RESUMEN
Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system and has a considerable impact on the quality of life. Neuropathic pain has a dynamic and complex aetiology and gives heterogeneous symptoms across patients; therefore, it represents an important clinical challenge. Current pharmacological treatment includes tricyclic antidepressant serotonin-noradrenaline uptake inhibitors such as duloxetine, pregabalin, and gabapentin. However, these drugs do not show efficacy in all patients suffering from neuropathic pain. In this work we used a nerve chronic constriction injury mice model based on the ligation of sciatic nerve to analyse, by two-dimensional electrophoresis and mass spectrometry, blood proteins significantly altered by neuropathic pain one-week after surgery. A sham-ligated group of mice acting as control and a group of ligated mice treated with gabapentin were also analysed. The results indicated that four haptoglobin isoforms were significantly more expressed, while transthyretin and alpha-2-macroglobulin expression decreased in the serum of the murine neuropathic pain model with respect to the control mice. Interestingly, the treatment with the gabapentin reversed these conditions. The outcomes of this study can provide a further understanding of the pathophysiological meaning of the biomarkers involved in neuropathic pain.
Asunto(s)
Haptoglobinas/metabolismo , Neuralgia/sangre , Prealbúmina/metabolismo , alfa 2-Macroglobulinas Asociadas al Embarazo/metabolismo , Nervio Ciático , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Neuralgia/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
The first demonstrations in the early seventies that adenosine had marked effects in the cerebral cortex, which were independent of its role in intermediary metabolism and could be antagonised by methylxanthines, were followed by the observations that other purine derivatives, notably ATP, may also play a critical role in cell function. In 1978 Burnstock first introduced the terms Pl for the nucleoside receptors and P2 for the nucleotide receptors, based on the most fundamental divisions of purine receptors between those for nucleosides such as adenosine and those for nucleotides such as ATP. At present, the P1 (adenosine) receptor family presents 4 subtypes, while the P2 (ATP, ADP and UTP) receptor family has been divided into P2X ionotropic receptors and P2Y metabotropic G protein-coupled receptors (GPCRs). While knowledge on the purinergic receptor pharmacology was increasing, the development of potent and selective ligands for these receptors has been a target of medicinal chemistry research for several decades. In particular, synthesis of 2-substituted adenosines was carried out in many laboratories starting from seventies aimed at finding adenosine derivatives more resistant than the parent nucleoside to rapid uptake into cells, to deamination by adenosine deaminase, and to phosphorylation by adenosine kinase. In the present review the synthesis of alkynyl derivatives of adenine, adenosine, N-alkylcarboxamidoadenosine, and adenine nucleotides, which have been tested on purinergic receptors, will be summarized. Furthermore, the contribution of chemistry, molecular modelling, and pharmacology to the development of structure-activity relationships in this class of purinergic receptor ligands will be outlined.
Asunto(s)
Nucleótidos de Adenina/química , Adenina/análogos & derivados , Nucleótidos/metabolismo , Nucleósidos de Purina/química , Receptores Purinérgicos/química , Adenina/química , Adenina/metabolismo , Nucleótidos de Adenina/metabolismo , Animales , Humanos , Nucleótidos/química , Nucleósidos de Purina/metabolismo , Receptores Purinérgicos/metabolismo , Relación Estructura-ActividadRESUMEN
Since the discovery of the biological effects of adenosine, the development of potent and selective agonists and antagonists of adenosine receptors has been the subject of medicinal chemistry research for several decades, even if their clinical evaluation has been discontinued. Main problems include side effects due to the ubiquity of the receptors and the possibility of side effects, or to low brain penetration (in particular for the targeting of CNS diseases), short half-life of compounds, lack of effects. Furthermore, species differences in the affinity of ligands make difficult preclinical testing in animal models. Nevertheless, adenosine receptors continue to represent promising drug targets. A(2A) receptor has proved to be a promising pharmacological target for small synthetic ligands, and while A(2A) agonists are undergoing clinical trials for myocardial perfusion imaging and as anti-inflammatory agents, A(2A) antagonists represent an attractive field of research to discover new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease. Furthermore, the information coming from bioinformatics and molecular modeling studies for the A(2A) receptor has made easier the understanding of ligand-target interaction and the rational design of agonists and antagonists for this subtype. The aim of this review is to show an overview of the most significant steps and progresses in developing A(2A) adenosine receptor agonists and antagonists.
