RESUMEN
In our screening program for new biologically active secondary metabolites, nine new polycyclic polyprenyled acylphloroglucinols, hyperscabins D-L, together with three known compounds, were obtained from the aerial parts of Hypericum scabrum. The chemical structures of 1-9 were characterized by extensive spectroscopic analyses, nuclear magnetic resonance calculation with DP4+ probability analysis, and the electronic circular dichroism spectra were calculated. Compound 1 was an unusual prenylated acylphloroglucinol decorated with a 5-oxaspiro [4,5] deca-1,9-dione skeleton. Compound 2 was a newly identified spirocyclic polyprenylated acylphloroglucinol possessing a rare 5,5-spiroketal segment. Compounds 3, 8, and 10 (10 µM) exhibited pronounced hepatoprotective activity against d-galactosamine-induced WB-F344 cell damage in vitro assays. All test compounds (1, 3, and 7-12) demonstrated potential inhibitory effects at 10 µM against noradrenalinet ([3H]-NE) reuptake in rat brain synaptosome.
Asunto(s)
Antidepresivos/farmacología , Hemiterpenos/farmacología , Hypericum/química , Floroglucinol/análogos & derivados , Floroglucinol/farmacología , Sustancias Protectoras/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/aislamiento & purificación , Línea Celular , Hemiterpenos/síntesis química , Hemiterpenos/aislamiento & purificación , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/aislamiento & purificación , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Floroglucinol/aislamiento & purificación , Componentes Aéreos de las Plantas/química , Sustancias Protectoras/síntesis química , Sustancias Protectoras/aislamiento & purificación , Ratas , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.
Asunto(s)
Diseño de Fármacos , Inhibidores de la Captación de Neurotransmisores/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Piperazina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Piperazina/síntesis química , Piperazina/química , Relación Estructura-ActividadRESUMEN
Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine-tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach.
Asunto(s)
Diseño de Fármacos , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperidinas/farmacología , Tetrazoles/farmacología , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Norepinefrina/antagonistas & inhibidores , Norepinefrina/metabolismo , Piperidinas/síntesis química , Piperidinas/química , Serotonina/metabolismo , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/químicaRESUMEN
Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50=158.7nM for 5-HT, 99nM for NE and 97.5nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.
Asunto(s)
Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperazinas/química , Piperazinas/farmacología , Piperidinas/química , Piperidinas/farmacología , Células HEK293 , Humanos , Técnicas In Vitro , Inhibidores de la Captación de Neurotransmisores/síntesis química , Piperazinas/síntesis química , Piperidinas/síntesis químicaRESUMEN
Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood-brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H(3))methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.
Asunto(s)
Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Inhibidores de la Captación de Neurotransmisores/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety. The resulting compound 9 exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.
Asunto(s)
Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Animales , Células CHO , Cricetulus , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Enlace de Hidrógeno , Espectrometría de Masas , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Espectroscopía de Protones por Resonancia Magnética , Ratas , Ratas Sprague-DawleyRESUMEN
We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
Asunto(s)
Azetidinas/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Inhibidores de la Captación de Neurotransmisores/farmacología , Éteres Fenílicos/farmacología , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/antagonistas & inhibidores , Serotonina/metabolismo , Azetidinas/síntesis química , Azetidinas/química , Transporte Biológico/efectos de los fármacos , Inhibidores Enzimáticos del Citocromo P-450/síntesis química , Inhibidores Enzimáticos del Citocromo P-450/química , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Éteres Fenílicos/síntesis química , Éteres Fenílicos/química , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/metabolismo , Relación Estructura-ActividadRESUMEN
A novel triple reuptake inhibitor with low potential of liabilities associated with cationic amphiphilic drug (CAD) was identified following an analysis of existing drugs. Low molecular weight (MW < ca. 300), low aromatic ring count (number = 1) and reduced lipophilicity (ClogP < 3.5) were hypothesized to be key factors to avoid the CAD associated liabilities (CYP2D6 inhibition, hERG inhibition and phospholipidosis). Based on the hypothesis, a series of piperidine compounds was designed with consideration of the common characteristic features of CNS drugs. Optimization of the side chain by adjusting overall lipophilicity suggested that incorporation of a methoxymethyl group could provide compounds with a balance of both potent reuptake inhibition and low liability potential. Compound (S)-3a showed a potent antidepressant-like effect in the mice tail suspension test (MED = 10 mg/kg, p.o.), proportional monoamine transporter occupancies and enhancement of monoamine concentrations in mouse prefrontal cortex.
Asunto(s)
Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Inhibidores de la Captación de Neurotransmisores/síntesis química , Piperidinas/química , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Relación Estructura-ActividadRESUMEN
Novel azetidines based on the 3-aryl-3-oxypropylamine scaffold were designed, synthesized, and evaluated as TRIs. Reduction of 1 followed by Swern oxidation and then Grignard reaction gave 3. The alkylation of 3 provided the corresponding azetidine derivatives 6, of which the two most promising, 6bd and 6be, were selected from 86 prepared analogues based on their biological profiles. Compound 6be showed activity in vivo in FST at 10 mg/kg IV or 20-40 mg/kg PO.
