RESUMEN
Bronchopulmonary dysplasia (BPD) is a chronic illness that usually originates in preterm newborns. Generally, BPD is a consequence of respiratory distress syndrome (RDS) which, in turn, comes from the early arrest of lung development and the lack of pulmonary surfactant. The need of oxygen therapy to overcome premature newborns' compromised respiratory function generates an increasing amount of reactive oxygen species (ROS), the onset of sustained oxidative stress (OS) status, and inflammation in the pulmonary alveoli deputies to respiratory exchanges. BPD is a severe and potentially life-threatening disorder that in the most serious cases, can open the way to neurodevelopmental delay. More importantly, there is no adequate intervention to hamper or treat BPD. This perspective article seeks to review the most recent and relevant literature describing the very early stages of BPD and hyperoxic lung injuries focussing on nuclear factor erythroid derived 2 (Nrf2)/heme oxygenase-1 (HO-1) axis. Indeed, Nrf2/HO1 activation in response to OS induced lung injury in preterm concurs to the induction of certain number of antioxidant, anti-inflammatory, and detoxification pathways that seem to be more powerful than the activation of one single antioxidant gene. These elicited protective effects are able to counteract/mitigate all multifaceted aspects of the disease and may support novel approaches for the management of BPD.
Asunto(s)
Displasia Broncopulmonar/fisiopatología , Hemo-Oxigenasa 1/fisiología , Lesión Pulmonar/fisiopatología , Factor 2 Relacionado con NF-E2/fisiología , Displasia Broncopulmonar/terapia , Humanos , Hiperoxia/fisiopatología , Estrés Oxidativo/fisiologíaRESUMEN
Pain relief achieved by co-administration of drugs acting at different targets is more effective than that obtained with conventional MOR selective agonists usually associated to relevant side effects. It has been demonstrated that simultaneously targeting different opioid receptors is a more effective therapeutic strategy. Giving the promising role for DOR in pain management, novel LP1-based analogues with different N-substituents were designed and synthesized with the aim to improve DOR profile. For this purpose, we maintained the phenyl ring in the N-substituent of 6,7-benzomorphan scaffold linked to an ethyl spacer bearing a hydroxyl/methyl or methoxyl group at carbon 2 or including it in a 1,4-benzodioxane ring. LP1 analogues were tested by competition binding assays. Compounds 6 (KiMOR=2.47nM, KiDOR=9.6nM), 7 (KiMOR=0.5nM and KiDOR=0.8nM) and 9 (KiMOR=1.08nM, KiDOR=6.6nM) retained MOR affinity but displayed an improved DOR binding capacity as compared to LP1 (KiMOR=0.83nM, KiDOR=29.1nM). Moreover, GPI and MVD functional assays indicated that compounds 6 (IC50=49.2 and IC50=10.8nM), 7 (IC50=9.9 and IC50=11.8nM) and 9 (IC50=21.5 and IC50=4.4nM) showed a MOR/DOR agonist profile, unlike LP1 that was a MOR agonist/DOR antagonist (IC50=1.9 and IC50=1240nM). Measurements of their antinociceptive effect was evaluated by mice radiant tail flick test displaying for compounds 6, 7 and 9 ED50 values of 1.3, 1.0 and 0.9mg/kg, i.p., respectively. Moreover, the antinociceptive effect of compound 9 was longer lasting with respect to LP1. In conclusion the N-substituent nature of compounds 6, 7 and 9 shifts the DOR profile of LP1 from antagonism to agonism.
Asunto(s)
Analgésicos/química , Benzomorfanos/química , Receptores Opioides delta/metabolismo , Analgésicos/metabolismo , Analgésicos/uso terapéutico , Animales , Unión Competitiva , Concentración 50 Inhibidora , Cinética , Masculino , Ratones , Dolor/tratamiento farmacológico , Unión Proteica , Receptores Opioides delta/química , Receptores Opioides kappa/química , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/química , Receptores Opioides mu/metabolismo , Relación Estructura-Actividad , Tritio/químicaRESUMEN
We previously reported bifunctional sigma-1 (σ1) ligands endowed with antioxidant activity (1 and 2). In the present paper, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy (6, 11), p-fluoro derivatives (7, 12) were synthesized. σ1 and σ2 affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong σ1 affinity, displayed improved σ1 selectivity compared to the parent compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed σ1 agonist pharmacological profile. Chemico-physical studies revealed that amides 2, 11 and 12 were more stable than corresponding esters 1, 6 and 7 under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives 7 and 12 being able to increase total antioxidant capacity (TAC). Our results underline that p-substituents have an important role on σ1 selectivity, TAC, chemical and enzymatic stabilities. In particular, our data suggest that new very selective compounds 7 and 12 could be promising tools to investigate the disorders in which σ1 receptor dysfunction and oxidative stress are contemporarily involved.
