RESUMEN
The serotonin type 6 receptor (5-HT6R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT6R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT6R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT6R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT6R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT6R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT6R and provide insight into the glioprotective properties of 5-HT6R neutral antagonists at Gs signaling.
Asunto(s)
Astrocitos , Pirroles , Receptores de Serotonina , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Humanos , Pirroles/farmacología , Pirroles/química , Pirroles/síntesis química , Receptores de Serotonina/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/síntesis química , Simulación de Dinámica Molecular , Relación Dosis-Respuesta a Droga , Transducción de Señal/efectos de los fármacos , AnimalesRESUMEN
5-HT7R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT7R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3, which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and ß-arrestin signaling pathways of 5-HT7R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT7R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3-/- transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT7R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.
Asunto(s)
Trastorno Autístico/tratamiento farmacológico , Pirazoles/uso terapéutico , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/uso terapéutico , Animales , Diseño de Fármacos , Aseo Animal/efectos de los fármacos , Masculino , Ratones Transgénicos , Proteínas de Microfilamentos/deficiencia , Proteínas de Microfilamentos/genética , Simulación del Acoplamiento Molecular , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Pirazoles/síntesis química , Pirazoles/metabolismo , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/metabolismoRESUMEN
We have previously reported that dual 5-HT1A and 5-HT7 receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit ß-arrestin to the D2 receptor. However, SYA16263 also binds with very high affinity to 5-HT1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT7R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT1AR and 5-HT7R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT1AR, Ki = 0.74 nM) and a low nanomolar (5-HT7R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT1AR and antagonist at the 5-HT7R, functional characteristics which point to its potential as an antidepressant agent.
Asunto(s)
Piperazinas/farmacología , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas de la Serotonina/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Piridinas/síntesis química , Piridinas/química , Agonistas del Receptor de Serotonina 5-HT1/síntesis química , Agonistas del Receptor de Serotonina 5-HT1/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-ActividadRESUMEN
G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT6R (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT6R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT6R.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Astrocitos/efectos de los fármacos , Humanos , Discapacidades para el Aprendizaje/inducido químicamente , Discapacidades para el Aprendizaje/prevención & control , Masculino , Conformación Molecular , Neuritas/efectos de los fármacos , Neuroglía/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HT7R ligand with antidepressant activity on mice. The combination of DFT calculations of 1H NMR chemical shifts with docking and dynamic simulations, in comparison to experimental screening results, provided prediction of the configuration for one of two present stereogenic centers. The experimental data for stereoisomers (MF-8A-MF-8D) confirmed the significant impact of stereochemistry on both, 5-HT7R affinity and antagonistic action, with Ki and Kb values in the range of 3-366 nM and 0.024-99 µM, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycoprotein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities.
Asunto(s)
Hidantoínas/farmacocinética , Piperazinas/farmacocinética , Antagonistas de la Serotonina/farmacocinética , Animales , Sitios de Unión , Línea Celular Tumoral , Citocromo P-450 CYP2C9/química , Citocromo P-450 CYP2C9/metabolismo , Inhibidores del Citocromo P-450 CYP3A/síntesis química , Inhibidores del Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/toxicidad , Teoría Funcional de la Densidad , Estabilidad de Medicamentos , Humanos , Hidantoínas/síntesis química , Hidantoínas/metabolismo , Hidantoínas/toxicidad , Ratones , Microsomas Hepáticos/metabolismo , Modelos Químicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Piperazinas/síntesis química , Piperazinas/metabolismo , Piperazinas/toxicidad , Unión Proteica , Espectroscopía de Protones por Resonancia Magnética , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/toxicidad , EstereoisomerismoRESUMEN
We report here the synthesis and characterization of a dual 5-HT7 / 5-HT2 receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT7 and 5-HT2A receptor ligand having a pKi = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT2A and as an inverse agonist in an in vitro functional assay for 5-HT7. In a validated in vivo model for central 5-HT7 activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED50 = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED50 = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT2A receptor binding sites in the frontal cortex of the rat brain with an ED50 in good agreement with the ED50 value for central functional effect mediated by 5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1 h).
