RESUMEN
Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress.
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Ansiedad , Indenos , Melatonina , Derrota Social , Estrés Psicológico , Animales , Indenos/farmacología , Ratones , Masculino , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Melatonina/farmacología , Ansiedad/tratamiento farmacológico , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/agonistas , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/metabolismo , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/psicología , Trastornos por Estrés Postraumático/metabolismoRESUMEN
Haloperidol decanoate (HD) has been implicated in cognitive impairment. Agomelatine (AGO) has been claimed to improve cognition. We aimed at investigating the effects of HD + low- or high-dose AGO on cognition, verifying the melatonergic/dopaminergic to the cholinergic hypothesis of cognition and exploring relevant cardiovascular issues in adult male Wistar albino rats. HD + high-dose AGO prolonged the step-through latency by +61.47% (P < 0.0001), increased the time spent in bright light by +439.49% (P < 0.0001), reduced the time spent in dim light by -66.25% (P < 0.0001), and increased the percent of alternations by +71.25% (P < 0.0001), despite the reductions in brain acetylcholine level by -10.67% (P < 0.0001). Neurodegeneration was minimal, while the mean power frequency of the source wave was reduced by -23.39% (P < 0.05). Concurrently, the relative expression of brain melatonin type 2 receptors was reduced by -18.75% (P < 0.05), against increased expressions of dopamine type 5 receptors by +22.22% (P < 0.0001) and angiopoietin-like 4 by +119.18% (P < 0.0001). Meanwhile, electrocardiogram (ECG) demonstrated inverted P wave, reduced P wave duration by -36.15% (P < 0.0001) and PR interval by -19.91% (P < 0.0001), prolonged RR interval by +27.97% (P < 0.05), increased R wave amplitude by +523.15% (P < 0.0001), and a depressed ST segment and inverted T wave. In rats administered AGO, HD, or HD+ low-dose AGO, Alzheimer's disease (AD)-like neuropathologic features were more evident, accompanied by extensive ECG and neurochemical alterations. HD + high-dose AGO enhances cognition but alters cardiac electrophysiology. SIGNIFICANCE STATEMENT: Given the issue of cognitive impairment associated with HD and the claimed cognitive-enhancing activity of AGO, combined high-dose AGO with HD improved cognition of adult male rats, who exhibited minimal neurodegenerative changes. HD+ high-dose AGO was relatively safe regarding triggering epileptogenesis, while it altered cardiac electrophysiology. In the presence of low acetylcholine, the melatonergic/dopaminergic hypothesis, added to angiopoietin-like 4 and Krüppel-like factor 9, could offer some clue, thus offering novel targets for pharmacologic manipulation of cognition.
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Acetamidas , Cognición , Haloperidol , Ratas Wistar , Receptor de Melatonina MT2 , Animales , Masculino , Haloperidol/farmacología , Ratas , Cognición/efectos de los fármacos , Acetamidas/farmacología , Acetamidas/administración & dosificación , Receptor de Melatonina MT2/metabolismo , Receptor de Melatonina MT2/agonistas , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Corazón/efectos de los fármacos , Relación Dosis-Respuesta a Droga , NaftalenosRESUMEN
The search for melatonin receptor agonists formed the main part of melatonin medicinal chemistry programs for the last three decades. In this short review, we summarize the two main aspects of these programs: the development of all the necessary tools to characterize the newly synthesized ligands at the two melatonin receptors MT1 and MT2, and the medicinal chemist's approaches to find chemically diverse ligands at these receptors. Both strategies are described. It turns out that the main source of tools were industrial laboratories, while the medicinal chemistry was mainly carried out in academia. Such complete accounts are interesting, as they delineate the spirits in which the teams were working demonstrating their strength and innovative character. Most of the programs were focused on nonselective agonists and few of them reached the market. In contrast, discovery of MT1-selective agonists and melatonergic antagonists with proven in vivo activity and MT1 or MT2-selectivity is still in its infancy, despite the considerable interest that subtype selective compounds may bring in the domain, as the physiological respective roles of the two subtypes of melatonin receptors, is still poorly understood. Poly-pharmacology applications and multitarget ligands have also been considered.