Asunto(s)
Antioxidantes/farmacología , Receptores sigma/antagonistas & inhibidores , Animales , Espectroscopía de Resonancia Magnética con Carbono-13 , Células Cultivadas , Cromatografía Líquida de Alta Presión , Ligandos , Masculino , Espectrometría de Masas , Ratones , Espectroscopía de Protones por Resonancia Magnética , Ratas , Ratas Sprague-Dawley , Espectrofotometría Ultravioleta , Receptor Sigma-1RESUMEN
σ-1 receptors (σ1R) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σ1R and selectivity over the σ-2 receptor (σ2R). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one (15) showed the highest σ1R receptor affinity (Ki σ1 = 1.6 nM) among the series with a significant improvement of the σ1R selectivity (Ki σ2/Ki σ1= 886) compared to the lead compound 8 (Ki σ2/Ki σ1= 432). Compound 15 was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3-60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound 15 demonstrated no significant effects in a rotarod assay, suggesting that this σ1R antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σ1R antagonists as potential therapeutics for chronic pain.
Asunto(s)
Receptores sigma , Analgésicos/farmacología , Animales , Hiperalgesia/tratamiento farmacológico , Ligandos , Ratones , Relación Estructura-Actividad , Receptor Sigma-1RESUMEN
Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonist LP1 resulted in retention of MOR affinity. Moreover, derivatives 7a, 7c, and 7d were biased MOR agonists toward ERK1,2 activity stimulation, whereas derivative 7e was a low potency MOR agonist on adenylate cyclase inhibition. They were further screened in the mouse tail flick test and PGE2-induced hyperalgesia and drug-induced gastrointestinal transit.
RESUMEN
We report the development of molecular hybrids in which a nitrate group serving as nitric oxide (NO) donor is covalently joined to σ receptor ligands to give candidates for double-targeted cancer therapy. The compounds have been evaluated in radioligand binding assay at both σ receptors and selected compounds tested for NO release. Compounds 9, 15, 18, 19, and 21 were subjected to MTT test. Compound 15 produced a significant reduction of MCF-7 and Caco-2 cellular viability with comparable IC50 as doxorubicin, being also not toxic for fibroblast HFF-1 cells. Compound 15 has shown a σ1 receptor antagonist/σ2 receptor agonist profile. Two derivatives of compound 15 lacking the nitrate group did not induce a reduction of MCF-7 cellular viability, suggesting a potential synergistic effect between the σ receptors and the NO-mediated events. Overall, the combination of NO donor and σ receptors ligands provided compounds with beneficial effects for the treatment of cancer.
RESUMEN
Previous studies have reported that selective sigma-1 agonists may improve cognitive abilities in experimental animals possibly via a cholinergic mechanism. However, the issue of a direct action on to sigma-1 receptors in memory-related brain areas has been much less investigated. The newly synthetised compound methyl(1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(+/-)-PPCC] has recently been shown to possess high affinity for the sigma-1 receptor where it specifically acts as an agonist. Here, the functional effects of (+/-)-PPCC were investigated in rat models of mild or severe cognitive dysfunction based on a sub-total (
Asunto(s)
Acetilcolina/metabolismo , Trastornos del Conocimiento/tratamiento farmacológico , Ciclopropanos/uso terapéutico , Nootrópicos/uso terapéutico , Piperidinas/uso terapéutico , Animales , Anticuerpos Monoclonales , Atropina , Conducta Animal , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Etilenodiaminas/uso terapéutico , Femenino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Antagonistas Muscarínicos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Receptores sigma/antagonistas & inhibidores , Proteínas Inactivadoras de Ribosomas Tipo 1 , SaporinasRESUMEN
The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (1) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/ß-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over ß-arrestin 2, behaving as biased agonist at MOR and mainly at DOR. Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity.
