New 2,6,9-trisubstituted adenines as adenosine receptor antagonists: a preliminary SAR profile

A new series of 2,6,9-trisubstituted adenines (5–14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A1, A2A and A3 adenosine receptors and in adenylyl cyclase experiments for their potency at the human A2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N6 position of 9-propyladenine significantly increased binding affinity at the human A1 and A3 adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending on the receptor subtype and/or on the substituent present in the N6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human A2B subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct receptor selectivity profiles

2- and 8-alkynyl-9-ethyladenines: Synthesis and biological activity at human and rat adenosine receptors

The synthesis of a series of 9-ethyladenine derivatives bearing alkynyl chains in 2- or 8-position was undertaken, based on the observation that replacement of the sugar moiety in adenosine derivatives with alkyl groups led to adenosine receptor antagonists. All the synthesized compounds were tested for their affinity at human and rat A1, A2A, and A3 adenosine receptors in binding assays; the activity at the human A2B receptor was determined in adenylyl cyclase experiments. Biological data showed that the 2-alkynyl derivatives possess good affinity and are slightly selective for the human A2A receptor. The same compounds tested on the rat A1 and A2A subtypes showed in general lower affinity for both receptors. On the other hand, the affinity of the 8-alkynyl derivatives at the human A1, A2A, and A2B receptors proved to be lower than that of the corresponding 2-alkynyl derivatives. On the contrary, the affinity of the same compounds for the human A3 receptor was improved, resulting in A3 selectivity. As in the case of the 2-alkynyl-substituted compounds, the 8-alkynyl derivatives showed decreased affinity for rat receptors. However, it is worthwhile to note that the 8-phenylethynyl-9-ethyladenine was the most active compound of the two series (Ki in the nanomolar range) at both the human and rat A3 subtype. Docking experiments of the 2- and 8-phenylethynyl-9-ethyladenines, at a rhodopsin-based homology model, gave a rational explanation of the preference of the human A3 receptor for the 8-substituted compound

GPR17 receptor modulators and their therapeutic implications: review of recent patents

Introduction: The GPR17 receptor, phylogenetically related to both purinergic P2Y and CysLT receptors, is mainly expressed in the CNS and, in general, in organs that can typically undergo ischemic damage. This receptor is involved in various pathologies including stroke, brain and spinal cord trauma, multiple sclerosis and in all diseases characterized by neuronal and myelin dysfunction. Therefore, there is a strong needed to identify molecules capable of binding specifically to GPR17 receptors. Areas covered: The review provides a summary of patents, published between 2009 and 2018, on chemicals and biologics and their clinical use. In this work, information is reported about the representative structures and biological activity of recently developed GPR17 receptor ligands. Expert opinion: The GPR17 receptor is an enigmatic receptor and an interesting therapeutic target in a variety of brain disorders and demyelinating diseases such as multiple sclerosis, stroke, schizophrenia, and depression. The modulation of this receptor could also be potentially useful in obesity treatment. Unfortunately, so far, there are no compounds under investigation in clinical trials but many researchers and companies are investing in the discovery of future potential GPR17 receptor drugs

Estimation of genetic diversity in viral populations from next generation sequencing data with extremely deep coverage

In this paper we propose a method and discuss its computational implementation as an integrated tool for the analysis of viral genetic diversity on data generated by high-throughput sequencing. Most methods for viral diversity estimation proposed so far are intended to take benefit of the longer reads produced by some NGS platforms in order to estimate a population of haplotypes. Our goal here is to take advantage of distinct virtues of a certain kind of NGS platform - the platform SOLiD (Life Technologies) is an example - that has not received much attention due to the short length of its reads, which renders haplotype estimation very difficult. However, this kind of platform has a very low error rate and extremely deep coverage per site and our method is designed to take advantage of these characteristics. We propose to measure the populational genetic diversity through a family of multinomial probability distributions indexed by the sites of the virus genome, each one representing the populational distribution of the diversity per site. The implementation of the method focuses on two main optimization strategies: a read mapping/alignment procedure that aims at the recovery of the maximum possible number of short-reads; the estimation of the multinomial parameters through a Bayesian approach, which, unlike simple frequency counting, allows one to take into account the prior information of the control population within the inference of a posterior experimental condition and provides a natural way to separate signal from noise, since it automatically furnishes Bayesian confidence intervals. The methods described in this paper have been implemented as an integrated tool called Tanden (Tool for Analysis of Diversity in Viral Populations).Comment: 30 pages, 5 figures, 2 tables, Tanden is written in C# (Microsoft), runs on the Windows operating system, and can be downloaded from: http://tanden.url.p

Adenosine receptor agonists: Synthesis and binding affinity of 2-(aryl)alkylthioadenosine derivatives

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CDC in brief 2013

With the start of the 113th Congress, we\u2019d like to take an opportunity to (re)introduce the Centers for Disease Control and Prevention (CDC), and provide some helpful information about our agency and its work. This E-Brief contains links to useful information about CDC\u2019s science, budget, and presence on the ground. For quick access to additional information about CDC\u2019s work, please contact the CDC Washington Office at (202) 245-0600, and see below for information about how CDC Washington can help you.CS238048-6What CDC does -- Fast facts -- CDC on the ground -- How can CDC Washington help you?201

Efecto de extractos de hojas y frutos de Schinus molle sobre la estabilidad oxidativa de aceites mediante oxidación acelerada