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Receptor de Melatonina MT2 , Ligandos , Humanos , Animales , Receptor de Melatonina MT2/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/antagonistas & inhibidores , Receptores de Melatonina/metabolismo , Receptores de Melatonina/agonistas , Melatonina/metabolismo , Historia del Siglo XXRESUMEN
Alterations in circadian sleep patterns constitute a salient manifestation in major depressive disorder. GW117, an emergent antidepressant, functions as an agonist for melatonin 1 and melatonin 2 (MT1/MT2) receptors, in tandem with antagonism of the serotonin (5-HT) 2C receptor. The present investigation is dedicated to elucidating the role and underlying mechanisms by which GW117 ameliorates circadian sleep disruptions. Utilizing an adapted chronic unpredictable mild stress protocol, we induced a depressive-like phenotype and perturbed circadian rhythms in rodent models. Our methodological approach integrated quantitative polymerase chain reaction (qPCR) in real-time, enzyme-linked immunosorbent assay (ELISA), and immunoblotting techniques to probe alterations in the expression of core circadian genes and homeostatic sleep markers. The impact of GW117 was assessed across various dosages (10, 20, and 40 mg/kg) on these molecular signatures. In a parallel examination, we evaluated the influence of GW117 (administered at 15, 40, and 60 mg/kg) on the sleep patterns of healthy mice. The results showed that GW117 significantly improved sleep-wake circadian rhythms, altered sleep architecture, and shortened sleep latency. Furthermore, GW117 increased the expression of several clock genes in the hypothalamus of chronic unpredictable mild stress model rats and normal mice. It also regulated circadian biomarkers, including melatonin and cortisol. Based on our findings, we propose that the beneficial effects of GW117 on sleep rhythms may be due to the melatonin system-mediated activation of the Wnt/ß-catenin signaling pathway.
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Trastorno Depresivo Mayor , Melatonina , Ratas , Animales , Ratones , Trastorno Depresivo Mayor/tratamiento farmacológico , Melatonina/uso terapéutico , Sueño , Ritmo Circadiano , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Serotonina/farmacología , Compuestos OrgánicosRESUMEN
The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT1 and MT2, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT1 receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT1 receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT1 receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT1 receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT1 rs2165666 variant. Overall, this work lends support to the potentiality of MT1 receptors as target for the treatment of BD.
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Trastorno Bipolar , Melatonina , Psicofarmacología , Humanos , Ratones , Animales , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Melatonina/uso terapéutico , Melatonina/farmacología , Receptor de Melatonina MT1/genética , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/agonistasRESUMEN
Melatonin is a human neurotransmitter and plant signalling metabolite that perceives and directs plant metabolism. The mechanisms of melatonin action in plants remain undefined. We hypothesized that roots have a melatonin-specific receptor and/or transporter that can respond to melatonin-mediating pharmaceuticals. To test this hypothesis Arabidopsis seedlings were grown with melatonin pharmaceutical receptor agonists: ramelteon and tasimelteon, and/or antagonists: luzindole and 4-P-PDOT. Ramelteon was found both to mimic and competitively inhibit melatonin metabolism in plants. Due to the higher selectivity of ramelteon for the MT1 receptor type in humans, a sequence homology search for MT1 in Arabidopsis identified the rhomboid-like protein 7 (RBL7). In physiological studies, Arabidopsis rbl7 mutants were less responsive to ramelteon and melatonin. Quantum dot visualizations of the effects of ramelteon on melatonin binding to root cell membranes revealed a potential mechanism. We propose that RBL7 is a melatonin-interacting protein that directs root architecture and growth in a mechanism that is responsive to environmental factors.
