RESUMEN
Twelve alkyl analogues (1-12) of the high-affinity serotonin transporter (SERT) inhibitor 6-nitroquipazine (6-NQ) were synthesized and studied using in vitro radioligand competition binding assays to determine their binding affinity (Ki ). The putative antidepressant activity of five of the binders with the highest SERT binding affinities was studied by the forced swim and locomotor activity mouse tests. The three-dimensional (3D) structures of 8 and 9 were determined using NOE NMR technique. Flexible docking of the compounds was undertaken to illustrate the binding of the compounds in the SERT model. Our results showed that several of the 6-NQ analogues are high-affinity SERT inhibitors and indicated that the octyl (8), decyl (10) and dodecyl (12) 6-NQ analogues exhibit moderate antidepressant activity.
Asunto(s)
Antidepresivos/síntesis química , Quipazina/análogos & derivados , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Animales , Antidepresivos/química , Antidepresivos/farmacología , Sitios de Unión , Masculino , Ratones , Simulación del Acoplamiento Molecular , Actividad Motora/efectos de los fármacos , Unión Proteica , Estructura Terciaria de Proteína , Quipazina/síntesis química , Quipazina/química , Quipazina/farmacología , Receptor de Serotonina 5-HT1A/química , Receptor de Serotonina 5-HT1A/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
It is well known that 6-nitroquipazine exhibits about 150-fold higher affinity for the serotonin transporter (SERT) than quipazine and recently we showed quipazine buspirone analogues with high to moderate SERT affinity. Now we have designed and synthesized several 6-nitroquipazine buspirone derivatives. Unexpectedly, their SERT binding affinities were moderate, and much lower than that of the previously studied quipazine buspirone analogues. To explain these findings, docking studies of both groups of compounds into two different homology models of human SERT was performed using a flexible target-ligand docking approach (4D docking). The crystal structures of leucine transporter from Aquifex aeolicus in complex with leucine and with tryptophan were used as templates for the SERT models in closed and outward-facing conformations, respectively. We found that the latter conformation represents the most reliable model for binding of buspirone analogues. Docking into that model showed that the nitrated compounds acquire a rod like shape in the binding pocket with polar groups (nitro- and imido-) at the ends of the rod. 6-Nitro substituents gave steric clashes with amino acids located at the extracellular loop 4, which may explain their lower affinity than corresponding quipazine buspirone analogues. The results from the present study may suggest chemical design strategies to improve the SERT modulators.
Asunto(s)
Buspirona/química , Buspirona/farmacología , Quipazina/análogos & derivados , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Bacterias/química , Bacterias/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Sitios de Unión , Buspirona/síntesis química , Humanos , Modelos Moleculares , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Quipazina/síntesis química , Quipazina/química , Quipazina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis químicaRESUMEN
The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT(3)R in the modulation of cardiac parameters.
Asunto(s)
Corazón/efectos de los fármacos , Miocardio/metabolismo , Pirroles/síntesis química , Pirroles/farmacología , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Receptores de Serotonina 5-HT3/efectos de los fármacos , Receptores de Serotonina 5-HT3/metabolismo , Animales , Barorreflejo/efectos de los fármacos , Fenómenos Químicos , Femenino , Cobayas , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Masculino , Ratones , Modelos Moleculares , Pirroles/farmacocinética , Quinoxalinas/farmacocinética , Quipazina/análogos & derivados , Quipazina/síntesis química , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT3 , Relación Estructura-ActividadRESUMEN
Five C2'-substituted 6-nitroquipazine (6-NQ) derivatives were prepared and evaluated in terms of their biological abilities (K(i)) to displace [(3)H]citalopram binding to serotonin transporter. The relationship between their structure and biological activities revealed that shorter alkyl groups tend to possess higher binding affinity. Both compounds 12a and 12c were found to have the equally highest binding affinity (K(i)=0.43+/-0.02 nM).