Asunto(s)
Agonistas del Receptor de Adenosina A2 , Antagonistas del Receptor de Adenosina A2 , Adenina/análogos & derivados , Adenina/química , Adenina/farmacología , Adenosina/análogos & derivados , Adenosina/química , Adenosina/farmacología , Animales , Diseño de Fármacos , Agonismo Parcial de Drogas , Humanos , Ligandos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Conformación Proteica , Radiofármacos/química , Radiofármacos/metabolismo , Receptor de Adenosina A2A/química , Relación Estructura-Actividad , Xantinas/química , Xantinas/farmacologíaRESUMEN
Levels of 18 polychlorinated biphenyl (PCB) congeners were determined by gas chromatography-mass spectrometry (GC-MS) in some marine species, living both in the coastal area and in deeper seawater. In some species analysis was performed separately in edible parts (fillets) and in viscera. The existence and degree of bioaccumulation was assessed studying individual species of very different size, with the smaller being younger. Furthermore, with a multivariate statistical analysis, a correlation between PCB congeners and the feeding habits and habitat of the fish was demonstrated. The results show that fat from edible parts (fish fillets) had total PCB levels in the range 22.6-601.9 µg kg⻹ (with 601.9 µg kg⻹ in anchovies), while fat from viscera showed much higher concentrations (407.3-916.6 µg kg⻹). Bioaccumulation was confirmed, comparing PCB levels between younger and older individual hake, squid, and horned octopus. The total PCB concentration ratio (older/younger individuals) ranges from 2.11 (squid = 292.1/137.8 µg kg⻹) to 3.46 (hake = 546.0/158.0 µg kg⻹).
Asunto(s)
Crustáceos/química , Peces , Contaminación de Alimentos , Moluscos/química , Bifenilos Policlorados/análisis , Alimentos Marinos/análisis , Mariscos/análisis , Animales , Carcinógenos Ambientales/análisis , Carcinógenos Ambientales/metabolismo , Crustáceos/crecimiento & desarrollo , Crustáceos/metabolismo , Dieta/etnología , Grasas de la Dieta/análisis , Peces/crecimiento & desarrollo , Peces/metabolismo , Cadena Alimentaria , Inspección de Alimentos , Humanos , Grasa Intraabdominal/química , Grasa Intraabdominal/crecimiento & desarrollo , Grasa Intraabdominal/metabolismo , Italia , Mar Mediterráneo , Moluscos/crecimiento & desarrollo , Moluscos/metabolismo , Bifenilos Policlorados/metabolismo , Análisis de Componente Principal , Alimentos Marinos/economía , Mariscos/economía , Vísceras/química , Vísceras/crecimiento & desarrollo , Vísceras/metabolismo , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/metabolismoRESUMEN
Viral infections have menaced human beings since time immemorial, and even today new viral strains that cause lethal diseases are being discovered with alarming frequency. One major example is HIV, the etiological agent of AIDS, which spread up in the last two decades. Very recently, other virus based diseases such as avian flu have spread fear around the world, and hemorrhagic fevers from central Africa serious threaten human health because of their very deadly effects. New antiviral agents are still greatly needed to counter these menaces. Many scientists are involved in this field of research, and many of the recently discovered effective antiviral compounds are nucleoside analogues. Among those derivatives, deazapurine nucleoside analogues have demonstrated potent inhibitory effect of viral replication. This review reports on recently generated data from preparing and testing deazapurine nucleoside derivatives as inhibitors in virus replication systems. Although most of the reported data have been produced in antiHIV, antiHCMV, and antiHSV biological testing, very recently other new important fields of application have been discovered, all in topical subjects of strong interest. In fact, deazapurine nucleosides have been found to be active as chemotherapeutics for some veterinary systemic viral infections, for which no antiviral drugs are licensed yet. Furthermore, they demonstrated efficacy in the inhibition of Hepatitis C virus replication. Finally, these compounds showed high potency as virucides against Ebola Virus, curing Ebola infected mice with a single dose administration.