Asunto(s)
Analgésicos Opioides/farmacología , Benzomorfanos/farmacología , Descubrimiento de Drogas , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/síntesis química , Analgésicos Opioides/química , Animales , Benzomorfanos/síntesis química , Benzomorfanos/química , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Dolor Nociceptivo/tratamiento farmacológico , Dimensión del Dolor , Relación Estructura-ActividadRESUMEN
A new set of 5-chlorobenzoxazole- and 5-chlorobenzothiazole-based derivatives containing the azepane ring as a basic moiety was designed, synthesized and evaluated through binding assays to measure their affinity and selectivity towards σ1 and σ2 receptors. Compounds 19, 22 and 24, with a four units spacer between the bicyclic scaffold and the azepane ring, showed nanomolar affinity towards both receptor subtype and the best Ki values (Ki σ1â¯=â¯1.27, 2.30, and 0.78 and Ki σ2â¯=â¯7.9, 3.8, and 7.61â¯nM, respectively). Evaluation of cytotoxic and apoptotic effects in MCF-7 human cancer cells was useful to assess σ2 receptor activity, while an in vivo mice model of inflammatory pain allowed to analyze σ1 receptor pharmacological properties. In vitro and in vivo results suggested that compound 19 is a σ1/σ2 agonist, compound 24 a σ1 antagonist/σ2 agonist, whereas compound 22 might act as σ1 antagonist/σ2 partial agonist. Due to their pharmacological profile, a potential therapeutic application in cancer of aforesaid novel σ1/σ2 receptor ligands, especially 22 and 24, is proposed.
Asunto(s)
Analgésicos/uso terapéutico , Benzotiazoles/uso terapéutico , Benzoxazoles/uso terapéutico , Receptores sigma/agonistas , Receptores sigma/antagonistas & inhibidores , Analgésicos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Animales , Apoptosis/efectos de los fármacos , Benzotiazoles/síntesis química , Benzotiazoles/química , Benzotiazoles/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/química , Benzoxazoles/farmacología , Humanos , Ligandos , Células MCF-7 , Ratones , Estructura MolecularRESUMEN
Sigma-1 (σ1) receptor has been identified as a chaperone protein that interacts with other proteins, such as N-methyl-D-aspartate (NMDA) and opioid receptors, modulating their activity. σ1 receptor antagonists have been developed to obtain useful compounds for the treatment of psychoses, pain, drug abuse and cancer. Some interesting compounds such as E-5842 (5) and MS-377 (24), haloperidol and piperazine derivatives, respectively, were endowed with high affinity for σ1 receptors (Ki σ1 = 4 and 73 nM; Ki σ2 = 220 and 6900, respectively). They were developed for the treatment of psychotic disorders and 5 also underwent Phase II clinical trials suggesting interesting potential therapeutic applications. Here, σ1 receptor antagonists have been grouped based on chemical structure and reviewed according to structure-activity relationship and potential therapeutic role.
Asunto(s)
Analgésicos Opioides/farmacología , Receptores sigma/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Analgésicos Opioides/química , Animales , Humanos , Estructura Molecular , Receptores sigma/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Receptor Sigma-1RESUMEN
Methoxycarbonyl-1-phenyl-2-cyclopropylmethyl based derivatives cis-(+)-1a [cis-(+)-MR200], cis-(-)-1a [cis-(-)-MR201], and trans-(±)-1a [trans-(±)-MR204], have been identified as new potent sigma (σ) receptor ligands. In the present paper, novel enantiomerically pure analogues were synthesized and optimized for their σ receptor affinity and selectivity. Docking studies rationalized the results obtained in the radioligand binding assay. Absolute stereochemistry was unequivocally established by X-ray analysis of precursor trans-(+)-5a as camphorsulfonyl derivative 9. The most promising compound, trans-(+)-1d, showed remarkable selectivity over a panel of more than 15 receptors as well as good chemical and enzymatic stability in human plasma. An in vivo evaluation evidenced that trans-(+)-1d, in contrast to trans-(-)-1d, cis-(+)-1d, or cis-(-)-1d, which behave as σ1 antagonists, exhibited a σ1 agonist profile. These data clearly demonstrated that compound trans-(+)-1d, due to its σ1 agonist activity and favorable receptor selectivity and stability, provided an useful tool for the study of σ1 receptors.
