Simulation and comparative analysis of binding modes of nucleoside and non-nucleoside agonists at the A2B adenosine receptor

PURPOSE: A(2B) receptor agonists are studied as possible therapeutic tools for a variety of pathological conditions. Unfortunately, medicinal chemistry efforts have led to the development of a limited number of potent agonists of this receptor, in most cases with a low or no selectivity versus the other adenosine receptor subtypes. Among the developed molecules, two structural families of compounds have been identified based on nucleoside and non-nucleoside (pyridine) scaffolds. The aim of this work is to analyse the binding mode of these molecules at 3D models of the human A(2B) receptor to identify possible common interaction features and the key receptor residues involved in ligand interaction. METHODS: The A(2B) receptor models are built by using two recently published crystal structures of the human A(2A) receptor in complex with two different agonists. The developed models are used as targets for molecular docking studies of nucleoside and non-nucleoside agonists. The generated docking conformations are subjected to energy minimization and rescoring by using three different scoring functions. Further analysis of top-score conformations are performed with a tool evaluating the interaction energy between the ligand and the binding site residues. RESULTS: Results suggest a set of common interaction points between the two structural families of agonists and the receptor binding site, as evidenced by the superimposition of docking conformations and by analysis of interaction energy with the receptor residues. CONCLUSIONS: The obtained results show that there is a conserved pattern of interaction between the A(2B) receptor and its agonists. These information and can provide useful data to support the design and the development of A(2B) receptor agonists belonging to nucleoside or non-nucleoside structural families. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2193-9616-1-24) contains supplementary material, which is available to authorized users

Effect of the replacement of the o-methoxyphenyl moiety with nitrogen-containing aromatic rings within N-phenyl-piperazine and phenoxy-ethylamine-based 1,3-dioxo/oxathio/dithiolanes as α1 and 5-HT1A receptor ligands

In the present work, nineteen analogues of 1-[(2,2-Diphenyl-1,3-dioxolan-4-yl)methyl]-4-(2-methoxyphenyl)piperazine 5 and N-[2-(2-Methoxyphenoxy)ethyl]-2,2-diphenyl-1,3-dioxolane-4-methanamine 18 were synthesized. The compounds were tested for binding affinity at 5-HT1AR and α1-AR subtypes. They were also tested using functional assays as α1-AR antagonists and the most promising were tested for functional activity at 5-HT1AR, where they were shown to behave as agonists. The results highlight that the replacement of the 1,3-dioxolane ring with a 1,3-oxathiolane or a 1,3-dithiolane moiety leads to an overall reduction in in-vitro affinity at the α1-AR, while affinity, potency and efficacy were strongly enhanced at the 5-HT1A receptor. Overall, the nitrogen-containing aromatic moieties scarcely affect the affinity at the 5-HT1A receptor, while reducing potency and increasing efficacy. The oxidation of the sulphur atom in the 1,3-oxathiolane to give sulfoxides and solfones has a negative effect on affinity and potency at both receptor systems. Regardless of the effect on the other parameters, selectivity toward 5-HT1AR with respect to the α1-AR is often favoured, but never the contrary. The most striking result is the inversion of selectivity. In fact, while the lead 5 is 100-fold selective for α1-AR, the new derivatives, although to differing degrees, are selective for 5-HT1AR

Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine. The ChE-Is currently available in the market are donepezil, rivastigmine and galantamine as tacrine is no longer in use, due to its hepatotoxicity. According to mechanism of action the ChE-Is are classified as short-acting or reversible agents such as tacrine, donepezil, and galantamine, as intermediate-acting or pseudo-irreversible agent such as rivastigmine. Overall, the efficacy of the three ChE-Is available in the market is similar and the benefit of administration of these compounds is mild and may not be clinically significant. Due to gastrointestinal side effects of these drugs, medicinal chemistry and pharmaceutical delivery studies have investigated solutions to improve the pharmacological activity of these compounds. In spite of the limited activity of ChE-Is, waiting for more effective approaches, these drugs still represent a pharmacotherapeutic resource for the treatment of AD. Other approaches in which ChE-Is were investigated is in their use in combination with other classes of drugs such as cholinergic precursors, N-methyl-d-aspartate (NMDA) receptor antagonists and antioxidant agents. After many years from the introduction in therapy of ChE-Is, the combination with other classes of drugs may represent the chance for a renewed interest of ChE-Is in the treatment of adult-onset dementia disorders

Overview on Radiolabel-Free in Vitro Assays for GPCRs

G-protein coupled receptors (GPCRs) represent important targets for drug discovery because they participate in a wide range of cellular signalling pathways that play a role in a variety of pathological conditions. The characterization of the patho-physiological profile and functional roles of new receptors is highly dependent on the availability of potent and selective ligands and new screening assays. The study of the pharmacological profile of new chemical entities is very important in order to predict the activity of drugs and their clinical adverse effect in humans. In the last decade, a large number of new in vitro radiolabel-free assays were developed and relevant information on diseases was upgraded. In particular, radiolabel-free assays led significant easy to handle and safer tools for operators. The aim of this review is to analyze these assays in terms of new drug activity and toxicology prediction and translation of non-clinical findings to humans in order to provide a powerful tool to aid drug development

The Length and Flexibility of the 2-Substituent of 9-Ethyladenine Derivatives Modulate Affinity and Selectivity for the Human A2A Adenosine Receptor