Asunto(s)
Quipazina/análogos & derivados , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Cromatografía en Capa Delgada , Técnicas In Vitro , Indicadores y Reactivos , Masculino , Espectrometría de Masas , Piperazina , Piperazinas/química , Quipazina/síntesis química , Quipazina/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Relación Estructura-Actividad , Membranas Sinápticas/efectos de los fármacos , Membranas Sinápticas/metabolismoRESUMEN
On the basis of the structure-activity relationship (SAR) of 4-chloro-6-nitroquipazine (Ki = 0.03 nM) and 3-fluoropropyl-6-nitroquipazine (Ki = 0.32 nM), 3-alkyl-4-halo-6-nitroquipazines were synthesized and tested for their potential abilities in vitro to displace [3H]citalopram binding to the rat cortical membranes. Binding affinities of 3b and 4d were Ki = 2.70+/-0.32 and 2.23+/-0.46 nM, respectively. The syntheses of 3-alkyl-4-halo-6-nitroquipazine, their in vitro binding affinities, and the SAR of C3, C4 position in 6-nitroquipazine are described.
Asunto(s)
Quipazina/análogos & derivados , Quipazina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/metabolismo , Animales , Unión Competitiva , Corteza Cerebral/metabolismo , Citalopram/metabolismo , Masculino , Quipazina/síntesis química , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Relación Estructura-Actividad , Membranas Sinápticas/metabolismoRESUMEN
3-(3-[18F]Fluoropropyl)-6-nitroquipazine ([18F]FPNQ) as a 5-HT transporter imaging agents was designed, synthesized, and evaluated. FPNQ was selected due to its potent in vitro biological activity (K(i)=0.32 nM) in rat brain cortical membranes. The 18F-labeled FPNQ was prepared by reaction of the propyl mesylate as a precursor with tetra-n-butylammonium [18F]fluoride generated under NCA conditions. The precursor mesylate was synthesized from commercially available hydrocarbostyril in nine steps in 21% overall yield. The specific activity of the [18F]FPNQ determined by radioreceptor assay was 27.0 GBq/micromol. Tissue distribution studies in mice showed the highest uptake in the frontal cortex (5.79 %ID/g) at 60 min post-injection.
Asunto(s)
Proteínas Portadoras/síntesis química , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/síntesis química , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso/síntesis química , Proteínas del Tejido Nervioso/metabolismo , Quipazina/análogos & derivados , Quipazina/síntesis química , Quipazina/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Espectroscopía de Resonancia Magnética , Ratones , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masa Bombardeada por Átomos Veloces , Distribución TisularRESUMEN
5-Methyl-6-nitroquipazine, a novel analogue of the potent and selective serotonin transporter inhibitor 6-nitroquipazine was synthesized and radiolabeled with tritium and the positron emitter carbon-11. [3H]5-methyl-6-nitroquipazine was found to have a K(d)=51+/-7 pM. The high affinity and the facile labeling of [11C]5-methyl-6-nitroquipazine makes it a promising radioligand for visualization of the serotonin transporter with positron emission tomography.