Asunto(s)
Analgésicos/química , Analgésicos/metabolismo , Ciclopropanos/química , Ciclopropanos/metabolismo , Piperidinas/química , Piperidinas/metabolismo , Receptores sigma/metabolismo , Analgésicos/farmacología , Animales , Ciclopropanos/farmacología , Femenino , Ligandos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Piperidinas/farmacología , Conformación Proteica , Receptores sigma/química , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por Sustrato , Agua/químicaRESUMEN
(−)-cis-N-Normetazocine represents a rigid scaffold able to mimic the tyramine moiety of endogenous opioid peptides, and the introduction of different N-substituents influences affinity and efficacy of respective ligands at MOR (mu opioid receptor), DOR (delta opioid receptor), and KOR (kappa opioid receptor). We have previously identified LP1, a MOR/DOR multitarget opioid ligand, with an N-phenylpropanamido substituent linked to (−)-cis-N-Normetazocine scaffold. Herein, we report the synthesis, competition binding and calcium mobilization assays of new compounds 10â»16 that differ from LP1 by the nature of the N-substituent. In radioligand binding experiments, the compounds 10â»13, featured by an electron-withdrawing or electron-donating group in the para position of phenyl ring, displayed improved affinity for KOR (Ki = 0.85â»4.80 μM) in comparison to LP1 (7.5 μM). On the contrary, their MOR and DOR affinities were worse (Ki = 0.18â»0.28 μM and Ki = 0.38â»1.10 μM, respectively) with respect to LP1 values (Ki = 0.049 and 0.033 μM). Analogous trends was recorded for the compounds 14â»16, featured by indoline, tetrahydroquinoline, and diphenylamine functionalities in the N-substituent. In calcium mobilization assays, the compound 10 with a p-fluorophenyl in the N-substituent shared the functional profile of LP1 (pEC50MOR = 7.01), although it was less active. Moreover, the p-methyl- (11) and p-cyano- (12) substituted compounds resulted in MOR partial agonists and DOR/KOR antagonists. By contrast, the derivatives 13â»15 resulted as MOR antagonists, and the derivative 16 as a MOR/KOR antagonist (pKBMOR = 6.12 and pKBKOR = 6.11). Collectively, these data corroborated the critical role of the N-substituent in (−)-cis-N-Normetazocine scaffold. Thus, the new synthesized compounds could represent a template to achieve a specific agonist, antagonist, or mixed agonist/antagonist functional profile.
RESUMEN
This contribution reports the synthesis and evaluation of novel hybrid compounds that conjugate a sigma (σ) receptor pharmacophore and a nitric oxide (NO) photodonor. All compounds preserve their capability to generate NO under visible light and possess overall σ receptor nanomolar affinity, with one of them (8b) exhibiting remarkable σ2 receptor selectivity. Compounds 8b, 11a, and 11b were tested on tumorigenic MCF-7 and A2058 cells expressing high levels of σ2 and σ1 receptor, respectively. Considerable loss of cell viability was detected under light excitation, while negligible effects in the dark were detected. Moreover, they did not show any significant cytotoxicity in the dark or under irradiation on nontumorigenic NCTC-2544 keratinocytes. NO-induced reduction of cellular viability was demonstrated by in-cell NO detection and total nitrite estimation. For the first time, a combination of σ receptor moieties and a NO photodonor is reported, providing distinctive ligands potentially useful for cancer management.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Donantes de Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Receptores sigma/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Luz , Células MCF-7 , Neoplasias/metabolismo , Óxido Nítrico/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Nowadays sigma-1 receptors are considered as new therapeutic objectives for central nervous system neurodegenerative diseases. Among different molecules, alpha lipoic acid has been identified as a natural potent antioxidant drug, whose therapeutic efficacy is limited by its many drawbacks, such as fast metabolism, poor bioavailability and high physico-chemical instability. Alfa-lipoic acid derivatives have been recently developed demonstrating their neuroprotective activity and effectiveness in different types of oxidative stress. In this work, two derivatives containing an amide or an ester functional group with different lipophilicity, were selected for their important affinity for sigma-1 receptors. Herein, in order to improve the in vitro stability and antioxidant effectiveness of alpha-lipoic acid derivatives, we focused our efforts in the nanoencapsulation strategies. Aqueous-core nanocapsules for the delivery of the hydrophilic compound and nanostructured lipid carrier for the lipophilic derivative, were properly designed and prepared using a direct or inverse eco-friendly organic solvent-free procedure. All nanosystems were characterized in terms of mean size, polydispersity, stability, morphology, encapsulation efficiency and in vitro release profiles. In order to evaluate the nanocarriers biocompatibility and antioxidant effectiveness, in vitro biological studies (cell viability, total antioxidant capacity and total oxidative status) were developed on primary human whole blood cell cultures, on both unloaded and derivatives-loaded nanodevices.
