RESUMEN
PURPOSE: Natural plant raw materials, previously underestimated in therapeutics, are becoming the subject of research for new applications in medicine. In our research, the hydroalcoholic extract of Isatis tinctoria leaf, rich in flavonoid compounds such as vicenin-2 and quercetin, was examined as a potential antidiabetic and neuroprotective agent. METHODS: The effect of the extract and its main flavonoid compounds on protein glycation, alpha-glucosidase activity, and acetylcholinesterase activity was tested. In vitro, in the mouse hippocampal neuronal cell line and in vivo, using a mouse model, the safety of the extract was screened for. RESULTS: Our experiments demonstrated significant inhibition of protein glycation, alpha-glucosidase activity, acetylcholinesterase activity, and ß-amyloid aggregation by the extract, in a concentration-dependent manner. The extract had a strong reducing effect and did not exhibit cytotoxicity up to a concentration of 25 mg/mL. Intraperitoneal administration of the extract to mice did not have negative effects on body mass, locomotor activity, coordination, and liver cell integrity. CONCLUSIONS: Our research sheds new light on this raw material and deepens knowledge of its activity. This may result in the recognition of its therapeutic effects and even in its introduction in the modern treatment of diseases characterized by pathological changes associated with hyperglycemia, oxidation, and inflammation.
Asunto(s)
Hipoglucemiantes , Fármacos Neuroprotectores , Extractos Vegetales , Hojas de la Planta , Animales , Extractos Vegetales/farmacología , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/aislamiento & purificación , Hipoglucemiantes/farmacología , Hojas de la Planta/química , Masculino , Línea Celular , Péptidos beta-Amiloides , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Acetilcolinesterasa/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Inhibidores de Glicósido Hidrolasas/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , alfa-Glucosidasas/metabolismoRESUMEN
In light of the biological targets alterations in dementia patients suffering from neuropsychiatric symptoms, particularly in the 5-HT6 receptor and SERT transporters, this study aimed to develop dual-acting molecules targeting both these targets. By combining a 5-substituted indole with piperazine scaffolds, we synthesized molecules with nanomolar affinities for these sites, avoiding interaction with off-targets detrimental to dementia patients. Preliminary pharmacodynamic and ADMET assays let the identification of compound 15 as a lead molecule. In vitro studies showed that 15 provided neuroprotection against Aß toxicity and reduced the levels of proapoptotic enzymes: caspase 3 and 7. In vivo, 15 reversed MK-801-induced memory deficits and exhibited antidepressant-like effects. Further studies showed that acute administration of compound 15 at a dose of 5 mg/kg increased BDNF levels, which are crucial for supporting neuronal survival and potentially slowing cognitive decline in dementia. These findings suggest 15's potential as a therapeutic for behavioral and psychological symptoms of dementia (BPSD), warranting further investigation.
Asunto(s)
Péptidos beta-Amiloides , Antidepresivos , Demencia , Fármacos Neuroprotectores , Receptores de Serotonina , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Animales , Humanos , Masculino , Ratones , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Antidepresivos/farmacología , Antidepresivos/química , Antidepresivos/síntesis química , Demencia/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Ligandos , Memoria/efectos de los fármacos , Estructura Molecular , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Receptores de Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Relación Estructura-Actividad , Maleato de Dizocilpina/química , Maleato de Dizocilpina/farmacologíaRESUMEN
GSK-3ß, IKK-ß, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer's disease due to their involvement in the misfolding and accumulation of amyloid ß (Aß) and tau proteins, as well as inflammatory processes. Among these kinases, GSK-3ß plays the most crucial role. In this study, we present compound 62, a novel, remarkably potent, competitive GSK-3ß inhibitor (IC50 = 8 nM, Ki = 2 nM) that also exhibits additional ROCK-1 inhibitory activity (IC50 = 2.3 µM) and demonstrates anti-inflammatory and neuroprotective properties. Compound 62 effectively suppresses the production of nitric oxide (NO) and pro-inflammatory cytokines in the lipopolysaccharide-induced model of inflammation in the microglial BV-2 cell line. Furthermore, it shows neuroprotective effects in an okadaic-acid-induced tau hyperphosphorylation cell model of neurodegeneration. The compound also demonstrates the potential for further development, characterized by its chemical and metabolic stability in mouse microsomes and fair solubility.