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Arabidopsis , Melatonina , Animales , Arabidopsis/genética , Arabidopsis/metabolismo , Humanos , Mamíferos/metabolismo , Melatonina/farmacología , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/metabolismoRESUMEN
Melatonin is crucial in reproduction due its antioxidant, hormonal, and paracrine action. Melatonin membrane receptors (MT1/MT2) have been confirmed on spermatozoa from several species, but functionality studies are scarce. To clarify their role in ruminants as reproductive models, bull (Bos taurus, non-seasonal) and red deer (Cervus elaphus, highly seasonal) spermatozoa were analyzed after 4 h of incubation (38 °C, capacitating media) in 10 nM melatonin, MT1/MT2 agonists (phenylmelatonin and 8M-PDOT), and antagonists (luzindole and 4P-PDOT). Motility and functionality (flow cytometry: viability, intracellular calcium, capacitation status, reactive oxygen species (ROS) production, and acrosomal and mitochondrial status) were assessed. In bull, MT1 was related to sperm viability preservation, whereas MT2 could modulate cell functionality to prevent excess ROS produced by the mitochondria; this action could have a role in modulating sperm capacitation. Deer spermatozoa showed resistance to melatonin and receptor activation, possibly because the samples were of epididymal origin and collected at the breeding season's peak, with high circulating melatonin. However, receptors could be involved in mitochondrial protection. Therefore, melatonin receptors are functional in the spermatozoa from bull and deer, with different activities. These species offer models differing from traditional laboratory experimental animals on the role of melatonin in sperm biology.
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Ciervos , Melatonina , Animales , Bovinos , Masculino , Melatonina/farmacología , Especies Reactivas de Oxígeno , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Receptores de Melatonina , Estaciones del Año , Espermatozoides/fisiologíaRESUMEN
INTRODUCTION: The neurohormone melatonin (N-acetyl-5-methoxytryptamine) regulates circadian rhythms exerting a variety of effects in the central nervous system and in periphery. These activities are mainly mediated by activation of MT1 and MT2 GPCRs. MT1/MT2 agonist compounds are used clinically for insomnia, depression, and circadian rhythm disturbances. AREA COVERED: The following review describes the design strategies that have led to the identification of melatonin receptor ligands, guided by in silico approaches and molecular modeling. Initial ligand-based design, mainly relying on pharmacophore modeling and 3D-QSAR, has been flanked by structure-based virtual screening, given the recent availability of MT1 and MT2 crystal structures. Receptor ligands with different activity profiles, agonist/antagonist and subtype-selective compounds, are available. EXPERT OPINION: An insight on the pharmacological characterization and therapeutic perspectives for relevant ligands is provided. In silico drug discovery has been instrumental in the design of novel ligands targeting melatonin receptors. Ligand-based approaches has led to the construction of a solid framework defining structure-activity relationships to obtain compounds with a tailored pharmacological profile. Structure-based techniques could integrate previous knowledge and provide compounds with novel chemotypes and pharmacological activity as drug candidates for disease conditions in which melatonin receptor ligands are currently being investigated, including cancer and pain.
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Melatonina , Receptor de Melatonina MT1 , Descubrimiento de Drogas , Humanos , Ligandos , Melatonina/farmacología , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistasRESUMEN
The effects of the neurohormone melatonin are mediated by the activation of the GPCRs MT1 and MT2 in a variety of tissues. Crystal structures suggest ligand access to the orthosteric binding site of MT1 and MT2 receptors through a lateral channel between transmembrane (TM) helices IV and V. We investigated the feasibility of this lipophilic entry route for 2-iodomelatonin, a nonselective agonist with a slower dissociation rate from the MT2 receptor, applying enhanced sampling simulations and free-energy calculations. 2-Iodomelatonin unbinding was investigated with steered molecular dynamics simulations which revealed different trajectories passing through the gap between TM helices IV and V for both receptors. For one of these unbinding trajectories from the MT1 receptor, an umbrella-sampling protocol with path-collective variables provided a calculated energy barrier consistent with the experimental dissociation rate. The side-chain flexibility of Tyr5.38 was significantly different in the two receptor subtypes, as assessed by metadynamics simulations, and during ligand unbinding it frequently assumes an open conformation in the MT1 but not in the MT2 receptor, favoring 2-iodomelatonin egress. Taken together, our simulations are consistent with the possibility that the gap between TM IV and V is a way of connecting the orthosteric binding site and the membrane core for lipophilic melatonin receptor ligands. Our simulations also suggest that the open state of Tyr5.38 generates a small pocket on the surface of MT1 receptor, which could participate in the recognition of MT1-selective ligands and may be exploited in the design of new selective compounds.
