Adenosine Receptors in Health and Disease

Wilson, Constance N.; Mustafa, S. Jamal; Abbracchio, Maria P.

doi:10.1007/978-3-540-89615-9

Cited by 29 publications

(9 citation statements)

References 198 publications

(266 reference statements)

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“…A 2A has a more specific and abundant distribution in the basal ganglia. This selective distribution for receptors can help guarantee fewer adverse effects and make nondopaminergic antagonists more promising for the treatment of PD [44].…”

Section: Parkinson's Diseasementioning

confidence: 99%

Computational Studies Applied to Flavonoids against Alzheimer’s and Parkinson’s Diseases

Monteiro

Viana

Nayarisseri³

et al. 2018

Oxidative Medicine and Cellular Longevity

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Neurodegenerative diseases, such as Parkinson's and Alzheimer's, are understood as occurring through genetic, cellular, and multifactor pathophysiological mechanisms. Several natural products such as flavonoids have been reported in the literature for having the capacity to cross the blood-brain barrier and slow the progression of such diseases. The present article reports on in silico enzymatic target studies and natural products as inhibitors for the treatment of Parkinson's and Alzheimer's diseases. In this study we evaluated 39 flavonoids using prediction of molecular properties and in silico docking studies, while comparing against 7 standard reference compounds: 4 for Parkinson's and 3 for Alzheimer's. Osiris analysis revealed that most of the flavonoids presented no toxicity and good absorption parameters. The Parkinson's docking results using selected flavonoids as compared to the standards with four proteins revealed similar binding energies, indicating that the compounds 8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, capensinidin, and rosinidin are potential leads with the necessary pharmacological and structural properties to be drug candidates. The Alzheimer's docking results suggested that seven of the 39 flavonoids studied, being those with the best molecular docking results, presenting no toxicity risks, and having good absorption rates (8-prenylnaringenin, europinidin, epicatechin gallate, homoeriodictyol, aspalathin, butin, and norartocarpetin) for the targets analyzed, are the flavonoids which possess the most adequate pharmacological profiles.

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Section: Parkinson's Diseasementioning

confidence: 99%

Computational Studies Applied to Flavonoids against Alzheimer’s and Parkinson’s Diseases

Monteiro

Viana

Nayarisseri³

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…1 A 3 AR antagonists are proposed for the treatment of cancer, inflammation, glaucoma, and asthma. 2–5 A 3 AR agonists are already in clinical trials for liver cancer, rheumatoid arthritis, psoriasis, and dry eye disease, 6,7 with additional envisioned applications for bowel inflammation, ischemia, and other autoimmune inflammatory disorders.…”

Section: Introductionmentioning

confidence: 99%

“…Selective A 3 AR antagonists encompass both non-purine heterocyclic antagonists 1,11 and nucleoside 12,13 antagonists. Nucleoside-derived A 3 AR antagonists have the advantage of a species-independent pharmacological profile; 4 i.e., they tend to maintain A 3 AR selectivity in both human and murine species, while most of the non-purine antagonists are selective for the human (h) but not rat (r) A 3 AR.…”

Section: Introductionmentioning

confidence: 99%

Functionalized Congeners of A₃ Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System

et al. 2009

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(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A3 adenosine receptor (AR) agonists (5′-uronamides) or antagonists (5′-truncated). Here, these two series were modified in parallel at the adenine C2 position. N6-3-Chlorobenzyl-5′-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating in a reactive carboxylate, ester, or amine group were full, potent human A3AR agonists. Flexibility of chain substitution allowed the conjugation with a fluorescent cyanine dye (Cy5) and biotin, resulting in binding Ki values of 17 and 36 nM, respectively. The distal end of the chain was predicted by homology modeling to bind at the A3AR extracellular regions. Corresponding l-nucleosides were nearly inactive in AR binding. In the 5′-truncated nucleoside series, 2-Cl analogues were more potent at A3AR than 2-H and 2-F, functional efficacy in adenylate cyclase inhibition varied, and introduction of a 2-alkynyl chain greatly reduced affinity. SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (Ki = 2.1 nM) and truncated partial agonist 22 (Ki = 4.9 nM).

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“…At this point, substitution at the 5 position was carried out using methylamine in ethanol and heating to 90-110°C in a sealed tube, yielding compound 1. Finally, in order to obtain different substitutions at the 8 position, the ethyl ester was hydrolyzed with lithium hydroxide to the corresponding carboxylic acid (47), which was in turn reacted with the corresponding alcohol or amine in the presence of phosphorous oxychloride and pyridine affording the desired esters (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and amides (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), respectively (Scheme 1). The only exception is represented by compound 33 which33, which was obtained by a coupling reaction between acid derivative 47 and phenylhydrazine in the presence of EDCI and HOBT.…”

Section: Chemistrymentioning

confidence: 99%

“…inflammation and cancer), also depending on the species involved. [12] Maybe for these reasons, even though a lot ofmany ligands targeting hA 3 AR are available, only few of them reached the clinical or preclinical phases of experimentation ( Figure 1). In particular, the agonist IB-MECA is advancing in phase II and II/III for conditions like psoriasis, rheumatoid arthritis and dry eye disease [13] while Cl-IB-MECA is under phase II clinical trial for the treatment of hepatocellular carcinoma, and phase I/II for chronic hepatitis genotype 1.…”

Section: Introductionmentioning

confidence: 99%

[1,2,4]Triazolo[1,5-c]pyrimidines as adenosine receptor antagonists: Modifications at the 8 position to reach selectivity towards A3 adenosine receptor subtype

Federico

Margiotta

Salmaso

et al. 2018

European Journal of Medicinal Chemistry

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[1,2,4]Triazolo[1,5-c]pyrimidine is a promising platform to develop adenosine receptor antagonists. Here, we tried to investigate the effect of the substituent at the 8 position of [1,2,4]triazolo[1,5-c]pyrimidine derivatives on affinity and selectivity at the human A adenosine receptor subtype. In particular, we have introduced both esters and amides, principally with a benzylic nature. In addition, a small series of 5-substituted [1,2,4]triazolo[1,5-c]pyrimidines was designed in order to complete the structure-activity relationship analysis. Several of these new compounds showed affinity towards human A adenosine receptor in the low nanomolar range, with the most potent derivative of the series bringing a 4-ethylbenzylester at the 8 position (compound 18, hAAR K = 1.21 nM). Docking studies performed on the synthesized compounds inside models of human A, A and A adenosine receptors showed similar binding modes, comparable with the typical crystallographic binding mode of the inverse agonist ZM-241,385.

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Adenosine Receptors in Health and Disease

Cited by 29 publications

References 198 publications

Computational Studies Applied to Flavonoids against Alzheimer’s and Parkinson’s Diseases

Computational Studies Applied to Flavonoids against Alzheimer’s and Parkinson’s Diseases

Functionalized Congeners of A₃ Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System

[1,2,4]Triazolo[1,5-c]pyrimidines as adenosine receptor antagonists: Modifications at the 8 position to reach selectivity towards A3 adenosine receptor subtype

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Adenosine Receptors in Health and Disease

Cited by 29 publications

References 198 publications

Computational Studies Applied to Flavonoids against Alzheimer’s and Parkinson’s Diseases

Computational Studies Applied to Flavonoids against Alzheimer’s and Parkinson’s Diseases

Functionalized Congeners of A3 Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System

[1,2,4]Triazolo[1,5-c]pyrimidines as adenosine receptor antagonists: Modifications at the 8 position to reach selectivity towards A3 adenosine receptor subtype

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Functionalized Congeners of A₃ Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System