RESUMEN
(1)H and (13)C NMR spectroscopic data of 20 new non-symmetrical compounds were assigned by a combination of 1D and 2D NMR experiments (DEPT, HSQC, and HMBC). These compounds contain a 4-(N,N-dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium moiety and a 3-nitro-, 3-amino-, or 3-hydroxyphenyl ring, linked by p-xylene, 4,4'-dimethylbiphenyl, 1,2-bis(p-tolyl)ethane, or 1,4-bis(p-tolyl)butane.
Asunto(s)
Aminofenoles/química , Espectroscopía de Resonancia Magnética/métodos , Compuestos de Piridinio/química , Isótopos de Carbono/análisis , Isomerismo , Protones , Sales (Química)/químicaRESUMEN
Dual binding modes: Combined empirical and computational studies of a series of compounds showed adenine and 1-benzyl-4-(dimethylamino)pyridinium fragments to function most efficiently in binding CHOKα1, and also determined how the latter fragment interacts with the choline binding site through two different binding modes. These data provide a basis for the future design of better and more selective inhibitors.
Asunto(s)
Colina Quinasa/metabolismo , Espectrometría de Fluorescencia , Adenina/química , Adenina/metabolismo , Sitios de Unión , Dominio Catalítico , Colina Quinasa/química , Humanos , Simulación del Acoplamiento Molecular , Unión ProteicaRESUMEN
In a preliminary article, we reported a series of 4,5-dihydro-1H-pyrazole derivatives as neuronal nitric oxide synthase (nNOS) inhibitors. Here we present the data about the inhibition of inducible nitric oxide synthase (iNOS) of these compounds. In general, we can confirm that these pyrazoles are nNOS selective inhibitors. In addition, taking these compounds as a reference, we have designed and synthesized a series of new derivatives by modification of the heterocycle in 1-position, and by introduction of electron-donating or electron-withdrawing substituents in the aromatic ring. These derivatives have been evaluated as nNOS and iNOS inhibitors in order to identify new compounds with improved activity and selectivity. Compound 3r, with three methoxy electron-donating groups in the phenyl moiety, is the most potent nNOS inhibitor, showing good selectivity nNOS/iNOS.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Acilación , Animales , Sitios de Unión , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. Choline kinase (ChoK) is the first enzyme in the CDP-choline pathway that synthesizes phosphatidylcholine (PC), the major phospholipid in eukaryotic cell membranes. In the present paper, a new family of non-symmetrical monocationic compounds is developed including a 3-aminophenol moiety, bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium cationic heads through several linkers. The most promising compounds in these series as ChoK inhibitors are 3f and 4f, while compounds 3c, 3d and 4c are the better antiproliferative agents. The analysis of the biological data observed in the described series of compounds mays represents a platform for the design of more active molecules.
Asunto(s)
Colina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Colina Quinasa/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Hemicolinio 3/química , Células Hep G2 , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de ProteínaRESUMEN
Applying a CHOK hold: Combined experimental and computational studies of the binding mode of a rationally designed inhibitor of the dimeric choline kinaseâ α1 (CHOKα1) explain the molecular mechanism of negative cooperativity (see scheme) and how the monomers are connected. The results give insight into how the symmetry of the dimer can be partially conserved despite a lack of conservation in the static crystal structures.
Asunto(s)
Colina Quinasa/antagonistas & inhibidores , Colina Quinasa/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Regulación Alostérica , Colina Quinasa/metabolismo , Diseño de Fármacos , Humanos , Simulación de Dinámica Molecular , Conformación Proteica , Difracción de Rayos XRESUMEN
(1)H and (13)C NMR spectral data of 13 new compounds containing a 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium moiety linked to the N-9 or N-3 nitrogen atom of an adenine moiety were assigned. 1D and 2D NMR experiments (DEPT, HSQC and HMBC) allowed the unequivocal identification of N-9 and N-3 isomers.
Asunto(s)
Adenina/química , Inhibidores Enzimáticos/síntesis química , Nitrógeno/química , Resonancia Magnética Nuclear Biomolecular/métodos , Compuestos de Piridinio/química , Isótopos de Carbono , Colina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Isomerismo , Estructura Molecular , ProtonesRESUMEN
The (1) H and (13) C NMR resonances of twenty-seven 2,2-dimethyl-5-(2-nitrophenyl-5-substituted)-2,3-dihydro-1,3,4-thiadiazoles, and twenty-seven 3-acyl-5-(2-amino-5-substituted)-2,2-dimethyl-2,3-dihydro-1,3,4-thiadiazoles were assigned completely using the concerted application of one-dimensional and two-dimensional experiments (DEPT, HMQC and HMBC). NOESY experiments, X-ray crystallography and conformational analysis confirm the preferred conformation of these compounds.