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Receptor de Melatonina MT2 , Sitios de Unión , Ligandos , Unión Proteica , Estructura Secundaria de Proteína , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/metabolismo , Receptores de Melatonina/metabolismoRESUMEN
Tissue injury healing is impaired in aging, and this impairment is caused in part by reduced angiogenesis. Melatonin, a neuroendocrine hormone that regulates sleep and circadian rhythm, is also produced in the gastrointestinal tract. The expression of melatonin receptors MT1 and MT2 in gastric endothelial cells and their roles in aging-related impairment of gastric angiogenesis have not been examined. We hypothesized that MT1 and MT2 expression is reduced in gastric endothelial cells of aging rats and that melatonin treatment can upregulate their expression and improve angiogenesis. We examined the expression of MT1 and MT2 in gastric endothelial cells (GECs) isolated from young and aging rats. We also examined the effects of melatonin treatment on angiogenesis, GEC mitochondrial function, expression of vascular endothelial growth factor (VEGF), its signaling receptor (VEGFR-2), and the inhibitor of apoptosis protein, survivin. Young and aging GECs expressed MT1 (in the cytoplasm and mitochondria) and MT2 (in nucleus and mitochondria). In aging GECs, MT1 and MT2 levels, in vitro angiogenesis, and mitochondrial membrane potential were significantly reduced (by 1.5-fold, 1.9-fold, 3.1-fold, and 1.63-fold, respectively) compared with young GECs. Melatonin treatment of aging GECs significantly increased MT1 and MT2 expression compared with the controls, induced nuclear translocation of MT1, and significantly ameliorated the aging-related impairment of angiogenesis and mitochondrial function. Aging GECs have significantly reduced MT1 and MT2 expression, angiogenesis, and mitochondrial membrane potential compared with young GECs. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function.NEW & NOTEWORTHY This study showed reduced expression of melatonin receptors MT1 and MT2, angiogenesis, and mitochondrial function in gastric endothelial cells (GECs) isolated from aging rats. Treatment of aging GECs with melatonin increases expression of VEGF receptor and survivin and ameliorates aging-related impaired angiogenesis and mitochondrial function. These studies provide new insight into the mechanisms of the aging-related impairment of angiogenesis and delayed tissue injury healing and provide a rationale for melatonin treatment to reverse these abnormalities.
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Inductores de la Angiogénesis/farmacología , Células Endoteliales/efectos de los fármacos , Mucosa Gástrica/irrigación sanguínea , Melatonina/farmacología , Mitocondrias/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Survivin/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factores de Edad , Animales , Células Cultivadas , Células Endoteliales/metabolismo , Mitocondrias/metabolismo , Ratas Endogámicas F344 , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/metabolismo , Transducción de SeñalRESUMEN
AIMS: To evaluate the antidepressant-like effect of compound GW117 in rodents using in vitro binding and uptake assays as well in vivo behavioral tests. METHODS: We investigated the target profile of GW117 using [35 S]-GTPγS and [3 H]PIP binding. Using the forced swimming test and chronic unpredictable stress in rats, tail suspension test in mice and rats, and learned helplessness model in mice, we further revealed the antidepressant-like and anxiolytic-like effects of GW117. RESULTS: The current study suggests that GW117 displays serotonin 2C (5-HT2C ) receptor antagonist and melatonin type 1 and 2 (MT1 /MT2 ) receptor agonist properties, as well as evident antidepressant and anxiolytic effects. CONCLUSION: These data suggest that GW117 is probably a potent antidepressant.