Asunto(s)
Azepinas/farmacología , Descubrimiento de Drogas , Receptores de Serotonina 5-HT2/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Animales , Azepinas/síntesis química , Azepinas/química , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Ratones , Estructura Molecular , Ratas , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-ActividadRESUMEN
The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT6R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.
Asunto(s)
Alquinos/farmacología , Indoles/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Receptores de Serotonina/metabolismo , Alquinos/síntesis química , Alquinos/farmacocinética , Animales , Astrocitos/efectos de los fármacos , Línea Celular Tumoral , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Masculino , Estructura Molecular , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacocinética , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacocinética , Nootrópicos/síntesis química , Nootrópicos/farmacocinética , Ratas Sprague-Dawley , Ratas Wistar , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic.
Asunto(s)
Antipsicóticos/química , Técnicas de Química Sintética , Diseño de Fármacos , Flavonas/química , Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Flavonas/síntesis química , Flavonas/farmacología , Ligandos , Receptores de Dopamina D2/química , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Relación Estructura-ActividadRESUMEN
Developing new and selective 5-HT7R ligands may have a key impact on the treatment of central nervous system diseases including depression. We have found that indoleaminotriazine core fused with alkyl aryl moiety exhibits high affinity and selectivity to 5-HT7R. SAR analysis demonstrated that the ethyl or ethoxy group (5c 5-HT7R Ki = 8 nM; 5d 5-HT7R Ki = 55 nM) is the optimal carbon linker between triazine and aryl moiety. The results of the molecular dynamics simulations show stable interaction with E7.34 upon binding to a 5-HT7R. Compounds 5c and 5d were tested for early ADMET parameters. Compounds are not hepatotoxic and exhibit moderate potential interaction with other drugs metabolized by CYP3A4 or CYP2D6.
Asunto(s)
Indoles/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Triazinas/farmacología , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Indoles/química , Ligandos , Modelos Moleculares , Estructura Molecular , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/química , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HT1AR, 5-HT2AR, 5-HT6R and 5-HT7AR. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HT7AR and also had moderate 5-HT7AR affinity. Compounds from the C10 N-monosubstituted series generally lacked affinity for 5-HT2AR and 5-HT6R and showed strong affinity for 5-HT1A or 5-HT7AR. Compounds in this series that contained an N6-methyl group were up to 27-fold selective for 5-HT7AR over 5-HT1AR, whereas compounds with an N6-propyl substituent showed a reversal in this selectivity. The C10 benzofused aminothiazole analogues showed a similar binding profile as the C10 N-monosubstituted series i.e. strong affinity for 5-HT1AR or 5-HT7AR, with selectivity between the two receptors being similarly influenced by N6-methyl or N6-propyl substituents. Compounds 29 and 34a exhibit high 5-HT7AR affinity, excellent selectivity versus dopamine receptors and function as antagonists in 5-HT7AR cAMP-based assays. Compounds 29 and 34a have been identified as new lead molecules for further tool and pharmaceutical optimization.
Asunto(s)
Aporfinas/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Aporfinas/síntesis química , Aporfinas/metabolismo , Línea Celular , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
Schizophrenia is a chronic, disabling mental disorder that affects about one percent of world's population. Drugs acting on multiple targets have been demonstrated to provide superior efficacy in schizophrenia than agents acting on single target. In this study, based on FW01, a selective potent 5-HT1A receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D2 and 5-HT2A receptors. The optimized compound 9f was found to show dual potent D2 and 5-HT2A receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t1/2 of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with Kp value of 4.03. These results demonstrated that the dual D2 and 5-HT1A receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents.