Asunto(s)
Enfermedad de Alzheimer , Glucógeno Sintasa Quinasa 3 beta , Quinasa I-kappa B , Tiazoles , Quinasas Asociadas a rho , Proteínas tau , Proteínas tau/metabolismo , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Tiazoles/farmacología , Tiazoles/química , Humanos , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo , Ratones , Quinasa I-kappa B/metabolismo , Quinasa I-kappa B/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Línea Celular , Antiinflamatorios/farmacología , Antiinflamatorios/química , Microglía/efectos de los fármacos , Microglía/metabolismo , Óxido Nítrico/metabolismo , Lipopolisacáridos , Agregado de Proteínas/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismoRESUMEN
In the text, the synthesis and characteristics of the novel ONS-type vanadium (V) complexes with thioanilide derivatives of amino acids are described. They showed the inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1, and SHP2) in the submicromolar range, as well as the inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxidovanadium(IV) (BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, including also glucose utilizatiand ONO Complexes are Inhibitors ofon in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.
RESUMEN
Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT6R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT6R affinity and selectivity over 5-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (13). Compound 15 displayed high selectivity for 5-HT6R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.
Asunto(s)
Enfermedad de Alzheimer , Fármacos Neuroprotectores , Selenio , Ratas , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Serotonina/uso terapéutico , Ratas Wistar , Neuroprotección , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Receptores de Serotonina , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
Alzheimer's disease (AD), a neurodegenerative disorder with a complex aetiology, is the most common memory dysfunction particularly affecting the elderly. Various protein targets have been classified to be involved in the AD treatment, including 5-HT6 receptor (5-HT6R). So far, the 5-HT6R ligands obtained by our research group have become a good basis for hydrophobicity modulation to give a chance for more effective action toward AD by additional influence on target enzymes, e.g. cyclin-dependent kinase 5 (CDK5). In the search for 5-HT6R agents with additional inhibitory action on the enzyme, a series of 25 new 1,3,5-triazines (7-31) as modifications of lead, 4-[1-(2,5-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (6), was rationally designed. Molecular modelling, synthesis, crystallographic studies, in vitro biological assays and behavioral studies in vivo were performed. The new triazines showed high affinity (Ki < 100 nM) and selectivity for 5-HT6R. The most effective one, 4-[1-(2,5-difluorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (8), exhibited the strong antagonistic action towards 5-HT6R (Ki = 5 nM, pKb = 8.16), had an impact on the memory processes in the Novel Object Recognition test and displayed anxiolytic-like activity in the Elevated Plus Maze test in rats. Moreover, it had the antiplatelet effect as well as very good permeability (PAMPA model), high metabolic stability (RLMs) and satisfactory safety in vitro. Although the CDK5 inhibitory effects in vitro for the tested compounds (8, 10, 14, 18, 26-31) missed the potency expected from in silico simulations, the novel antagonist (8) with a very satisfying pharmacological and ADMET profile can serve as a new lead structure in further searches for innovative therapy against AD with accompanying symptoms.
Asunto(s)
Enfermedad de Alzheimer , Ansiolíticos , Animales , Ratas , Enfermedad de Alzheimer/tratamiento farmacológico , Serotonina , Aminas , MemoriaRESUMEN
Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (Ki < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.
Asunto(s)
Enfermedad de Alzheimer , Calcógenos , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Serotonina , Estructura Molecular , Relación Estructura-Actividad , Receptores de Serotonina/metabolismo , Ligandos , Triazinas/química , Éteres , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Acetilcolinesterasa/metabolismoRESUMEN
The new dual 5HT1A/5HT7 receptor ligands were designed based on the purine-2,6-dione scaffold with the fluorine atom. Twenty-one new derivatives were synthesized, and their structure-activity relationship was summarized. Compound 11 (7-(2-(3-fluorophenyl)-2-oxoethyl)-8-((4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione) showed the highest affinity to 5HT1AR and 5HT7R, and was the most potent antagonist of 5-HT1AR (Kb = 0.26 ± 0.1 nM) which activity can be to reference compound NAN-190 (Kb = 0.26 ± 0.1 nM). The experimentally established physicochemical parameters of compound 11 showed that compound, as slightly ionized in the blood, could penetrate the blood-brain barrier. A molecular docking study showed that the fluorine substitution introduces additional stabilization effects on binding to 5HT1A/5HT7Rs. In animal assays of depression and anxiety, compound 11 revealed activity in terms of dosage compared to marketed psychotropics such as fluoxetine, citalopram, and sertraline.