Asunto(s)
Tiadiazoles/química , Espectroscopía de Resonancia Magnética/normas , Estructura Molecular , Estándares de ReferenciaRESUMEN
The (13) C NMR resonances of 19 1-acyl-3-(2-nitro-5-substitutedphenyl)-4,5-dihydro-1H-pyrazoles, and 19 1-acyl-3-(2-amino-5-substituted)-4,5-dihydro-1H-pyrazoles, were completely assigned using the concerted application of one- and two-dimensional NMR experiments (DEPT, gs-HSQC and gs-HMBC).
Asunto(s)
Pirazoles/química , Isótopos de Carbono , Espectroscopía de Resonancia Magnética/normas , Pirazoles/síntesis química , Estándares de ReferenciaRESUMEN
Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC(50)=0.061 microM and COX-2 IC(50)=0.325 microM; selectivity index (SI)=0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC(50)=0.011 microM and 0.398 microM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC(50)=1 microM, COX-2 IC(50)=0.011 microM; SI= approximately 92). Molecular docking studies of compounds 6b and 11b-d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Sitios de Unión , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Humanos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Melatonin prevents mitochondrial failure in models of sepsis through its ability to inhibit the expression and activity of both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases. Because Parkinson's disease (PD), like sepsis, is associated with iNOS induction, we assessed the existence of changes in iNOS/i-mtNOS and their relation with mitochondrial dysfunction in the MPTP model of PD, which also displays increased iNOS expression. We also evaluated the role of melatonin (aMT) and its brain metabolite, N(1)-acetyl-5-methoxykynuramine (AMK), in preventing i-mtNOS induction and mitochondrial failure in this model of PD. Mitochondria from substantia nigra (SN) and, to a lesser extent, from striatum (ST) showed a significant increase in i-mtNOS activity, nitrite levels, oxidative stress, and complex I inhibition after MPTP treatment. MPTP-induced i-mtNOS was probably related to mitochondrial failure, because its prevention by aMT and AMK reduced oxidative/nitrosative stress and restored complex I activity. These findings represent the first experimental evidence of a potential role for i-mtNOS in the mitochondrial failure of PD and support a novel mechanism in the neuroprotective effects of aMT and AMK.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Kinuramina/análogos & derivados , Intoxicación por MPTP/metabolismo , Melatonina/farmacología , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/biosíntesis , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/efectos de los fármacos , Animales , Calcio/farmacología , Cuerpo Estriado/enzimología , Citosol/enzimología , Complejo I de Transporte de Electrón/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Kinuramina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/enzimología , Proteínas Mitocondriales/genética , Óxido Nítrico Sintasa de Tipo I/biosíntesis , Óxido Nítrico Sintasa de Tipo I/genética , Óxido Nítrico Sintasa de Tipo II/genética , Nitritos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancia Negra/enzimologíaRESUMEN
The 1H and 13C NMR resonances of 22 5-(5-substituted-2-nitrophenyl)-1H-pyrrole-2-carboxamides, 22 5-(5-substituted-2-aminophenyl)-1H-pyrrole-2-carboxamides, and 9 5-phenyl-1H-pyrrole-2-carboxamides were assigned completely using the concerted application of one- and two-dimensional experiments (DEPT, gs-HMQC and gs-HMBC). NOE studies and conformational analysis confirm the preferred conformations of such compounds.
Asunto(s)
Pirazoles/química , Isótopos de Carbono , Espectroscopía de Resonancia Magnética , Conformación Molecular , Protones , Pirazoles/síntesis química , Estándares de Referencia , EstereoisomerismoRESUMEN
We have previously described a series of 4,5-dihydro-1H-pyrazole as moderately potent nNOS inhibitors. As a follow up of these studies, we report here the preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1H-pyrazole and 1-alkyl-3-benzoyl-1H-pyrazole as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS). None of the reported compounds exhibited significant iNOS or nNOS inhibition, although the 1-benzyl-3-(2-amino-5-chlorobenzoyl)-1H-pyrazole-5-carboxylic acid ethyl ester derivative (10l), which shows an inhibition of 50% versus iNOS at a 1mM final concentration and no activity against nNOS, is potentially amenable of further optimization. The reasons for the inactivity of the reported series are discussed on the basis of docking studies.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Alquilación , Animales , Inhibidores Enzimáticos/química , Masculino , Modelos Moleculares , Estructura Molecular , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Unión Proteica , Pirazoles/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
AIM: Choline kinase α inhibitors represent one of the newest classes of cytotoxic drugs for cancer treatment, since aberrant choline metabolism is a characteristic shared by many human cancers. RESULTS: Here, we present a new class of asymmetrical pyridinium/quinolinium derivatives developed and designed based on drug optimization. CONCLUSION: Among all compounds described here, compound 8, bearing a 7-chloro-4N-methyl-p-chloroaniline quinolinium moiety, exhibited the greatest inhibitory activity at the enzyme (IC50 = 0.29 µM) and antiproliferative activity in cellular assays (GI50 = 0.29-0.92 µM). Specifically, compound 8 strongly induces a cell-cycle arrest in G1 phase, but it does not significantly induce apoptosis while causing senescence in the MDA-MB-231 cell line.