Asunto(s)
Antipsicóticos/farmacología , Descubrimiento de Drogas , Piperidinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas de la Serotonina/farmacología , Animales , Antipsicóticos/síntesis química , Antipsicóticos/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-ActividadRESUMEN
The present paper describes the synthesis and the binding properties for the serotonergic 5-HT7 and 5-HT1A receptors of three new series (A-C) of (benzo)thienopyrimidinone derivatives. All series exhibit a basic moiety at the 2-position of the heterocyclic scaffold such as N,N-dialkylaminoalkylthio chain in series A and phenylpiperazine, benzylpiperazine, or benzylpiperidine alkyl chain in series B and C. Compounds endowed with the best binding properties at 5-HT7R belong to the B and C types. In particular, derivatives B2 and C1 (RSC4) exhibit notable affinity for 5-HT7R (Kiâ¯=â¯9.08 and 0.85â¯nM, respectively) and selectivity over the 5-HT1AR (254- and 48-fold, respectively). The structure-affinity relationships for these three new classes of 5-HT7R ligands are discussed and, in order to rationalize and deeply investigate the observed results, molecular modeling studies were performed. In particular, the binding poses of the synthesized compounds were studied by docking them in the two receptor proteins suitably built by homology modeling. The calculated binding energies resulted in an excellent agreement with the experimental measured Ki, further validating the quality of the models.
Asunto(s)
Pirimidinas/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Tiofenos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/química , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
Serotonin 5-HT6 receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5-HT 6 antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease-modifying effect. Combining BuChE inhibition, 5-HT 6 antagonism, and antioxidant properties may result in multitarget-directed ligands providing cognition-enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5-HT 6 antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5-HT 6 receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K i and K b values against 5-HT 6 receptors of 41.8 and 74 nM, respectively, an IC 50 value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti-Alzheimer's agents.
Asunto(s)
Antioxidantes/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Electrophorus , Caballos , Humanos , Modelos Moleculares , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Triazinas/antagonistas & inhibidoresRESUMEN
This research has provided the most active 5-HT6R agents among 1,3,5-triazine derivatives investigated to date and has also identified the world's first selenium-containing 5-HT6R ligands. The studies are focused on design, synthesis, biological evaluation and docking-supported SAR analysis for novel 5-HT6R agents as derivatives of lead structure 4-(4-methylpiperazin-1-yl)-6-(phenoxymethyl)-1,3,5-triazin-2-amine (7). The lead modifications included an introduction of: (i) various small substituents at benzene ring, (ii) a branched ether linker or (iii) the ether oxygen replacement with other chalcogen (S, Se) or sulfonyl moiety. Hence, a series of new compounds (7-24) was synthesized and examined on their affinities for 5-HT6R and selectivity, in respect to the 5-HT1AR, 5-HT2AR, 5-HT7R and dopamine D2 receptor, in the radioligand binding assays. For representative most active compounds functional bioassays and toxicity profile in vitro and antidepressant-like activity in vivo were examined. The 2-isopropyl-5-methylphenyl derivative (10) was found as the most active triazine 5-HT6R antagonist (Kiâ¯=â¯11â¯nM). SAR analysis indicated, that an exchange of oxygen to selenium (7 vs. 22), and especially, to sulfur (7 vs. 19) was beneficial to increase both affinity and antagonistic action for 5-HT6R. Surprisingly, an introduction of SO2 caused a drastic decrease of the 5-HT6R affinity, which was explained at a molecular level based on docking studies. All in vivo tested compounds (10, 18 and 21) did not show any risk of toxicity in the safety studies in vitro.
Asunto(s)
Procesamiento de Imagen Asistido por Computador , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Locomoción/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Ratas , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-ActividadRESUMEN
A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT6R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT6R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT6R and very high selectivity over 5-HT1A, 5-HT2A, 5-HT7 and D2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential.
Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Diseño de Fármacos , Imidazoles/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Animales , Células Cultivadas , Disfunción Cognitiva/inducido químicamente , Relación Dosis-Respuesta a Droga , Células HEK293 , Células Hep G2 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Escopolamina/administración & dosificación , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-ActividadRESUMEN
More than 300 million people are suffering from depression, one of the civilization diseases in the 21st century. Serotonin 5-HT1AR and dopamine D2R play an important role in the treatment and pathogenesis of depression. Moreover, in recent years, the efficacy of dual 5-HT1A/D2 receptors ligands has been demonstrated in the fight against depression. In this work the new bulky arylpiperazine derivatives (LCAP) were synthesized in microwave radiation field. The affinities for the selected serotonin (5-HT1A,5-HT2A,5-HT6,5-HT7) and dopamine (D2) receptors have been evaluated in vitro. Compounds 5.3a, 5.4, 5.1c, 5.3d, 5.2a are promising dual 5-HT1AR/D2R ligands. The SAR analysis were additionally supported with molecular docking studies.