Asunto(s)
Antidepresivos , Flúor , Animales , Ligandos , Simulación del Acoplamiento Molecular , Antidepresivos/farmacología , Relación Estructura-Actividad , Purinas/químicaRESUMEN
Multitarget drugs based on a hybrid dopamine-xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 receptor (D2R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A2AAR affinity, significant enhancement of PDE-inhibitory and D2R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer's and Parkinson's diseases is warranted.
Asunto(s)
Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Xantina/farmacología , Xantina/uso terapéutico , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/química , Dopamina , Ligandos , Relación Estructura-Actividad , Antagonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A2/química , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Monoaminooxidasa/metabolismo , Dopaminérgicos/farmacologíaRESUMEN
While monoaminergic deficits are evident in all depressed patients, nonresponders are characterized by impaired GABA-ergic signaling and the simultaneous presence of the inflammatory component. Pharmacological agents able to curb pathological immune responses and modulate ineffective GABA-ergic neurotransmission are thought to improve therapeutic outcomes in the treatment-resistant subgroup of depressed patients. Here, we report on a set of dually acting molecules designed to simultaneously modulate GABA-A and 5-HT6 receptor activity. The serotonin 5-HT6 receptor was chosen as a complementary molecular target, due to its promising antidepressant-like activities reported in animal studies. Within the study we identified that lead molecule 16 showed a desirable receptor profile and physicochemical properties. In pharmacological studies, 16 was able to reduce the secretion of proinflammatory cytokines and decrease oxidative stress markers. In animal studies, 16 exerted antidepressant-like activity deriving from a synergic interplay between 5-HT6 and GABA-A receptors. Altogether, the presented findings point to hybrid 16 as an interesting tool that interacts with pharmacologically relevant targets, matching the pathological dysfunction of depression associated with neuroinflammation.
RESUMEN
Modulation of α1ß2γ2GABA-A receptor subpopulation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided compelling evidence for the validity of this strategy, the current chemical space of molecules able to modulate the α1/γ2 interface of the GABA-A receptor is limited to imidazo[1,2-a]pyridine derivatives that undergo rapid biotransformation. In response to a deficiency in the chemical repertoire of GABA-A receptors, we identified a series of 2-(4-fluorophenyl)-1H-benzo[d]imidazoles as positive allosteric modulators (PAMs) with improved metabolic stability and reduced potential for hepatotoxicity, where lead molecules 9 and 23 displayed interesting features in a preliminary investigation. We further disclose that the identified scaffold shows a preference for interaction with the α1/γ2 interface of the GABA-A receptor, delivering several PAMs of the GABA-A receptor. The present work provides useful chemical templates to further explore the therapeutic potential of GABA-A receptor ligands and enriches the chemical space of molecules suitable for the interaction with the α1/γ2 interface.
Asunto(s)
Imidazoles , Receptores de GABA-A , Receptores de GABA-A/metabolismo , Imidazoles/farmacología , Ligandos , Regulación AlostéricaRESUMEN
There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT6 receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT6 receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.
