Modification of the 5' position of purine nucleosides. 2. Synthesis and some cardiovascular properties of adenosine-5'-(N-substituted)carboxamides

Prasad, Raj Nandan; Bariana, D. S.; Fung, Anthony K. L.; Savic, Milica; Tietje, Karin; Stein, Herman H.; Brondyk, Harold D.; Egan, Richard S.

doi:10.1021/jm00177a021

Cited by 68 publications

(50 citation statements)

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“…19 If only partial agonistic activity was observed, efficacy was compared to 100 μ M NECA 41 as a full agonist. All values are given as geometric means with 95% confidence intervals ( n ≥ 3).…”

Section: Methodsmentioning

confidence: 99%

Exploring the Role of N⁶-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

et al. 2017

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Structural determinants of affinity of N6-substituted-5′-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N6-cycloalkyl and 3-halobenzyl groups furnished potent dual acting A1AR agonists and A3AR antagonists. 4 was the most potent dual acting human (h) A1AR agonist (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 11 and 26 were most potent at both h and rat (r) A3AR. All N6-substituted-5′-C-(ethyltetrazol-2-yl)adenosine derivatives proved to be antagonists at hA3AR but agonists at the rA3AR. Analgesia of 11, 22, and 26 was evaluated in the mouse formalin test (A3AR antagonist blocked and A3AR agonist strongly potentiated). N6-Methyl-5′-C-(ethyltetrazol-2-yl)adenosine (22) was most potent, inhibiting both phases, as observed combining A1AR and A3AR agonists. This study demonstrated for the first time the advantages of a single molecule activating two AR pathways both leading to benefit in this acute pain model.

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Section: Methodsmentioning

confidence: 99%

Exploring the Role of N⁶-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

et al. 2017

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“…(1)). NECA, was reported to be a potent coronary dilator and hypotensive [47], but showed little A 2A AR selectivity [48][49][50]. On the basis of the observation that CV 1808 (8), was slightly A 2A AR vs A 1 AR selective [26], a series of 2-(arylalkylamino)-NECA derivatives was synthesized and evaluated for their A 1 AR and A 2A AR binding profile in rat brain membranes.…”

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

confidence: 99%

“…(1)) exhibited a 36 fold A 2A AR selectivity vs A 1 AR and its pharmacological profile was characterized using in vitro and in vivo models [13,54]. The therapeutic potential of HENECA for the treatment of cardiovascular and psychotic diseases led to the synthesis of a series of 2-alkynyl, 2-cycloalkynyl, 2-aralkynyl and 2-heteroaralkynyl derivatives of NECA [47,55]. (R,S).2-phenylhydroxypropynylNECA (PHPNECA, 27, (Fig.…”

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

confidence: 99%

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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“…Since the early eighties the 4'-uronic acid ethyl ester analogue of adenosine, NECA, (22, Figure 2) was reported to be a potent coronary dilator and hypotensive, [89] and a good inhibitor of platelet aggregation induced by ADP. [25] However, NECA showed little or no A 2 -selectivity in either functional or binding studies (Table 1).…”

Section: -Substituted Derivatives Of Necamentioning

confidence: 99%

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

et al. 2007

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Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.

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Modification of the 5' position of purine nucleosides. 2. Synthesis and some cardiovascular properties of adenosine-5'-(N-substituted)carboxamides

Cited by 68 publications

References 0 publications

Exploring the Role of N⁶-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

Exploring the Role of N⁶-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

A2A Receptor Ligands: Past, Present and Future Trends

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists

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Modification of the 5' position of purine nucleosides. 2. Synthesis and some cardiovascular properties of adenosine-5'-(N-substituted)carboxamides

Cited by 68 publications

References 0 publications

Exploring the Role of N6-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

Exploring the Role of N6-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

A2A Receptor Ligands: Past, Present and Future Trends

Highlights on the Development of A2A Adenosine Receptor Agonists and Antagonists

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Exploring the Role of N⁶-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

Exploring the Role of N⁶-Substituents in Potent Dual Acting 5′-C-Ethyltetrazolyladenosine Derivatives: Synthesis, Binding, Functional Assays, and Antinociceptive Effects in Mice

Highlights on the Development of A_2A Adenosine Receptor Agonists and Antagonists