The most highly recommended oils for the diet are those which are rich in unsaturated fatty acids. However, the presence of these components in the oils is related to oxidation, which can be determined by the induction period. Further safety and the prolongation of the storage period for such oils can be achieved by the addition of efficient antioxidants, which today are preferably from natural sources. In order to contribute to the related research, the main objective of this study was to evaluate the efficacy of Schinus molle extracts compared to synthetic antioxidants (BHT) in delaying the oxidation of some vegetable oils. The results of the present study showed that the fruit and leaf extracts of Schinus molle presented activities and potential for being used as antioxidants in vegetable oils based on the tested methods (DPPH and ABTS). The extracts were also characterized as containing phenolic compounds by the Folin Ciocalteau method and by high performance liquid chromatography (HPLC). The action of the extracts as natural antioxidants was proven in the vegetal oils of chia (Salvia hispanica) and peanut (Arachis hypogaea) by the Rancimat method. It was observed that the oils increased their resistance to oxidation when incorporated with the extracts of Schinus molle, and the extract from the leaves increased the induction period of peanut oil by more than three hours (from 19.5 to 22.9 hours) with an extract concentration of 2.5%. The fruit extract was more efficient in delaying the oxidation of chia oil, prolonging its induction period by more than one hour with a concentration of 2.5% (from 3.1 to 4.3 hours). According to the results, the extracts of Schinus molle have favorable properties for possible use as an additive which inhibits the oxidation process of the tested vegetables oils.Los aceites más recomendados para la dieta son los ricos en ácidos grasos insa­turados. Sin embargo, la presencia de estos componentes está relacionada con la oxidación del aceite, que puede determinarse por el período de inducción. La seguridad adicional de tales aceites y la prolongación del almacenamiento se pueden lograr mediante la adición de antioxidantes eficientes, que hoy en día se prefieren los provenientes de fuentes naturales. Para contribuir con estas investigaciones, el objetivo principal de este estudio fue evaluar la eficacia de los extractos de Schinus molle en comparación con el antioxidante sintético BHT, para retrasar la oxidación de algunos aceites vegetales. Los resultados del presente estudio mostraron que los extractos de frutas y hojas de Schinus molle presentan potencial para ser utilizados como antioxidan­tes en aceites vegetales, presentando actividades basadas en métodos probados, DPPH y ABTS. Los extrac­tos también se caracterizaron por la presencia de compuestos fenólicos determinados mediante el método de Folin Ciocalteau y por cromatografía líquida de alta resolución (HPLC). La acción de los extractos como antioxidantes naturales se evidenció en aceites vegetales de chía (Salvia hispanica) y maní (Arachis hypogaea) por el método Rancimat. Se observó que los aceites aumentan la resistencia a la oxidación cuando se le incor­poran extractos de Schinus molle, aumentando el periodo de inducción en más de tres horas (de 19,5 a 22,9 horas) del aceite de cacahuete con una concentración de extracto del 2,5%. El extracto de fruta fue más efi­ciente en retrasar la oxidación del aceite de chia, prolongando el período de inducción de este aceite en más de una hora con una concentración del 2,5% (de 3,1 a 4,3 horas). De acuerdo con los resultados, los extractos de Schinus molle tienen propiedades favorables para un posible uso como un aditivo inhibidor del proceso de oxidación de los aceites vegetales ensayados

Erratum to: Molecular modelling study of 2-phenylethynyladenosine (PEAdo) derivatives as highly selective A3 adenosine receptor ligands

A series of 2-phenylethynyladenosine (PEAdo) derivatives substituted in the N6- and 4′position was synthesised and the new derivatives were tested at the four human adenosine receptors stably transfected into Chinese hamster ovary (CHO) cells, using radioligand binding studies (A1, A2A, A3) or adenylyl cyclase activity assay (A2B). Binding studies showed that the presence of a phenyl ethynyl group in the 2 position of adenosine favoured the interaction with A3 receptors, resulting in compounds endowed with high affinity and selectivity for the A3 subtype. Additional substitution of the N6- and 4′position increases both A3 affinity and selectivity. The results showed that the new compounds have a good affinity for the A3 receptor and in particular, the N6-methoxy-2-phenylethynyl-5′N-methylcarboxamidoadenosine, with a Ki at A3 of 1.9 nM and a selectivity A1/A3 and A2A/A3 of 4,800- and 8,600-fold, respectively. Therefore, it is one of the most potent and selective agonists at the human A3 adenosine receptor subtype reported so far. Furthermore, functional assays of inhibition of 10 μM forskolin-stimulated cAMP production via the adenosine A3 receptor revealed that the new trisubstituted adenosine derivatives behave as full agonist of this receptor subtype. Docking analysis of these compounds was performed at a homology model of the human A3 receptor based on the bovine rhodopsin crystal structure as template, and the results are in accordance with the biological data

Adenosine Receptors as Neuroinflammation Modulators: Role of A1 Agonists and A2A Antagonists

The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are A1AR and A2AAR. Evidence suggests that A1AR activation produces a neuroprotective effect and A2AARs block prevents neuroinflammation. The aim of this work is to elucidate the effects of these receptors in neuroinflammation using the partial agonist 2'-dCCPA (2-chloro-N6-cyclopentyl-2'-deoxyadenosine) (C1 KiA1AR = 550 nM, KiA2AAR = 24,800 nM, and KiA3AR = 5560 nM, α = 0.70, EC50A1AR = 832 nM) and the newly synthesized in house compound 8-chloro-9-ethyl-2-phenethoxyadenine (C2 KiA2AAR = 0.75 nM; KiA1AR = 17 nM and KiA3AR = 227 nM, IC50A2AAR = 251 nM unpublished results). The experiments were performed in in vitro and in in vivo models of neuroinflammation. Results showed that C1 was able to prevent the inflammatory effect induced by cytokine cocktail (TNF-α, IL-1β, and IFN-γ) while C2 possess both anti-inflammatory and antioxidant properties, counteracting both neuroinflammation in mixed glial cells and in an animal model of neuroinflammation. In conclusion, C2 is a potential candidate for neuroinflammation therapy