Asunto(s)
Depresión , Serotonina , Humanos , Depresión/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ácido gamma-AminobutíricoRESUMEN
Carbon dots (CDs) are carbon-based zero-dimensional nanomaterials that can be prepared from a number of organic precursors. In this research, they are prepared using fat-free UHT cow milk through the hydrothermal method. FTIR analysis shows C=O and C-H bond presence, as well as nitrogen-based bond like C-N, C=N and -NH2 presence in CDs, while the absorption spectra show the absorption band at 280 ± 3 nm. Next, the Biuret test was performed, with the results showing no presence of unreacted proteins in CDs. It can be said that all proteins are converted in CDs. Photo luminance spectra shows the emission of CDs is 420 nm and a toxicity study of CDs was performed. The Presto Blue method was used to test the toxicity of CDs for murine hippocampal cells. CDs at a concentration of 4 mg/mL were hazardous independent of synthesis time, while the toxicity was higher for lower synthesis times of 1 and 2 h. When the concentration is reduced in 1 and 2 h synthesized CDs, the cytotoxic effect also decreases significantly, ensuring a survival rate of 60-80%. However, when the synthesis time of CDs is increased, the cytotoxic effect decreases to a lesser extent. The CDs with the highest synthesis time of 8 h do not show a cytotoxic effect above 60%. The cytotoxicity study shows that CDs may have a concentration and time-dependent cytotoxic effect, reducing the number of viable cells by 40%.
Asunto(s)
Puntos Cuánticos , Animales , Ratones , Puntos Cuánticos/toxicidad , Puntos Cuánticos/química , Leche , Carbono/toxicidad , Carbono/química , Colorantes Fluorescentes/químicaRESUMEN
Schizophrenia is a chronic mental illness, which remains difficult to treat. A high resistance to the available therapies, their insufficient efficacy, and numerous side effects are the reasons why there is an urgent need to develop new antipsychotics. This study aimed to assess the antipsychotic-like effects of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide, in rodents. First, considering the JJGW08 receptor profile, we investigated the compound's intrinsic activity towards dopamine D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors using functional assays. Next, we assessed the effect of JJGW08 on MK-801- and amphetamine-induced hyperlocomotion, its risk of inducing catalepsy and impairing motor coordination, as well as the anxiolytic-like effects in the four-plate and marble burying tests in mice. Finally, we investigated the antipsychotic-like properties of JJGW08 in rats using MK-801-induced hyperlocomotion and prepulse inhibition tests. We found that JJGW08 showed antagonistic properties at dopamine D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors. However, the effect on the 5-HT2A and 5-HT7 receptors was very weak. Moreover, the tested compound showed an antipsychotic-like effect in MK-801- and amphetamine-induced hyperlocomotion but not in a prepulse inhibition test in rats. Notably, JJGW08 demonstrated anxiolytic-like properties in both behavioral tests. Importantly, the compound did not induce catalepsy or motor coordination impairment in mice at antipsychotic-like doses. Our study suggests it is worth searching for new potential antipsychotics among arylpiperazine alkyl derivatives of salicylamide.
Asunto(s)
Ansiolíticos , Antipsicóticos , Ratas , Ratones , Animales , Antipsicóticos/efectos adversos , Serotonina/efectos adversos , Ansiolíticos/farmacología , Dopamina/efectos adversos , Roedores , Maleato de Dizocilpina/efectos adversos , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Anfetamina/farmacologíaRESUMEN
The µ-opioid receptors belong to the family of G protein-coupled receptors (GPCRs), and their activation triggers a cascade of intracellular relays with the final effect of analgesia. Classical agonists of this receptor, such as morphine, are the main targets in the treatment of both acute and chronic pain. However, the dangerous side effects, such as respiratory depression or addiction, significantly limit their widespread use. The allosteric centers of the receptors exhibit large structural diversity within particular types and even subtypes. Currently, a considerable interest is aroused by the modulation of µ-opioid receptors. The application of such a technique may result in a reduction in the dose or even discontinuation of classical opiates, thus eliminating the side effects typical of this class of drugs. Our aim is to obtain a series of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[1,2-a]imidazole derivatives and provide more information about their activity and selectivity on OP3 (MOP, human mu opioid receptor). The study was based on an observation that some carbonyl derivatives of 1-aryl-2-aminoimidazoline cooperate strongly with morphine or DAMGO in sub-threshold doses, producing similar results to those of normal active doses. To elucidate the possible mechanism of such enhancement, we performed a few in vitro functional tests (involving cAMP and ß-arrestin recruitment) and a radioligand binding assay on CHO-K1 cells with the expression of the OP3 receptor. One of the compounds had no orthosteric affinity or intrinsic activity, but inhibited the efficiency of DAMGO. These results allow to conclude that this compound is a negative allosteric modulator (NAM) of the human µ-opioid receptor.