Asunto(s)
Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Antagonistas de la Serotonina/síntesis química , Animales , Radioisótopos de Carbono , Proteínas Portadoras/antagonistas & inhibidores , Ligandos , Glicoproteínas de Membrana/antagonistas & inhibidores , Corteza Prefrontal/metabolismo , Quipazina/análogos & derivados , Quipazina/síntesis química , Quipazina/metabolismo , Quipazina/farmacología , Radiofármacos/síntesis química , Radiofármacos/metabolismo , Radiofármacos/farmacología , Ratas , Antagonistas de la Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Relación Estructura-Actividad , TritioRESUMEN
Radiohalogenated 5-halo-6-nitroquipazine analogues have been shown to be potential radioligands for visualization of the serotonin transporter (5-HTT) with PET and SPECT. In the present study a methylated analogue, 5-methyl-6-nitroquipazine (MNQP), was radiolabeled with carbon-11 in a two step reaction via a palladium catalyzed cross coupling reaction between N-t-BOC-protected 5-tributylstannyl-6-nitroquipazine and [(11)C]methyl iodide as key step. [(11)C]MNQP was examined in the cynomolgus monkey brain with positron emission tomography (PET) and the appearance of labeled metabolites in monkey plasma was measured with gradient HPLC. Radioactivity increased continuously in all brain regions during the 90 minutes acquisition time. Highest accumulation of radioactivity was observed in the thalamus and brainstem, regions with a known high density of 5-HTT. The calculated ratios between the thalamus and brainstem to the 5-HTT poor cerebellum were 1.5 and 1.3-1.4, respectively, 80 minutes after radioligand injection. Pretreatment with citalopram prior to the PET measurement markedly reduced the binding in the thalamus and the brainstem. At 15 and 30 minutes after injection of [(11)C]MNQP approximately 90% and 60%, respectively, of radioactivity in plasma represented unchanged radioligand. The slow kinetics and moderate ratios recorded however, may limit its use as a PET radioligand for quantitative studies of the serotonin transporter with PET.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Quipazina/farmacocinética , Tomografía Computarizada de Emisión , Animales , Proteínas Portadoras/sangre , Haplorrinos , Glicoproteínas de Membrana/sangre , Quipazina/análogos & derivados , Quipazina/síntesis química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Sensibilidad y Especificidad , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Eleven 4-substituted derivatives of 6-nitroquipazine were synthesized and evaluated for their abilities to displace [3H]citalopram binding to the rat cortical synaptic membranes. Among them, 4-chloro-6-nitroquipazine was shown to possess the highest binding affinity (K(i=)0.03 nM) which was approximately 6 times higher than that of 6-nitroquipazine (K(i)=0.17 nM) itself. In this paper, we describe the syntheses of 4-substituted 6-nitroquipazine derivatives, the results of corresponding biological evaluation and the SAR study.
Asunto(s)
Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Quipazina/análogos & derivados , Quipazina/síntesis química , Quipazina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/metabolismo , Animales , Unión Competitiva , Corteza Cerebral/metabolismo , Citalopram/farmacocinética , Diseño de Fármacos , Fluoxetina/farmacología , Concentración 50 Inhibidora , Cinética , Masculino , Modelos Estructurales , Paroxetina/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Relación Estructura-ActividadRESUMEN
Racemic 2'-methyl- and 3'-methyl-6-nitroquipazine ligands were selected as targets, synthesized and evaluated at the serotonin transporter employing an in vitro competitive inhibition assay with [3H]paroxetine and rat cortical membrane. The 2'-methyl-6-nitroquipazine was found to be 50 times more potent than the 3'-methyl-substituted counterpart and of comparable potency to the known high affinity agent 5-iodo-6-nitroquipazine.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Quipazina/síntesis química , Animales , Unión Competitiva , Proteínas Portadoras/metabolismo , Corteza Cerebral/metabolismo , Glicoproteínas de Membrana/metabolismo , Paroxetina/metabolismo , Quipazina/análogos & derivados , Quipazina/metabolismo , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismoRESUMEN
6-Nitroquipazine has been known as one of the most potent and selective inhibitors of serotonin transporter in vitro and in vivo. Nine derivatives of 6-nitroquipazine were synthesized and tested for their potential abilities to displace [3H]citalopram binding to the rat cortical membranes.