Asunto(s)
Antineoplásicos/farmacología , Colina Quinasa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Compuestos de Piridinio/farmacología , Compuestos de Quinolinio/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Colina Quinasa/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/química , Compuestos de Quinolinio/síntesis química , Compuestos de Quinolinio/química , Relación Estructura-ActividadRESUMEN
Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite's growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase.
Asunto(s)
Antimaláricos/farmacología , Colina Quinasa/antagonistas & inhibidores , Fosfatidiletanolaminas/biosíntesis , Plasmodium falciparum/enzimología , Proteínas Protozoarias/antagonistas & inhibidores , Antimaláricos/química , Dominio Catalítico , Células Cultivadas , Colina Quinasa/química , Colina Quinasa/metabolismo , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Eritrocitos/parasitología , Humanos , Concentración 50 Inhibidora , Cinética , Modelos Moleculares , Plasmodium falciparum/efectos de los fármacos , Unión Proteica , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Trofozoítos/efectos de los fármacos , Trofozoítos/enzimologíaRESUMEN
A novel family of compounds derivative of 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bispyridinium or -bisquinolinium bromide (10a-l) containing a pair of oxygen atoms in the spacer of the linker between the biscationic moieties, were synthesized and evaluated as inhibitors of choline kinase against a panel of cancer-cell lines. The most promising compounds in this series were 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))bis(4-(dimethylamino)pyridinium) bromide (10a) and 1,1'-(((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methylene))-bis(7-chloro-4-(pyrrolidin-1-yl)quinolinium) bromide (10l), which inhibit human choline kinase (ChoKα1) with IC50 of 1.0 and 0.92 µM, respectively, in a range similar to that of the previously reported biscationic compounds MN58b and RSM932A. Our compounds show greater antiproliferative activities than do the reference compounds, with unprecedented values of GI50 in the nanomolar range for several of the cancer-cell lines assayed, and more importantly they present low toxicity in non-tumoral cell lines, suggesting a cancer-cell-selective antiproliferative activity. Docking studies predict that the compounds interact with the choline-binding site in agreement with the binding mode of most previously reported biscationic compounds. Moreover, the crystal structure of ChoKα1 with compound 10a reveals that this compound binds to the choline-binding site and mimics HC-3 binding mode as never before.
Asunto(s)
Antineoplásicos/química , Colina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Compuestos de Piridinio/química , Compuestos de Quinolinio/química , Antineoplásicos/síntesis química , Sitios de Unión , Butanos/química , Cationes , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colina Quinasa/química , Cristalización , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Simulación del Acoplamiento Molecular , Especificidad de Órganos , Unión Proteica , Compuestos de Piridinio/síntesis química , Relación Estructura-Actividad Cuantitativa , Compuestos de Quinolinio/síntesis químicaRESUMEN
To find new compounds with potential neuroprotective activity, we have designed, synthesized, and characterized a series of neural nitric oxide synthase (nNOS) inhibitors with a kynurenamine structure. Among them, N-[3-(2-amino-5-methoxyphenyl)-3-oxopropyl]acetamide is the main melatonin metabolite in the brain and shows the highest activity in the series, with an inhibition percentage of 65% at a 1 mM concentration. The structure-activity relationship of the new series partially reflects that of the previously reported 2-acylamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acids, endowed with a kynurenine-like structure. Structural comparisons between these new kinurenamine derivatives, kynurenines, and 1-acyl-3-(2-amino-5-methoxyphenyl)-4,5-dihydro-1H-pyrazole derivatives also reported confirm our previous model for the nNOS inhibition.
