Adenosine receptor agonists: Synthesis and biological evaluation of the diastereoisomers of 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)NECA

Camaioni, Emidio; Francesco, Emanuela Di; Vittori, Sauro; Volpini, Rosaria; Cristalli, Gloria

doi:10.1016/s0968-0896(97)00172-7

Cited by 21 publications

(17 citation statements)

References 17 publications

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“…Table 2 shows that the S-diastereomer (6S) is about sevenfold more potent at A 3 -receptor than the R-form. The S-form is also 20-fold more potent on A 2A receptors whereas no difference for the diastereomers was found on A 1 receptors ( Table 2) according to the data reported for rat membranes (Camaioni et al 1997). Klotz et al 1998 2-Substitution with alkyl chains adjacent to the triple bond ( Fig.…”

Section: Resultsmentioning

confidence: 69%

“…In this study we present a series of NECA derivatives substituted in the 2-position with alkynyl or aralkynyl chains as a novel group of compounds as a basis for improved A 3 selectivity. Previously, such NECA derivatives have been shown to bind with high affinity to rat A 2A adenosine receptors (Cristalli et al 1992(Cristalli et al , 1994(Cristalli et al , 1995Camaioni et al 1997). Testing some of these compounds on human A 2A receptors stably transfected into CHO cells (Klotz et al 1998) revealed that their affinity was typically three-to tenfold lower than at the rat receptor, whereas the parent compound NECA was equipotent in both species (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…The 2-substituted adenosine derivatives 1-14 (see Fig. 1) were synthesized as described earlier (Cristalli et al 1992(Cristalli et al , 1994(Cristalli et al , 1995Camaioni et al 1997). The 96-well microplate filtration system (MultiScreen MAFC) was obtained from Millipore, Eschborn, Germany.…”

Section: Materialmentioning

confidence: 99%

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2-Substituted N-ethylcarboxamidoadenosine derivatives as high-affinity agonists at human A3 adenosine receptors

Klotz

Camaioni

Volpini

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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A number of 2-substituted 5'-N-ethylcarboxamidoadenosine (NECA) derivatives was investigated for their affinity and selectivity at human A3 adenosine receptors. The compounds were tested in radioligand competition studies and modulation of adenylyl cyclase activity on membranes from CHO cell lines stably transfected with the four human adenosine receptor subtypes. In binding studies the most potent compound, 2-(3-hydroxy-3-phenyl)propyn-1-yl-NECA (PHPNECA), exhibited a subnanomolar affinity for A3 adenosine receptors with a Ki value of 0.4 nM. As opposed to the limited A3 selectivity of PHPNECA, a 100-fold selectivity compared to both A1 and A2A receptors was found for 2-(2-phenyl)ethynyl-NECA (PENECA; Ki 6 nM). The EC50 values for activation of adenylyl cyclase via A2A adenosine receptors were in good agreement with the respective Ki values from binding experiments. In contrast, IC50 values for A1 and A3 receptor-mediated inhibition of adenylyl cyclase were shifted to higher values compared to the respective affinities determined in radioligand competition studies. Similar discrepancies between binding and functional data have been observed for the inhibitory A1 adenosine receptor in previous studies. Therefore, the same A3 selectivity of PENECA compared to A1 receptors was found in binding and adenylyl cyclase inhibition whereas the selectivity compared to A2A receptors that was detected in ligand binding was obscured in the functional assay. The series of compounds presented in this study identifies 2-substitution of the purine system as a promising target for the development of A3-selective high-affinity ligands.

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Section: Resultsmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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2-Substituted N-ethylcarboxamidoadenosine derivatives as high-affinity agonists at human A3 adenosine receptors

Klotz

Camaioni

Volpini

et al. 1999

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Adenosine and NECA derivatives containing various alkynyl substituents at the 2-position of the adenine ring were recently proposed as effective agonists for the adenosine receptors [20,[64][65][66][67][68]. With the purpose of understanding the reasons of specific ligand-receptor interactions for such agonists we have performed a molecular docking of ligands 24-37 to each adenosine receptor subtype.…”

Section: -Substituted Derivatives Of the Adenosine And Necamentioning

confidence: 99%

Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors

Иванов

Palyulin

Зефиров

2007

Journal of Molecular Graphics and Modelling

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“…As PHPNECA bears a chiral carbon in the side chain, the diastereomer separation was accomplished. Binding assays in rat membranes showed that the (S)-diastereomer is about 5 fold more potent and selective than the (R)-diastereomer as agonist of the A 2A AR [56].…”

Section: A 2a Ar Agonists: Development and Struc-ture-activity-relatimentioning

confidence: 97%

A2A Receptor Ligands: Past, Present and Future Trends

Manera

Saccomanni²

2010

CTMC

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The adenosine A(2A) receptor is a member of the G protein-coupled receptor family and mediates multiple physiological effects of adenosine, both at the central nervous system and at peripheral tissues. Increasing evidence relates the A(2A) receptor with several pathological conditions such as neurodegenerative disorders, inflammation, pharmacological stress, and wound healing renewing the interest in A(2A) receptor agonists and antagonists as promising leads for drugs. However some of them initially tested in clinical trials presented several side effects, short half-life, lower solubility, and in some cases a lack of effects, perhaps attributable to receptor desensitization or to low receptor density in the targeted tissue. For these reasons it is evident that additional rational chemical modifications of the existing A(2A) receptor ligands to improve their affinity/selectivity and bioavailability as well as further studies to get new template for A(2A)AR ligands are necessary. The purpose of this review is to analyze and summarize the past and the present aspects related to the medicinal chemistry of A(2A) receptor ligands. Moreover their current and possible therapeutic applications have been also highlighted.

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Adenosine receptor agonists: Synthesis and biological evaluation of the diastereoisomers of 2-(3-hydroxy-3-phenyl-1-propyn-1-yl)NECA

Cited by 21 publications

References 17 publications

2-Substituted N-ethylcarboxamidoadenosine derivatives as high-affinity agonists at human A3 adenosine receptors

2-Substituted N-ethylcarboxamidoadenosine derivatives as high-affinity agonists at human A3 adenosine receptors

Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors

A2A Receptor Ligands: Past, Present and Future Trends

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