Asunto(s)
Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Quipazina/análogos & derivados , Quipazina/síntesis química , Animales , Unión Competitiva , Membrana Celular/metabolismo , Corteza Cerebral/metabolismo , Citalopram/farmacocinética , Diseño de Fármacos , Indicadores y Reactivos , Cinética , Modelos Estructurales , Conformación Molecular , Quipazina/química , Quipazina/farmacocinética , Quipazina/farmacología , Ratas , Proteínas de Transporte de Serotonina en la Membrana Plasmática , 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 , Relación Estructura-ActividadRESUMEN
The development of suitable radioligands for brain imaging of the serotonin transporter is of great importance for the study of depression and other affective disorders. The potent and selective serotonin transporter ligand, 5-iodo-6-nitro-2-piperazinylquinoline, has been labelled with iodine-123 and used as a radioligand for single photon emission computerized tomography. To evaluate the potential of the bromine-76-labelled analogue, 5-bromo-6-nitroquipazine, as a radioligand for positron emission tomography (PET), its brain distribution and binding characteristics were examined in rats. In vivo brain distribution and ex vivo autoradiography demonstrated that [76Br]5-bromo-6-nitroquipazine enters the brain rapidly. The regional brain distribution of [76Br]5-bromo-6-nitroquipazine was consistent with the known distribution of serotonin transporters in the midbrain, pons, thalamus, striatum, and neocortex. Specific binding was inhibited by the selective serotonin reuptake inhibitor citalopram. The peripheral metabolism in plasma was rapid, but more than 90% of the radioactivity in brain represented unchanged radioligand 2 h postinjection (p.i.). A preliminary PET study was also performed in a baboon. Following the intravenous injection of [76Br]5-bromo-6-nitroquipazine in a baboon, there was a conspicuous accumulation of radioactivity in thalamus, striatum, and pons. The radioactivity in these brain regions was 1.5 times higher than in the cerebellum at 3 h and 2.5-4 times higher at 24 h. A rapid metabolism of the radioligand in plasma was observed (38% unchanged after 5 min). The results indicate that [76Br]5-bromo-6-nitroquipazine has potential for PET imaging of the serotonin transporter.
Asunto(s)
Encéfalo/metabolismo , Radioisótopos de Bromo/farmacocinética , Proteínas Portadoras/análisis , Glicoproteínas de Membrana/análisis , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Quipazina/análogos & derivados , Animales , Autorradiografía , Biotransformación , Barrera Hematoencefálica , Encéfalo/diagnóstico por imagen , Proteínas Portadoras/metabolismo , Indicadores y Reactivos , Masculino , Glicoproteínas de Membrana/metabolismo , Quipazina/síntesis química , Quipazina/farmacocinética , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Distribución Tisular , Tomografía Computarizada de Emisión/métodosRESUMEN
The syntheses of some 3-substituted-2-(4-methyl-1-piperazinyl)-4-phenylquinolines are reported. The title compounds were tested for their potential activities on 5-HT receptor subtypes and 5-HT uptake site; compounds 4b-d showed micromolar affinity for 5-HT3 and 5-HT uptake site.
Asunto(s)
Piperazinas/síntesis química , Quinolonas/síntesis química , Quipazina/análogos & derivados , Antagonistas de la Serotonina , Serotonina/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Técnicas In Vitro , Ligandos , Masculino , Paroxetina , Piperazinas/farmacología , Piperidinas/metabolismo , Quinolonas/farmacología , Quipazina/síntesis química , Quipazina/farmacología , Ratas , Ratas EndogámicasRESUMEN
The synthesis of 6-nitroquipazine, a very potent and selective 5-hydroxytryptamine (5-HT; serotonin) uptake inhibitor, labeled with tritium is described. High specific activity [3H]6-nitroquipazine could be prepared by the nitration of [3H]quipazine using a mixture of equal volumes of sulfuric acid and nitric acid. The radiochemical yield was approximately 50% based on [3H]quipazine. The radiochemical purity was more than 95% from high performance liquid chromatography(HPLC) and thin layer chromatography(TLC) determinations. [3H]6-Nitroquipazine would be a new suitable radioligand for studying 5-HT transporter complex in brain and platelets.
Asunto(s)
Quipazina/análogos & derivados , Antagonistas de la Serotonina/síntesis química , Quinolinas , Quipazina/síntesis química , TritioRESUMEN
The synthesis of a series of 4-phenylquinolines with substituents in 2,3 and 6-position of the quinoline nucleus is described. Serotoninergic activity towards 5HT1A, 5HT1B, 5HT2, 5HT1A + B receptors and the 5-HT-uptake site was also studied.