Asunto(s)
Antivirales/farmacología , Tubercidina/análogos & derivados , Tubercidina/uso terapéutico , Animales , Antivirales/química , Humanos , Concentración 50 Inhibidora , Relación Estructura-Actividad , Tubercidina/farmacología , Virus/efectos de los fármacosRESUMEN
In an attempt to improve the AzA selectivity of the 2-(aryl)alkylthio derivatives of adenosine, we planned the synthesis of the corresponding derivatives of the 5-N-ethylcarboxamidoadenosine (NECA). For this purpose, we designed the synthesis of 2-mercapto-NECA to be pursued by means of an opening-closure method We obtained the open AICAR analog; however, ring closure efforts failed to give the desired compound. The newly synthesized AICAR derivative could potentially be endowed with antiviral or antitumoral activity.
Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Antimetabolitos/síntesis química , Ribonucleótidos/síntesis química , Adenosina-5'-(N-etilcarboxamida)/síntesis química , Adenosina-5'-(N-etilcarboxamida)/farmacología , Aminoimidazol Carboxamida/síntesis química , Aminoimidazol Carboxamida/farmacología , Antimetabolitos/farmacología , Antineoplásicos/síntesis química , Antivirales/síntesis química , Química Farmacéutica/métodos , Diseño de Fármacos , Modelos Químicos , Ribonucleótidos/farmacologíaAsunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Receptor de Adenosina A3/química , Adenosina/síntesis química , Adenosina/química , Animales , Células CHO , Carbono/química , Cricetinae , Cinética , Ligandos , Modelos Químicos , Biología Molecular , Receptor de Adenosina A3/metabolismo , Receptores Purinérgicos P1/metabolismo , TransfecciónRESUMEN
In the search for agonists for the elusive A2B adenosine receptor subtypes, 2-phenylhydroxypropynyl-5'-N-methylcarboxamido adenosine (PHPMECA, 14), 2-phenylhydroxypropynyl-5'-N-propylcarboxamido adenosine (PHPPECA, 15), and N6-ethyl-2-phenylhydroxypropynyl-5'-N-ethylcarboxamidoadenosine (19) were synthesized on the basis that introduction of alkynyl chains in 2-position of adenosine derivatives resulted in reasonably good A2B potency compared to NECA [see N6-ethyl-2-phenylhydroxypropynyl adenosine (5) EC50 = 1,700 nM and 2-phenylhydroxypropynyl-5'-N-ethylcarboxamido adenosine (PHPNECA, 8) EC50 = 1,100 nM, respectively]. Radioligand binding studies and adenylyl cyclase assays, performed with recently cloned human A1, A2A, A2B, and A3 adenosine receptors, showed that these modifications produced a decrease in potency at A2B receptor, as well as a general reduction in affinity at the other receptor subtypes. On the other hand, the contemporary presence of an ethyl substituent in N6-position and of a 4'-ethylcarboxamido group in the same compounds led to (R,S)-N6-ethyl-2-phenylhydroxypropynyl-5'-N-ethylcarboxamidoadenosine and (S)-N6-ethyl-2-phenylhydroxypropynyl-5'-N-ethylcarboxamidoadenosine, which did not show the expected increase in potency at A2B subtype. Hence, (S)-2-phenylhydroxypropynyl-5'-N-ethylcarboxamidoadenosine [(S)-PHPNECA] with EC50 A2B = 220 nM remains the most potent agonist at A2B receptor reported so far.
Asunto(s)
Agonistas del Receptor de Adenosina A2 , Adenosina-5'-(N-etilcarboxamida)/análogos & derivados , Adenosina/síntesis química , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida)/síntesis química , Adenosina-5'-(N-etilcarboxamida)/farmacología , Animales , Células CHO , Cricetinae , Humanos , Ligandos , Ensayo de Unión RadioliganteRESUMEN
Adenosine derivatives bearing in 2-position the (R,S)-phenylhydroxypropynyl chain were evaluated for their potency at human A2B adenosine receptor, stably transfected on CHO cells, on the basis that (R,S)-2-phenylhydroxy-propynyl-5'-N-ethylcarboxyamidoadenosine [(R,S)-PHPNECA] was found to be a good agonist at the A2B receptor subtype. Biological studies demonstrated that the presence of small alkyl groups in N6-position of these molecules are well tolerated, whereas large groups abolished A2B potency. On the other hand, the presence of an ethyl group in the 4'-carboxamido function seems to be optimal, the (S)-PHPNECA resulting the most potent agonist at A2B receptor reported so far.