Asunto(s)
Kinuramina/análogos & derivados , Kinuramina/farmacología , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Kinuramina/síntesis química , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Conformación Molecular , RatasRESUMEN
Bispyridinium cyclophanes are novel templates for human choline kinase inhibitors. Molecular modelling of these compounds suggests three anchorage places at the binding site of the enzyme: (i) two anionic centres of the enzyme active site separated from each other at a distance of approximately 6.2 A that bind the two positively charged nitrogen atoms; (ii) a wide hydrophobic pocket that is fulfilled by the upper linker, the benzene ring that links the two amino groups; and (iii) a smaller hydrophobic pocket that can accommodate the lower benzene ring that links both benzylic carbons. This study may be useful for the development of more potent inhibitors of the enzyme.
Asunto(s)
Colina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Modelos Moleculares , Colina Quinasa/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Choline kinase (CK) catalyses the transfer of the ATP γ-phosphate to choline to generate phosphocholine and ADP in the presence of magnesium leading to the synthesis of phosphatidylcholine. Of the three isoforms of CK described in humans, only the α isoforms (HsCKα) are strongly associated with cancer and have been validated as drug targets to treat this disease. Over the years, a large number of Hemicholinium-3 (HC-3)-based HsCKα biscationic inhibitors have been developed though the relevant common features important for the biological function have not been defined. Here, selecting a large number of previous HC-3-based inhibitors, we discover through computational studies a pharmacophore model formed by five moieties that are included in the 1-benzyl-4-(N-methylaniline)pyridinium fragment. Using a pharmacophore-guided virtual screening, we then identified 6 molecules that showed binding affinities in the low µM range to HsCKα1. Finally, protein crystallization studies suggested that one of these molecules is bound to the choline and ATP-binding sites. In conclusion, we have developed a pharmacophore model that not only allowed us to dissect the structural important features of the previous HC-3 derivatives, but also enabled the identification of novel chemical tools with good ligand efficiencies to investigate the biological functions of HsCKα1.
Asunto(s)
Antineoplásicos/química , Colina Quinasa , Inhibidores Enzimáticos/química , Modelos Moleculares , Proteínas de Neoplasias , Neoplasias/enzimología , Colina Quinasa/antagonistas & inhibidores , Colina Quinasa/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Neoplasias/tratamiento farmacológicoRESUMEN
In an attempt to find new compounds with neuroprotective activity, we have designed, synthesized and characterized 19 new nNOS inhibitors with a 4,5-dihydro-1H-pyrazole structure. Compounds 11r [1-cyclopropanecarbonyl-3-(2-amino-5-chlorophenyl)-4,5-dihydro-1H-pyrazole] and 11e [1-cyclopropanecarbonyl-3-(2-amino-5-methoxyphenyl)- 4,5-dihydro-1H-pyrazole] show the highest activities with inhibition percentages of 70% and 62%, respectively. A structure-activity relationship for the nNOS inhibition can be established from the structural comparison of these new pyrazole derivatives and the described synthetic kynurenines 10.
Asunto(s)
Compuestos de Anilina/síntesis química , Cuerpo Estriado/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Pirazoles/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Cuerpo Estriado/enzimología , Técnicas In Vitro , Quinurenina/análogos & derivados , Quinurenina/química , Quinurenina/farmacología , Modelos Moleculares , Conformación Molecular , Óxido Nítrico Sintasa de Tipo I , Pirazoles/química , Pirazoles/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is involved in excitotoxicity, a process participating in neurodegeneration that characterizes some neurological disorders and acute cerebral insults. In looking for compounds with neuroprotective properties, a series of kynurenine derivatives were synthesized, and their effects on both the NMDA and nNOS activity in rat striatum were evaluated. Two compounds, 15a (2-acetamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) and 15c (2-butyramido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid), displayed more potent activities than the other synthetic compounds tested for the inhibition of NMDA excitability and nNOS activity. Two other compounds, 18a (2-acetamido-4-(3-methoxyphenyl)-4-oxobutyric acid) and 18c (2-butyramido-4-(3-methoxyphenyl)-4-oxobutyric acid), that have the same structure as 15a and 15c, except the amino group in R(1), showed different effects. Whereas compound 18a showed lower electrophysiological potency than compounds 15a and 15c in the inhibition of the NMDA-dependent excitability, compound 18c showed the opposite effect. Moreover, compounds 18a and 18c were unable to modify nNOS activity. The remaining kynurenines tested behave like compound 18a. These results suggest that a structure-related activity of these synthetic kynurenines and a N-H bond in a specific direction is necessary for some kynurenine analogues to inhibit nNOS activity.