Asunto(s)
Antidepresivos/química , Antidepresivos/farmacología , Azetidinas/química , Azetidinas/farmacología , Diseño de Fármacos , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacocinética , Azetidinas/síntesis química , Azetidinas/farmacocinética , Conducta Animal/efectos de los fármacos , Células HEK293 , Humanos , Concentración 50 Inhibidora , Ratones , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacocinéticaRESUMEN
The present work describes a series of novel chiral amines that potently inhibit the in vitro reuptake of serotonin, norepinephrine and dopamine (triple reuptake inhibitors) and were active in vivo in a mouse model predictive of antidepressant like activity. The detailed synthesis and in vitro activity and ADME profile of compounds is described, which represent a previously undisclosed triple reuptake inhibitor chemotype.
Asunto(s)
Naftalenos/síntesis química , Naftalenos/farmacología , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Evaluación Preclínica de Medicamentos , Ratones , Norepinefrina/metabolismo , Serotonina/metabolismoRESUMEN
Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.
Asunto(s)
Antidepresivos Tricíclicos/farmacología , Dopamina/metabolismo , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Pirrolidinas/farmacología , Serotonina/metabolismo , Animales , Antidepresivos Tricíclicos/síntesis química , Antidepresivos Tricíclicos/química , Antidepresivos Tricíclicos/farmacocinética , Células CACO-2 , Depresión/tratamiento farmacológico , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/farmacocinética , Inhibidores de Captación de Dopamina/farmacología , Diseño de Fármacos , Humanos , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Dolor/tratamiento farmacológico , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Recently a class of compounds known as triple reuptake inhibitors has emerged as a new strategy for the treatment of depression. These compounds work by simultaneously inhibiting the synaptic reuptake of serotonin, norepinephrine and dopamine. In this Letter we describe the optimization of a novel series of 2-substituted N-aryl piperazine based triple reuptake inhibitors.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperazinas/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Norepinefrina/metabolismo , Piperazinas/síntesis química , Piperazinas/química , Serotonina/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Sinapsis/efectos de los fármacos , Sinapsis/metabolismoRESUMEN
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
Asunto(s)
Trastorno Depresivo/tratamiento farmacológico , Heptanos/química , Heptanos/farmacología , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/farmacología , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Encéfalo/metabolismo , Trastorno Depresivo/metabolismo , Dopamina/metabolismo , Heptanos/síntesis química , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Microdiálisis , Modelos Moleculares , Inhibidores de la Captación de Neurotransmisores/síntesis química , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
Asunto(s)
Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Descubrimiento de Drogas/métodos , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Animales , Línea Celular , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/farmacocinética , Femenino , Humanos , Masculino , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Ratas , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinéticaRESUMEN
A series of heterocyclic cycloalkanol ethylamines have been prepared to expand our norepinephrine reuptake inhibitor (NRI) program. Synthesis of a variety of heterocycles identified (+)-S-21, a potent NRI efficacious in an animal model for thermoregulatory dysfunction.
Asunto(s)
Etilaminas/química , Inhibidores de la Captación de Neurotransmisores/química , Norepinefrina/metabolismo , Piperazinas/química , Tiofenos/química , Animales , Cristalografía por Rayos X , Etilaminas/síntesis química , Etilaminas/farmacología , Humanos , Conformación Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/química , Piperazinas/síntesis química , Piperazinas/farmacología , Ratas , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/farmacologíaRESUMEN
Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
Asunto(s)
Indoles/farmacología , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Propanolaminas/farmacología , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Femenino , Indoles/síntesis química , Indoles/química , Espectroscopía de Resonancia Magnética , Inhibidores de la Captación de Neurotransmisores/síntesis química , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Dolor/tratamiento farmacológico , Propanolaminas/síntesis química , Propanolaminas/química , Ratas , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
To explore novel monoamine reuptake inhibitor with antidepressant activity, a series of substituted aryl alkanol piperidine derivatives were designed and synthesized. All of them were new compounds, and their structures were confirmed with 1H NMR and HR-MS. The results showed that compounds 4, 5 and 8 displayed strong 5-HT, NA and DA reuptake inhibiting activities in vitro. Among the tested compounds, 4, 5 and 13 exhibited potent antidepressant activities in the mice forced swimming test. Compounds 4 and 5 have potent antidepressant activities and are worth further development.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Antidepresivos/química , Dopamina/metabolismo , Masculino , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Piperidinas/química , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Relación Estructura-Actividad , Natación , Sinaptosomas/metabolismoRESUMEN
Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1(A) partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT(1A) receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1(A) partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT(1A) in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented.
Asunto(s)
Descubrimiento de Drogas , Éteres/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Dopamina/metabolismo , Éteres/síntesis química , Éteres/química , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Piperazinas/síntesis química , Piperazinas/química , Piperidinas/síntesis química , Piperidinas/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
Asunto(s)
Indoles/farmacología , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2 , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Transporte Biológico/efectos de los fármacos , Línea Celular , Humanos , Indoles/síntesis química , Indoles/metabolismo , Inhibidores de la Captación de Neurotransmisores/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas de la Serotonina/metabolismo , Relación Estructura-ActividadRESUMEN
A variety of novel aminoheterocycle scaffolds as selective monoamine reuptake inhibitors have been prepared and one of these scaffolds is achiral. The main elements responsible for hERG channel, CYP2D6 and CYP3A4 inhibition were identified.