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Ansiolíticos/farmacología , Antidepresivos/farmacología , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Antagonistas del Receptor de Serotonina 5-HT2 , Animales , Desamparo Adquirido , Suspensión Trasera , Masculino , Ratones , Ratones Endogámicos ICR , Compuestos Orgánicos/farmacología , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/farmacologíaRESUMEN
Based on our previous study in follicles, the first aim of this work was to evaluate the effect of melatonin in the swine corpus luteum (CL). Luteal cells were exposed to 10 and 20pg mL-1 melatonin. We evaluated the effect on proliferation (bromo-deoxy-uridine uptake), steroidogenesis (progesterone) and redox status by means of Griess test (nitric oxide production), WST-1 test (superoxide anion generation) and FRAP test (non-enzymatic antioxidant power). The results showed a significant increase in antioxidant power, as well as a reduction in the other parameters analysed. These data and the expression of MT2 observed in luteal cells allow us to hypothesise a physiological role of melatonin in the regulation of CL functionality. The reproductive function is dependent on energy reserves stored in adipose tissue. Therefore, we sought to verify the effect of melatonin on adipose stromal cells (ASCs). MT2 receptor expression was detected in ASCs and the presence of gene markers (PPARγ and leptin) before and after adipogenic differentiation was verified. The differentiation was significantly inhibited by melatonin, as well as cell viability. In conclusion, present results suggest that melatonin exerts a potential inhibitory action on luteal function and adipogenesis, possibly mediated by MT2.
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Tejido Adiposo/efectos de los fármacos , Cuerpo Lúteo/efectos de los fármacos , Melatonina/farmacología , Células del Estroma/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cuerpo Lúteo/citología , Cuerpo Lúteo/metabolismo , Femenino , Leptina/metabolismo , Óxido Nítrico/metabolismo , Oxidación-Reducción , PPAR gamma/metabolismo , Progesterona/biosíntesis , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismo , Células del Estroma/metabolismo , Sus scrofaRESUMEN
The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.
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Acetamidas/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Bencimidazoles/uso terapéutico , Hígado Graso/tratamiento farmacológico , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Acetamidas/síntesis química , Acetamidas/farmacocinética , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Compuestos de Bencidrilo/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Dieta Alta en Grasa , Diseño de Fármacos , Hígado Graso/patología , Glucósidos/farmacología , Hígado/patología , Masculino , Ratones , Estructura Molecular , Obesidad/tratamiento farmacológico , Ratas Sprague-Dawley , Ratas Wistar , Relación Estructura-Actividad , Triglicéridos/metabolismoRESUMEN
Sleep disorders adversely affect daily activities and cause physiological and psychiatric problems. The shortcomings of benzodiazepine hypnotics have led to the development of ramelteon, a melatonin MT1 and MT2 agonist. Although the sleep-promoting effects of ramelteon have been documented, few studies have precisely investigated the structure of sleep and neural oscillatory activities. In this study, we recorded electrocorticograms in the primary motor cortex, the primary somatosensory cortex and the olfactory bulb as well as electromyograms in unrestrained rats treated with either ramelteon or vehicle. A neural-oscillation-based algorithm was used to classify the behavior of the rats into three vigilance states (e.g., awake, rapid eye movement (REM) sleep, and non-REM (NREM) sleep). Moreover, we investigated the region-, frequency- and state-specific modulation of extracellular oscillations in the ramelteon-treated rats. We demonstrated that in contrast to benzodiazepine treatment, ramelteon treatment promoted NREM sleep and enhanced fast gamma power in the primary motor cortex during NREM sleep, while REM sleep was unaffected. Gamma oscillations locally coordinate neuronal firing, and thus, ramelteon modulates neural oscillations in sleep states in a unique manner and may contribute to off-line information processing during sleep.