Asunto(s)
Antagonistas de los Receptores de Dopamina D2/farmacología , Piperazina/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas de la Serotonina/farmacología , Antagonistas de los Receptores de Dopamina D2/síntesis química , Antagonistas de los Receptores de Dopamina D2/química , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Estructura Molecular , Piperazina/síntesis química , Piperazina/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-ActividadRESUMEN
A series of 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazines was designed based on previously published 2-amino-4-benzyl-(4-methylpiperazin-1-yl)-1,3,5-triazines in order to evaluate the role of a linker between the triazine moiety and an aromatic substituent for the human serotonin 5-HT6 receptor affinity. As new linkers two carbon atoms (ethyl or ethenyl) or an oxyalkyl chain (methoxy, 2-ethoxy, 2-propoxy) were introduced. Affinities of the compounds for the 5-HT6R as the main target, and for the 5-HT1AR, 5-HT7R and D2R as competitive ones, were determined in the radioligand binding assays. Docking to the 5-HT6R homology model was performed to support SAR analysis. Results showed that the branching of the methoxyl linker increased affinity for the human 5-HT6R whereas an unsaturated bond within the linker dramatically reduced desirable activity. Both experimental and theoretical studies confirmed the previously postulated beneficial role of the aromatic size for interaction with the 5-HT6R. Thus, the largest naphthyl moiety yielded the highest activity. In particular, 4-(4-methylpiperazin-1-yl)-6-(1-(naphthalen-1-yloxy)ethyl)-1,3,5-triazin-2-amine (24), the most potent 5-HT6R agent found (Kiâ¯=â¯23â¯nM), can be a new lead structure for further search and development.
Asunto(s)
Piperazinas/química , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Sitios de Unión , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Piperazinas/síntesis química , Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
Carbon-11-labeled serotonin (5-hydroxytryptamine) 6 receptor (5-HT6R) antagonists, 1-[(2-bromophenyl)sulfonyl]-5-[11C]methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (O-[11C]2a) and 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-[11C]methyl-1-piperazinyl)methyl]-1H-indole (N-[11C]2a), 5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (O-[11C]2b) and 5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (N-[11C]2b), 1-((4-isopropylphenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]2c) and 1-((4-isopropylphenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]2c), 1-((4-fluorophenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]2d) and 1-((4-fluorophenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]2d), were prepared from their O- or N-desmethylated precursors with [11C]CH3OTf through O- or N-[11C]methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370-740â¯GBq/µmol with a total synthesis time of â¼40-min from EOB.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Antagonistas de la Serotonina/síntesis química , Enfermedad de Alzheimer/diagnóstico por imagen , Radioisótopos de Carbono/química , Humanos , Indoles/química , Marcaje Isotópico , Radiofármacos/química , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/químicaRESUMEN
We report the in vitro drug-likeness studies and in vivo pharmacological evaluation for a new potent 5-HT7 receptor antagonist MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylhydantoin). The in vitro tests showed good permeability, very good metabolic stability, low risk of drug-drug interactions and satisfying safety profile. Moreover, MF-8 showed excellent antidepressant-like activity in the forced swim test in rodents and promising anxiolytic-like activity in the four-plate test in mice. Regarding the potent affinity, high selectivity and antagonistic activity of MF-8 for the 5-HT7 receptor as well as excellent drug - like properties in vitro and confirmed in vivo pharmacological activity, MF-8 should be considered as a very significant molecule in the search for a new class of anti-depressant drugs.
Asunto(s)
Hidantoínas/farmacología , Piperazinas/farmacología , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Hidantoínas/síntesis química , Hidantoínas/química , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Relación Estructura-ActividadRESUMEN
This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT7 receptor (5-HT7R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT7R and selectivity over 5-HT1AR, dopamine D2R and α1-, α2-and ß-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT7R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12,Kiâ¯≤â¯10â¯nM). Antidepressant-like activity in vivo for all tested compounds (5-8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT7R affinity than the di-phenyl ones.