieved with benzofuran (5c, 5g) and quinoline (5a, 5e) derivatives. These compounds revealed the highest affinity for both receptor subtypes. In particular, the 3,4-dimethoxyphenyl derivatives 5e and 5g showed the highest selectivity profile for S2R, especially the quinoline derivative 5e exhibited a 35-fold higher affinity for S2R subtype. The cytotoxic activity of aforementioned compounds was evaluated against SKBR3 and MCF7 cell lines, widely used for breast cancer studies. Whereas the potency of 5g was similar that of Siramesine and Haloperidol in both cell lines, compounds 5a, 5c and 5e exhibited a potency at least comparable to that of Haloperidol in SKBR3 cells. A molecular modelling evaluation towards the S2R binding site, confirmed the strong interaction of compound 5e thus justifying its highest S2R affinity.
Assuntos
Quinolinas , Receptores sigma , Haloperidol , Ligantes , Piperidinas , Quinolinas/farmacologia , Receptores sigma/metabolismo , Relação Estrutura-AtividadeRESUMO
To extend our screening for novel antimycobacterial molecules, we have designed, synthesized, and biologically evaluated a library of 14 new hydrazide derivatives containing 1,3,4-oxadiazole core. A variety of mycobacterial strains, including some drug-resistant strains, were tested for antimycobacterial activity. Among the compounds tested, five showed high antimycobacterial activity (MIC values of 8 µg/mL) against M. tuberculosis H37Ra attenuated strain, and two derivatives were effective (MIC of 4 µg/mL) against pyrazinamide-resistant strains. Furthermore, the novel compounds were tested against the fungal C. albicans strain, showing no antimycotic activity, and thus demonstrating a good selectivity profile. Notably, they also exhibited low cytotoxicity against human SH-SY5Y cells. The molecular modeling carried out suggested a plausible mechanism of action towards the active site of the InhA enzyme, which confirmed our hypothesis. In conclusion, the active compounds were predicted in silico for ADME properties, and all proved to be potentially orally absorbed in humans.
Assuntos
Mycobacterium tuberculosis , Neuroblastoma , Humanos , Antituberculosos/química , Hidrazinas/farmacologia , Testes de Sensibilidade Microbiana , Neuroblastoma/tratamento farmacológico , Fungos , Relação Estrutura-Atividade , Simulação de Acoplamento MolecularRESUMO
This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250⯵g/mL (0.37-0.75⯵M) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.
Assuntos
Antituberculosos/síntese química , Benzoxazinas/química , Desenho de Fármacos , Animais , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Benzoxazinas/farmacologia , Sítios de Ligação , Domínio Catalítico , Chlorocebus aethiops , Farmacorresistência Bacteriana/efeitos dos fármacos , Isoniazida/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/química , Oxirredutases/metabolismo , Relação Estrutura-Atividade , Células VeroRESUMO
The sigma receptor (σR) family has been considered mysterious for a long time. In fact, the σ2R subtype has been cloned only recently, revealing its identity as TMEM97, a NPC1-binding protein involved in cholesterol biosynthesis and implicated in the pathogenesis of cancer and neurologic disorders. With the aim of developing new chemical entities gifted with σR affinity, herein we report the design and synthesis of new piperidine-based alkylacetamide derivatives with mixed affinity towards both σ1 and σ2R subtypes.
Assuntos
Piperidinas/química , Receptores sigma/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Ligantes , Piperidinas/síntese química , Piperidinas/farmacologiaRESUMO
N(1)-[1-[1-aryl-3-[4-(1H-imidazol-1-yl)phenyl]-3-oxo]propyl]-pyridine-2-carboxamidrazone derivatives were design, synthesized and tested for their in vitro antimycobacterial activity. The new compounds showed a moderate antimycobacterial activity against the tested strain of Mycobacterium tuberculosis H37Ra and a significant antimycobacterial activity against several mycobacteria other than tuberculosis strains.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Imidazóis/farmacologia , Piridinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Imidazóis/síntese química , Imidazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
We describe here the synthesis and the binding interaction with σ1 and σ2 receptors of a series of new arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaffold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution on σ binding. The synthesized compounds have been tested to estimate their affinity and selectivity toward σ1 and σ2 receptors. Two out of 16 derivatives showed an interesting σ1 affinity (21.2 and 13.6 nM-compounds 2m and 2p) and a good selectivity (Ki(σ2)/Ki(σ1) >140 and >40, respectively).