The A2A adenosine receptor (A2A AR) is a key target for the development of pharmacological tools for the treatment of central nervous system disorders. Previous works have demonstrated that the insertion of substituents at various positions on adenine leads to A2A AR antagonists with affinity in the micromolar to nanomolar range. In this work, a series of 9-ethyladenine derivatives bearing phenylalkylamino, phenylakyloxy or phenylakylthio groups of different lengths at the 2-position were synthesised and tested against the human adenosine receptors. The derivatives showed sub-micromolar affinity for these membrane proteins. The further introduction of a bromine atom at the 8-position has the effect of improving the affinity and selectivity for all ARs and led to compounds that are able bind to the A2A AR subtype at low nanomolar levels. Functional studies confirmed that the new adenine derivatives behave as A2A AR antagonists with half-maximal inhibitory concentration values in the nanomolar range. Molecular modelling studies provide a description of the possible binding mode of these compounds at the A2A AR and an interpretation of the affinity data at this AR subtype

Adenosine receptors as neuroinflammation modulators: role of A1 agonists and A2A antagonists

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).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.This research was funded by Cofinanziamento Assegno di Ricerca Volpini-Marucci, n° FPI400037 and by Fundação para a Ciência e a Tecnologia (PTDC/BIM-MEC/47778/2014). This work was supported by the University of Camerino (Fondo di ricerca di Ateneo) and by a grant from the Ministry of Research (PRIN N° 2015E8EMCM_008, 2015).info:eu-repo/semantics/publishedVersio

Blue honeysuckle fruit (Lonicera caerulea L.) from eastern Russia: phenolic composition, nutritional value and biological activities of its polar extracts

In the present work we conducted a comprehensive chemical analysis of blue honeysuckle (Lonicera caerulea) spontaneously growing in eastern Russia. HPLC-DAD-ESI/MS analysis showed cyanidin-3-glucoside as the major constituent among phenolics, while nutritional analysis revealed fibre, protein, calcium and magnesium as the most important macro- and micronutrients, respectively. Fatty acid composition was dominated by polyunsaturated fatty acids, linoleic acid being the most abundant. Furthermore, we evaluated several in vitro biological activities such as antioxidant, antimicrobial, antiproliferative, wound healing and immunomodulatory effects of blue honeysuckle aqueous and ethanolic extracts that are often incorporated in food and nutraceutical preparations. While the fruit extracts were revealed to be potent radical scavengers with significant inhibition of ABTS radical, thus confirming the literature data, their inhibitory effects against microbial pathogens and tumor cell lines were negligible. The fruit aqueous extract did not show toxicity to human fibroblasts, but 24 h treatment with 150–200 μg per mL of extract slightly enhanced the cell migration when tested by scratched wound assay. Worth mentioning was the inhibitory effect displayed by the blue honeysuckle fruit aqueous extract on human lymphocytes

The G Protein-Coupled Receptor GPR17: Overview and Update

The GPR17 receptor is a G protein-coupled receptor (GPCR) that seems to respond to two unrelated families of endogenous ligands: nucleotide sugars (UDP, UDP-galactose, and UDP-glucose) and cysteinyl leukotrienes (LTD4 , LTC4 , and LTE4 ), with significant affinity at micromolar and nanomolar concentrations, respectively. This receptor has a broad distribution at the level of the central nervous system (CNS) and is found in neurons and in a subset of oligodendrocyte precursor cells (OPCs). Unfortunately, disparate results emerging from different laboratories have resulted in a lack of clarity with regard to the role of GPR17-targeting ligands in OPC differentiation and in myelination. GPR17 is also highly expressed in organs typically undergoing ischemic damage and has various roles in specific phases of adaptations that follow a stroke. Under such conditions, GPR17 plays a crucial role; in fact, its inhibition decreases the progression of ischemic damage. This review summarizes some important features of this receptor that could be a novel therapeutic target for the treatment of demyelinating diseases and for repairing traumatic injury

Choline-Containing Phospholipids: Structure-Activity Relationships Versus Therapeutic Applications.

Choline is a quaternary ammonium salt, and being an essential component of different membrane phospholipids (PLs) contributes to the structural integrity of cell membranes. Choline-containing phospholipids (CCPLs) include phosphatidylcholine (PC), sphingomyelin (SM), and choline alphoscerate (GPC). PC is the major phospholipid in most eukaryotic cells. It is involved in SM synthesis, choline/choline metabolite re-generation, and fatty acid/GPC formation. This paper has reviewed chemical, biological and therapeutic features of CCPLs by analyzing: a) effects of exogenous CCPLs, b) influence of GPC treatment on brain cholinergic neurotransmission, and c) neuroprotective effects of GPC alone or in association with acetylcholinesterase inhibitors in animal models of brain vascular injury, d) synthesis of the choline analogs, containing a short alkyl chain instead of a methyl group. Cytidine-diphosphocholine and GPC, protect cell membranes and could be helpful in the sequelae of cerebrovascular accident treatment. Moreover, cellular membrane breakdown is suggested as a feature of neurodegeneration both in acute (stroke) and in chronic (Alzheimer and vascular dementia) brain disorders. Published data were focused to a larger extent on the biosynthesis, relevant role in cell life, and crucial involvement of CCPLs in cholinergic neurotransmission. The possibility of their use in the treatment of cerebrovascular and neurodegenerative disorders is suggested by published clinical studies. In line with these potential practical applications in pharmacotherapy, the need of further research in the field of the synthesis of new choline derivatives with possible activity in nervous system diseases characterized by cholinergic impairment is discussed