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Ritmo Gamma/efectos de los fármacos , Indenos/farmacología , Corteza Motora/fisiología , Sueño REM/efectos de los fármacos , Sueño REM/fisiología , Animales , Electrocorticografía , Masculino , Ratas Wistar , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistasRESUMEN
Melatonin MT1 and MT2 receptor ligands have been vigorously explored for the last 4 decades. Inspection of approximately 80 publications in the field revealed that most melatonergic ligands were structural analogues of melatonin combining three essential features of the parent compound: an aromatic ring bearing a methoxy group and an amide side chain in a relative arrangement similar to that present in melatonin. While several series of MT2 -selective agents-agonists, antagonists, or partial agonists-were reported, the field was lacking MT1 -selective agents. Herein, we describe various approaches toward the development of melatonergic ligands, keeping in mind that most of the molecules/pharmacophores obtained were essentially melatonin copies, even though diverse tri- or tetra-cyclic compounds were explored. In addition to lack of structural diversity, only few studies examined the activity of the reported melatonergic ligands in vivo. Moreover, an extensive pharmacological characterization including biopharmaceutical stability, pharmacokinetic properties, specificity toward other major receptors to name a few remained scarce. For example, many of the antagonists described were not stable in vivo, were not selective for the melatonin receptor subtype of interest, and were not fully characterized from a pharmacological standpoint. Indeed, virtual screening of large compound libraries has led to the recent discovery of potent and selective melatonin receptor agonists and partial agonists of new chemotypes. Having said this, the melatonergic field is still lacking subtype-selective melatonin receptor antagonists "active" in vivo, which are critical to our understanding of melatonin and melatonin receptors' role in basic physiology and disease.
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Melatonina/química , Receptor de Melatonina MT1 , Receptor de Melatonina MT2 , Animales , Humanos , Ligandos , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/antagonistas & inhibidores , Receptor de Melatonina MT1/química , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/antagonistas & inhibidores , Receptor de Melatonina MT2/químicaRESUMEN
PURPOSE: To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization. MATERIALS AND METHODS: Pubmed (1946 to December 2019) and Embase (1947 to December 2019) were queried using the search term combination: delirium, confusion, cognitive defect, encephalopathy, critically ill patient, critical illness, or hospitalization and suvorexant or orexin receptor antagonist. Studies analyzed for relevance evaluated clinical outcomes of patients treated with suvorexant for prevention of delirium. Studies appropriate to the objective were evaluated, including two randomized controlled trials and four retrospective studies. RESULTS: In acutely hospitalized patients, treatment with suvorexant 15 to 20 mg alone or in combination with ramelteon resulted in a reduction in development of delirium, time until delirium onset, and length of hospital stay. When assessed, suvorexant was well tolerated and adverse effects were no worse than placebo. CONCLUSION: Based on the reviewed literature, suvorexant has shown positive outcomes in the prevention of delirium during an acute hospitalization. Larger trials comparing the efficacy of suvorexant to other sleep modulating options are necessary to further delineate its role for the prevention of delirium.
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Azepinas/administración & dosificación , Azepinas/efectos adversos , Cuidados Críticos/métodos , Delirio/prevención & control , Tiempo de Internación , Antagonistas de los Receptores de Orexina/administración & dosificación , Antagonistas de los Receptores de Orexina/efectos adversos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Triazoles/administración & dosificación , Triazoles/efectos adversos , Anciano , Anciano de 80 o más Años , Enfermedad Crítica , Quimioterapia Combinada , Femenino , Humanos , Indenos/administración & dosificación , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Estudios Retrospectivos , Sueño/efectos de los fármacos , Resultado del TratamientoRESUMEN
Previous studies have shown that melatonin (Mel) can effectively ameliorate myocardial ischemia/reperfusion (MI/R) injury, but the mechanism is yet to be fully elucidated. Mel receptors are expressed in the paraventricular nucleus (PVN), which is also involved in regulating cardiac sympathetic nerve activity. The aim of this study was to examine whether Mel receptors in the PVN are involved in the protective effects of Mel against MI/R injury. The results of quantitative polymerase chain reaction, western blot, and immunofluorescence assays indicated that Mel receptor 2 (MT2) expression in the PVN was upregulated after MI/R. Intraperitoneal administration of Mel significantly improved post-MI/R cardiac function and reduced the infarct size, whereas shRNA silencing of MT2 in the PVN partially blocked this effect. Intraperitoneal administration of Mel reduced sympathetic nerve overexcitation caused by MI/R, whereas shRNA silencing of MT2 in the PVN partially diminished this effect. Furthermore, enzyme-linked immunosorbent assay and western blot results indicated that intraperitoneal administration of Mel lowered the levels of inflammatory cytokines in the PVN after MI/R injury, whereas the application of sh-MT2 in the PVN reduced this effect of Mel. Mel significantly reduced the levels of NF-κB after astrocyte oxygen and glucose deprivation/reoxygenation injury, and this effect was offset when MT2 was silenced. The above experimental results suggest that MT2 in the PVN partially mediated the protective effects of Mel against MI/R injury, and its underlying mechanisms may be related to postactivation amelioration of PVN inflammation and reduction of cardiac sympathetic nerve overexcitation.