Assuntos
Amidas/farmacologia , Receptores sigma/metabolismo , Amidas/síntese química , Amidas/química , Animais , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cobaias , Ligantes , Simulação de Dinâmica Molecular , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Receptor Sigma-1RESUMO
Originally considered an enigmatic polypeptide, the σ(1) receptor has recently been identified as a unique ligand-regulated protein. Many studies have shown the potential of σ(1) receptor ligands for the treatment of various diseases of the central nervous system (CNS); nevertheless, almost no information about the 3D structure of the receptor and/or the possible modes of interaction of the σ(1) protein with its ligands have been unveiled so far. With the present work we validated our σ(1) 3D homology model and assessed its reliability as a platform for σ(1) ligand structure-based drug design. To this purpose, the 3D σ(1) model was exploited in the design of 33 new σ(1) ligands and in their ranking for receptor affinity by extensive molecular dynamics simulation-based free energy calculations. Also, the main interactions involved in receptor/ligand binding were analyzed by applying a per residue free energy deconvolution and in silico alanine scanning mutagenesis calculations. Subsequently, all compounds were synthesized in our laboratory and tested for σ(1) binding activity in vitro. The agreement between in silico and in vitro results confirms the reliability of the proposed σ(1) 3D model in the a priori prediction of the affinity of new σ(1) ligands. Moreover, it also supports and corroborates the currently available biochemical data concerning the σ(1) protein residues considered essential for σ(1) ligand binding and activity.
Assuntos
Desenho Assistido por Computador , Desenho de Fármacos , Receptores sigma/metabolismo , Simulação por Computador , Humanos , Ligantes , Modelos Moleculares , Simulação de Dinâmica Molecular , Mutagênese , Mutação/genética , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Receptores sigma/química , Receptores sigma/genéticaRESUMO
Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our "wet" screen and used "dry" machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo ("wet") and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor ß pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis.
Assuntos
Bleomicina/efeitos adversos , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Ensaios de Triagem em Larga Escala/métodos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/terapia , Pneumopatias/induzido quimicamente , Pneumopatias/terapia , Aprendizado de Máquina/normas , Miofibroblastos/metabolismo , Animais , Diferenciação Celular , Humanos , Fibrose Pulmonar Idiopática/patologia , Pneumopatias/patologia , Camundongos , TransfecçãoRESUMO
In this work we developed a 3D-pharmacophore model for sigma(2) receptor based on 19 benzooxazolone derivatives. The best 3D-pharmacophore hypothesis, consisting of five features: a positive ionizable, a hydrogen bond acceptor, a hydrophobic aromatic, a hydrophobic aliphatic, and a generic hydrophobic provided a 3D-QSAR model with a correlation coefficient of 0.97 and a RMSD of 0.48.
Assuntos
Modelos Químicos , Modelos Moleculares , Oxazolona/química , Receptores sigma/antagonistas & inibidores , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Oxazolona/síntese química , Oxazolona/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptores sigma/metabolismoRESUMO
In order to investigate the molecular features involved in sigma receptors (sigma-Rs) binding, new compounds based on arylalkylaminoalcoholic, arylalkenyl- and arylalkylaminic scaffolds were synthesized and their affinity towards sigma(1)- and sigma(2)-Rs subtypes was evaluated. The most promising compounds were also screened for their affinity at micro-opioid, delta-opioid and kappa-opioid receptors. Biological results are herein presented and discussed.
Assuntos
Aminas/química , Aminas/farmacologia , Receptores sigma/metabolismo , Alcenos/química , Alcenos/farmacologia , Amino Álcoois/química , Amino Álcoois/farmacologia , Animais , Cobaias , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/farmacologia , Ligantes , Modelos Moleculares , Ligação Proteica , Ratos , Receptores Opioides/metabolismo , Relação Estrutura-AtividadeRESUMO
Among several potential applications, sigma receptor ligands can be used as antipsychotics, antiamnesics, and against other neurodegenerative disorders as well as neuroprotective agents. We present herein a new series of diazepane-containing derivatives as σR ligands obtained by a conformational expansion approach of our previously synthesized piperidine-based compounds. The best results were reached by benzofurane 2c, 3c and quinoline 2d, 3d-substituted diazepane derivatives, which showed the highest σR affinity. The cytotoxic activities of synthesized compounds were evaluated against two cancer cell lines, and the results indicated that none of the compounds induced significant toxicity in these cells. We also evaluated the antioxidant activity by radical scavenging capacity of our best compounds on ABTS and H2O2. The results obtained reveal that our new derivatives possess an excellent antioxidant profile and could be protective for the cells. Overall, the benzofurane derivative 2c due to its strong interaction with the active site of the receptor, as confirmed by molecular dynamic simulations, emerged as the optimum compound with high σ1R affinity, low cytotoxicity, and a potent antioxidant activity.
RESUMO
3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H(37)Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14alpha-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/química , Oxidiazóis/farmacologia , Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Simulação por Computador , Inibidores das Enzimas do Citocromo P-450 , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/fisiologia , Oxidiazóis/síntese química , Ligação Proteica , Esterol 14-Desmetilase , Termodinâmica , Tuberculose/tratamento farmacológicoRESUMO
2-Aryl-3-(1H-imidazol-1-yl and 1H-1,2,4-triazol-1-yl)-1H-indole derivatives were synthesized and tested for their in-vitro antifungal and antimycobacterial activities. These indole derivatives were devoid of antifungal activity against the tested strains of Candida spp. Yet, they exhibited an interesting antitubercular activity against Mycobacterium tuberculosis reference strain H(37)Rv.
Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Candida/efeitos dos fármacos , Química Farmacêutica/métodos , Indóis/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Indóis/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Superficial wounds that require suturing are often the reason children visit the Paediatric Emergency Department. Suturing is usually accompanied by perilesional administration of lidocaine, a local anaesthetic drug that improves pain tolerance. In paediatric patients, this approach has a low compliance because lidocaine has to be injected, which in children generates fear and anxiety, a sterile anaesthetic gel could improve the child compliance. OBJECTIVE: To develop a sterile and stable sterile gel capable of remaining in place over time for topical anaesthesia. METHOD: Different formulations were analysed by HPLC, by UV and fluorimetric detection. Two different sterilisation methods were tested. MAIN OUTCOME: To maintain the original stability of the gel also after sterilisation process. RESULTS: Four different gels were prepared and analysed; the most stable gel lasts over 3â¯months with a degradation less than 10%. CONCLUSION: The use of Poloxamer 407 guarantees stability of the preparation, showing a reduction in oxidative reaction, and gives the gel the right texture for application to a bleeding wound.
Assuntos
Epinefrina/química , Géis/química , Lidocaína/química , Tetracaína/química , Anestésicos Locais/química , Química Farmacêutica/métodos , Dor/tratamento farmacológico , Medição da Dor/métodosRESUMO
Among several potential applications, sigma receptors (σRs) can be used as neuroprotective agents, antiamnesic, antipsychotics and against other neurodegenerative disorders. On the other hands, antagonists of the GluN2b-subunit-containing-N-methyl-D-aspartate (NMDA) receptors are of major interest for the same purpose, being this subunit expressed in specific areas of the central nervous system and responsible for the excitatory regulation of nerve cells. Under these premises, we have synthesized and biologically tested novel hybrid derivatives obtained from the combination of phenyloxadiazolone and dihydroquinolinone scaffolds with different amine moieties, peculiar of σ2R ligands. Most of the new ligands exhibited a pan-affinity towards both σR subtypes and high affinity against GluN2b subunit. The most promising compounds belong to the dihydroquinolinone series, with the best affinity profile for the cyclohexylpiperazine derivative 28. Investigation on their biological activity showed that the new compounds were able to protect SH-SY5Y cells against oxidative stress induced by hydrogen peroxide treatment. These results proved that our dual σR/GluN2b ligands have beneficial effects in a model of neuronal oxidative stress and can represent strong candidate pharmacotherapeutic agents for minimizing oxidative stress-induced neuronal injuries.
Assuntos
Antioxidantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxidiazóis/farmacologia , Quinolonas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores sigma/antagonistas & inibidores , Antioxidantes/síntese química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Ligantes , Modelos Moleculares , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxidiazóis/síntese química , Oxidiazóis/química , Estresse Oxidativo/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidoresRESUMO
1-(3,5-Diaryl-4,5-dihydro-1H-pyrazol-4-yl)-1H-imidazole derivatives were synthesized and tested for their in vitro antifungal and antimycobacterial activities. These imidazole derivatives showed an excellent antifungal activity against a clinical strain of Candida albicans and an interesting antitubercular activity against Mycobacterium tuberculosis H(37)Rv reference strain.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Pirazóis/química , Antibacterianos/química , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Hidrogênio/química , Imidazóis/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
In the attempt to develop new sigma ligands we synthesized a series of N-benzyl-3-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylpropan-1-amines and N-benzyl-4-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylbutan-1-amines variously substituted on the phenyl ring. The displacement percentages of [3H]-DTG and [3H]-(+)-pentazocine determined in rat liver homogenates by these compounds at the fixed 100 nM concentration have been determined as a preliminary evaluation of their sigma1 and sigma2 affinity, respectively. The results suggested that the phenyl substituents may positively modulate, in comparison with the unsubstituted compound, the ability to displace [3H]-DTG from sigma2 sites, whereas the same phenyl substituents reduced the displacement percentages of [3H]-(+)-pentazocine from sigma1 sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for sigma2 over sigma1 receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest sigma2 affinity (sigma2Ki=5.9 nM) and an appreciable sigma2 over sigma1 selectivity (sigma1Ki/sigma2Ki=22). The obtained results suggest that a butylene chain separating the indole moiety from variously substituted benzylamino groups may be required to their interaction with a hypothetical secondary sigma2 binding site.
Assuntos
Benzeno/química , Indóis/química , Indóis/metabolismo , Receptores sigma/metabolismo , Animais , Sítios de Ligação , Ligação Proteica , Ratos , Especificidade por SubstratoRESUMO
In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new σ1 receptor (σ1R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based σ1 ligands, the three-dimensional homology model of the σ1R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the σ1R binding cavity was explored, and the effect on σ1R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward σ1 and σ2 receptors were tested. Finally, a representative series of best σ1R binders were assayed for cytotoxic activity on the SH-SY5Y human neuroblastoma cell line. Specifically, the new 4-phenyloxazolidin-2-one derivatives 2b (i.e., (R)-2b and (S)-2b) emerged as potential leads for further development as σ1R agents, as they were found endowed with the highest σ1R affinity (Kiσ1 values in the range 0.95-9.3 nM), and showed minimal cytotoxic levels exhibited in the selected, cell-based test, in line with a σ1R agonist behavior.