Asunto(s)
Antioxidantes/farmacología , Linfocitos/efectos de los fármacos , Nanocápsulas/química , Fármacos Neuroprotectores/farmacología , Ácido Tióctico/farmacología , Adulto , Antioxidantes/química , Antioxidantes/metabolismo , Supervivencia Celular/efectos de los fármacos , Composición de Medicamentos/métodos , Tecnología Química Verde , Humanos , Linfocitos/citología , Masculino , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/metabolismo , Tamaño de la Partícula , Cultivo Primario de Células , Unión Proteica , Receptores sigma/metabolismo , Ácido Tióctico/química , Ácido Tióctico/metabolismo , Receptor Sigma-1RESUMEN
BACKGROUND: Sigma-1 receptors (σ1R) are highly expressed in neurons as well as microglia and have been shown to modulate the inflammatory response in the central nervous system and thus may serve as possible target for neuroprotective strategies. The aim of the present study was to test the effect of (+)-pentazocine, a putative σ 1R agonist, in an in vitro model of microglia activation. METHODS: Microglia (BV2 cells) was exposed (3h) to 1% oxygen and reoxygenation was allowed for 24h. Cells were treated with different concentrations (1, 10, 25 and 50µM) of (+)-pentazocine in the presence or absence of NE-100 (1µM), a well established σ1R antagonist. Cell viability and apoptosis were measured by cytofluorimetric analysis, whereas oxidative stress was evaluated by reduced glutathione (GSH) content and mitochondrial potential analysis. RESULTS: Our results showed that (+)-pentazocine was able to increase cell viability and restore mitochondrial potential at all concentrations whereas only 1 and 10µM were able to reduce significantly apoptotic cell death, to restore reduced glutathione intracellular content and prevent ERK1/2 phosphorylation. All these effects were abolished by concomitant treatment with NE-100. CONCLUSIONS: (+)-pentazocine exhibits significant dose dependent protective effects in our in vitro model of microglial activation thus suggesting that σ1R may represent a possible target for neuroprotection.
Asunto(s)
Apoptosis/efectos de los fármacos , Hipoxia/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Estrés Oxidativo/efectos de los fármacos , Pentazocina/administración & dosificación , Receptores sigma/agonistas , Animales , Anexina A5/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Glutatión/metabolismo , Hipoxia/fisiopatología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Microglía/fisiología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Receptor Sigma-1RESUMEN
(±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Células Endoteliales/efectos de los fármacos , Haloperidol/farmacología , Microvasos/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Retina/citología , Ácido Valproico/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Endoteliales/citología , Haloperidol/síntesis química , Haloperidol/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Ácido Valproico/síntesis química , Ácido Valproico/químicaRESUMEN
As an extension of our studies, novel indole derivatives were rationally designed and synthesized as ligands targeted to GluN2B/NMDA receptors. The 2-(4-benzylpiperidin-1-yl)-1-(6-hydroxy-1H-indol-3-yl)ethanone (4i) and 1-(4-benzylpiperidin-1-yl)-2-(6-hydroxy-1H-indol-3-yl)ethane-1,2-dione (6i) showed high binding affinity in [3H]ifenprodil displacement assay. By computational studies, we suggested the hypothetical interactions playing a significant role during the binding process. However, in functional and in vivo studies the most potent compound 4i did not show any activity whereas it displayed relevant affinity toward the σ2 receptor.
Asunto(s)
Anticonvulsivantes/síntesis química , Indoles/síntesis química , Piperidinas/síntesis química , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Sitios de Unión , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Ligandos , Ratones , Ratones Endogámicos DBA , Modelos Moleculares , Técnicas de Placa-Clamp , Piperidinas/química , Piperidinas/farmacología , Ensayo de Unión Radioligante , Receptores Opioides delta/metabolismo , Relación Estructura-ActividadRESUMEN
The enantiomers of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (+/-)-PPCC], a selective sigma ligand, were synthesized. The (+)- and (-)-enantiomers bind predominantly to sigma(1) receptors and have a reduced sigma(2) affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on kappa opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly sigma(1) agonist activity and that they have neuroprotective effects.