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Astrocitos/efectos de los fármacos , Corazón/inervación , Melatonina/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/patología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Receptor de Melatonina MT2/agonistas , Sistema Nervioso Simpático/fisiopatología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Hipoxia de la Célula , Células Cultivadas , Modelos Animales de Enfermedad , Glucosa/deficiencia , Masculino , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/patología , Núcleo Hipotalámico Paraventricular/fisiopatología , Receptor de Melatonina MT2/genética , Receptor de Melatonina MT2/metabolismo , Transducción de SeñalRESUMEN
PURPOSE: The melatonin receptor (MT) agonist ramelteon has a higher affinity to MT1 than for MT2 receptors and induces cardioprotection by involvement of mitochondrial potassium channels. Activation of mitochondrial potassium channels leads to release of free radicals. We investigated whether (1) ramelteon-induced cardioprotection is MT2 receptor specific and (2) if free radicals are involved in ramelteon-induced cardioprotection. METHODS: Hearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia hearts were perfused with ramelteon (Ram) with or without the MT2 receptor inhibitor 4-phenyl-2-propionamidotetralin (4P-PDOT+Ram, 4P-PDOT). In subsequent experiments, ramelteon was administered together with the radical oxygen species (ROS) scavenger N-2-mercaptopropionylglycine (MPG+Ram). To determine whether the blockade of ramelteon-induced cardioprotection can be restored, we combined ramelteon and MPG with mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A (CsA) at different time points. Infarct size was determined by triphenyltetrazolium chloride (TTC) staining. RESULTS: Ramelteon-induced infarct size reduction was completely blocked by 4P-PDOT and MPG. Ramelteon and MPG combined with CsA before ischemia were not cardioprotective but CsA at the onset of reperfusion could restore infarct size reduction. CONCLUSIONS: This study shows for the first time that despite the higher affinity to MT1 receptors, (1) ramelteon-induced cardioprotection involves MT2 receptors, (2) cardioprotection requires ROS release, and (3) inhibition of the mPTP can restore infarct size reduction.
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Fármacos Cardiovasculares/farmacología , Indenos/farmacología , Mitocondrias Cardíacas/efectos de los fármacos , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Receptor de Melatonina MT2/agonistas , Animales , Modelos Animales de Enfermedad , Preparación de Corazón Aislado , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas Wistar , Receptor de Melatonina MT2/metabolismo , Transducción de Señal , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Melatonin receptors MT1 and MT2 are involved in synchronizing circadian rhythms and are important targets for treating sleep and mood disorders, type-2 diabetes and cancer. Here, we performed large scale structure-based virtual screening for new ligand chemotypes using recently solved high-resolution 3D crystal structures of agonist-bound MT receptors. Experimental testing of 62 screening candidates yielded the discovery of 10 new agonist chemotypes with sub-micromolar potency at MT receptors, with compound 21 reaching EC50 of 0.36 nM. Six of these molecules displayed selectivity for MT2 over MT1. Moreover, two most potent agonists, including 21 and a close derivative of melatonin, 28, had dramatically reduced arrestin recruitment at MT2, while compound 37 was devoid of Gi signaling at MT1, implying biased signaling. This study validates the suitability of the agonist-bound orthosteric pocket in the MT receptor structures for the structure-based discovery of selective agonists.
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Descubrimiento de Drogas/métodos , Receptores de Melatonina/agonistas , Sitios de Unión , Evaluación Preclínica de Medicamentos/métodos , Humanos , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Relación Estructura-ActividadRESUMEN
The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle1-4. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep5,6 and depression1-4,7-9. Despite their importance, few in vivo active MT1-selective ligands have been reported2,8,10-12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.