Asunto(s)
Morfina , Receptores Opioides mu , Analgésicos Opioides/uso terapéutico , Animales , Cricetinae , Cricetulus , Encefalina Ala(2)-MeFe(4)-Gli(5) , Humanos , Imidazoles/farmacología , Morfina/farmacología , Receptores Opioides mu/metabolismoRESUMEN
This research allowed us to find the first highly potent 5-HT6/5-HT2A receptor (5-HT6/5-HT2AR) dual antagonists in a group of 1,3,5-triazine compounds as a result of an exit beyond the hydrophobic feature of the pharmacophore model for 5-HT6R antagonists. Design and synthesis of the series (2-16) of new O- and S-containing ether derivatives of 1,3,5-triazines with the double-ring aromatic region have been performed. The new compounds were examined within the comprehensive pharmacological screening, including: radioligand binding assays, functional and ADMET studies in vitro as well as behavioral tests in rats. Crystallographic aspects and computer-aided structure-activity relationship were analyzed, as well. The comprehensive approach led to selection of compound 12 (4-(4-methylpiperazin-1-yl)-6-(2-(naphthalen-2-ylthio)propan-2-yl)-1,3,5-triazin-2-amine) with the most significant dual 5-HT6/5-HT2AR antagonistic action (5-HT6R Ki = 11 nM, 5-HT2AR Ki = 39 nM). Moreover, the compound 12 has satisfactory ADMETox properties in vitro, i.e.: the high permeability through biological membranes, high metabolic stability, neither mutagenic nor hepatotoxic effects, and moderate ability to inhibit CYP3A4. Above all, 12 showed ability to reverse the pharmacologically-induced (MK-801) memory impairment at low doses (1-3 mg/kg) in Novel Object Recognition (NOR) test in rats. Our results indicate a promising potency of dual 5-HT6/5-HT2AR antagonism in the search for novel strategy to fight Alzheimer's disease, which remains an unmet clinical need.
Asunto(s)
Receptores de Serotonina , Antagonistas de la Serotonina , Animales , Estructura Molecular , Ratas , Receptores de Serotonina/metabolismo , Serotonina , Triazinas/química , Triazinas/farmacologíaRESUMEN
Neuropsychiatric symptoms (NPS), such as psychosis, depression and anxiety are frequently observed among patients with dementia. NPS is treated by off-label psychotropic medications that are only modestly effective in dementia patients, with a high risk of adverse events and cognitive decline. Considering the above, there is an unmet need for a well-tolerated and effective therapy of NPS in dementia. We designed and synthesized a library of dual-acting compounds as phosphodiesterase type-10A inhibitors and serotonin 5-HT1AR ligands. The most potent molecules, compounds 4 and 8, as partial agonists of 5-HT1AR and PDE10A inhibitors, exhibited a very high permeability of the blood-brain barrier. Compounds 4 and 8 displayed antipsychotic- and antidepressant-like activity and restored recognition memory deficits in mice. The overall effectiveness, pharmacokinetic and bioavailability studies imply the therapeutic-like potential of the presented dual-acting compounds as a method of treatment of NPS in dementia.
Asunto(s)
Antipsicóticos , Demencia , Animales , Antipsicóticos/farmacología , Demencia/tratamiento farmacológico , Demencia/psicología , Humanos , Ligandos , Ratones , Hidrolasas Diéster Fosfóricas , SerotoninaRESUMEN
Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1-3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Demencia/tratamiento farmacológico , Receptores de Serotonina/química , Antagonistas de la Serotonina/farmacología , Triazinas/farmacología , Animales , Células CACO-2 , Humanos , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and ß-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Aß aggregation (53% at 10 µM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Desarrollo de Medicamentos , Fármacos Neuroprotectores/farmacología , Receptores de Serotonina/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Electrophorus , Células Hep G2 , Caballos , Humanos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Agregado de Proteínas/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
BACKGROUND: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties. OBJECTIVE: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT;7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease. METHODS: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively. RESULTS: Synthesized aminoalkanamides were characterized as potent 5-HT1Areceptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability. CONCLUSION: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.