Asunto(s)
Agonistas del Receptor de Adenosina A2 , Adenosina/análogos & derivados , Adenosina/síntesis química , Adenosina/química , Adenosina/farmacología , Indicadores y Reactivos , Modelos Moleculares , Estructura MolecularRESUMEN
In the absence of an experimentally elucidated three-dimensional structure of the human CDA, we built an homology model of this enzyme starting from the crystal structure of its E. coli homologous. Furthermore, we docked in the active site alternatively the substrate, the intermediate or the product. By means of molecular dynamics simulations, we determined the topology of the active site, identifying the amino acids involved in the catalytic mechanism, and outlining the central role played by E67.
Asunto(s)
Citidina Desaminasa/química , Citidina Desaminasa/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Catálisis , Escherichia coli , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Humanos , Modelos Moleculares , Conformación Proteica , Estructura Secundaria de Proteína , Subunidades de Proteína/química , Subunidades de Proteína/metabolismoRESUMEN
2,6-Dichloro-1-deazapurine and 2,6-dichloro-3-deazapurine were coupled with 1,2-O-diacetyl-5-O-benzoyl-3-deoxy-beta-D-ribofuranose. Deprotection of the obtained compounds and reaction with liquid ammonia gave the desired 2-chloroadenine nucleosides, which were dechlorinated to afford the corresponding 1-deaza and 3-deazaadenosine derivatives. Biological studies performed on ADA from calf intestine showed that these new nucleosides are inhibitors of the enzyme.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Adenosina/análogos & derivados , Desoxirribosa/análogos & derivados , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Adenosina/farmacología , Animales , Bovinos , Desoxirribosa/química , Desoxirribosa/farmacología , Inhibidores Enzimáticos/síntesis química , Intestinos/enzimología , Cinética , Espectroscopía de Resonancia Magnética , Espectrofotometría UltravioletaRESUMEN
Adenosine derivatives bearing different (ar)alkynyl chains at the 8-position were synthesized and tested at human adenosine receptors. Binding studies showed that all compounds possess affinity for the A3 subtype in the high nM range. Moreover, guanosine 5'-O-(3-[35S]thio)triphosphate binding assay indicated that the 8-alkynyl adenosines behaved as antagonists of NECA at A3 receptors.
Asunto(s)
Adenosina/análogos & derivados , Receptores Purinérgicos P1/metabolismo , Adenosina/síntesis química , Adenosina/metabolismo , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida)/antagonistas & inhibidores , Adenosina-5'-(N-etilcarboxamida)/metabolismo , Adenosina-5'-(N-etilcarboxamida)/farmacología , Alquilación , Animales , Células CHO , Cricetinae , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Agonistas del Receptor Purinérgico P1 , Receptor de Adenosina A3RESUMEN
1,2,3-Tri-O-acetyl-N-ethyl-beta-D-ribofuranuronamide was synthesized in three steps starting from 1-O-methyl-(2,3-O-isopropylidene)-beta-D-ribofuranuronic acid. Both the triacetyl and the 1-O-methyl-2,3-di-O-acetyl derivatives were coupled to the 2,6-dichloropurine to obtain the acetylated 1-(2,6-dichloro-9H- purin-9-yl)-1-deoxy-N-ethyl-beta-D-erythro-pentofuranuronamide. 1H NMR and n.O.e. data accounted for both anomeric and N-7/N-9 isomeric configuration.
Asunto(s)
Monosacáridos/síntesis química , Purinas/síntesis química , Ribosa/análogos & derivados , Ligandos , Receptores Purinérgicos P1/metabolismoRESUMEN
2-Phenylethynyladenosine and its N6-methyl derivative were synthesized and evaluated in binding assays at human adenosine receptors stably transfected on CHO cells. Results showed that the N6-methyl-2-phenylethynyladenosine is endowed with very high affinity and selectivity at A3 receptor subtype. Hence, an alternative procedure for the synthesis of tritiated N6-methyl-2-phenylethynyladenosine was set up to introduce tritiated methylamine in the final step.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/química , Receptores Purinérgicos P1/metabolismo , Adenosina/metabolismo , Animales , Células CHO , Cricetinae , Humanos , Marcaje Isotópico/métodos , Ligandos , Receptor de Adenosina A3 , Especificidad por Sustrato , TritioRESUMEN
Some 8-alkynyladenosines were synthesized and evaluated for their adenosine receptor activity, utilizing radioligand binding studies (A(1), A(2A), A(3)) or adenylyl cyclase activity assays (A(2B)). Furthermore, the maximal induction of guanosine 5'-(gamma-thio)triphosphate ([35S]GTPgammaS) binding to G proteins and the inhibition of NECA-stimulated binding, in membranes of CHO cells which express the human A(3) receptor, were used to determine the intrinsic activity of these nucleosides at the A(3) adenosine receptor. The results showed that these new adenosine derivatives are very selective ligands for the A(3) receptor subtype and behave as adenosine antagonists, since they do not stimulate basal [35S]GTPgammaS binding, but inhibit NECA-stimulated binding. This is the first report that adenosine derivatives, with unmodified ribose moiety, are adenosine receptor antagonists.
Asunto(s)
Adenosina/análogos & derivados , Adenosina/farmacología , Proteínas de Unión al GTP/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Antagonistas de Receptores Purinérgicos P1 , Adenosina/síntesis química , Adenosina-5'-(N-etilcarboxamida)/farmacología , Adenilil Ciclasas/análisis , Adenilil Ciclasas/metabolismo , Animales , Sitios de Unión/fisiología , Células CHO , Cricetinae , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ensayo de Unión Radioligante , Sensibilidad y EspecificidadRESUMEN
Analogues of Taxol (paclitaxel) with the side chain conformationally restricted by insertion of a carbon linker between the 2'-carbon and the ortho-position of the 3'-phenyl ring were synthesized. Biological evaluation of these new taxoids showed that activity was dependent on the length of the linker and the configuration at C2' and C3'. Two analogues in the homo series, 9a and 24a, showed tubulin binding and cytotoxicity comparable to that of Taxol. NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution of the averaged 2-D NMR spectra for 9a yields seven conformations. Within the latter set, the hydrophobically collapsed "nonpolar" and "polar" classes are represented by one conformation each with predicted populations of 12-15%. The five remaining conformers, however, are extended, two of which correspond to the T-conformation (47% of the total population). The latter superimpose well with the recently proposed T-Taxol binding conformer in beta-tubulin. The results provide evidence for the existence of two previously unrecognized structural features that support Taxol-like activity: (1) a reduced torsion angle between C2' and C3' and (2) an orthogonal arrangement of the mean plane through C1', C2' and the 2'-hydroxyl and the 3'-phenyl plane, the latter ring bisected by the former plane. By contrast, epimerization at 2',3' and homologation of the tether to CH2-CH2 were both detrimental for activity. The decreased activity of these analogues is apparently due to configurational and steric factors, respectively.
Asunto(s)
Antineoplásicos/síntesis química , Paclitaxel/análogos & derivados , Paclitaxel/síntesis química , Taxoides , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Paclitaxel/química , Paclitaxel/farmacología , Tubulina (Proteína)/química , Células Tumorales CultivadasRESUMEN
Adenosine deaminase (ADA) is an enzyme of the purine metabolism which catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. This ubiquitous enzyme has been found in a wide variety of microorganisms, plants, and invertebrates. In addition, it is present in all mammalian cells that play a central role in the differentiation and maturation of the lymphoid system. However, despite a number of studies performed to date, the physiological role played by ADA in the different tissues is not clear. Inherited ADA deficiency causes severe combined immunodeficiency disease (ADA-SCID), in which both B-cell and T-cell development is impaired. ADA-SCID has been the first disorder to be treated by gene therapy, using polyethylene glycol-modified bovine ADA (PEG-ADA). Conversely, there are several diseases in which the level of ADA is above normal. A number of ADA inhibitors have been designed and synthesized, classified as ground-state and transition-state inhibitors. They may be used to mimic the genetic deficiency of the enzyme, in lymphoproliferative disorders or immunosuppressive therapy (i.e., in graft rejection), to potentiate the effect of antileukemic or antiviral nucleosides, and, together with adenosine kinase, to reduce breakdown of adenosine in inflammation, hypertension, and ischemic injury.