scholarly journals Nucleoside Prodrugs of A3 Adenosine Receptor Agonists and Antagonists

2006 ◽  
Vol 71 (6) ◽  
pp. 912-928 ◽  
Author(s):  
Pedro Besada ◽  
Liaman K. Mamedova ◽  
Krishnan K. Palaniappan ◽  
Zhan-Guo Gao ◽  
Bhalchandra V. Joshi ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Radioligand Binding ◽  
Parent Compound ◽  
Parent Drug ◽  
Biologically Active ◽  
Functional Assay ◽  
Adenosine Receptor Agonists ◽  
A3 Adenosine Receptor ◽  
Future Evaluation

9-(β-D-Ribosfuranosyluronamide)adenine derivatives that are selective agonists and antagonists of the A3 adenosine receptor (AR) have been derivatized as prodrugs for in vivo delivery. The free hydroxy groups at the 2' and 3' positions of the agonists 2-chloro-N6-(3-iodobenzyl)-9-(N-methyl-(β-D-ribosfuranosyluronamide)adenine 2b, the corresponding 4'-thio nucleoside 2c, and antagonists 4a and 4b (5'-N,N-dimethylamides related to 2b and 2c, respectively) were derivatized through simple acylation reactions. The prodrug derivatives were tested in radioligand binding assays at ARs and in a functional assay of adenylate cyclase at the A3AR and found to be considerably less active than the parent drugs. The hydrolysis of nucleoside 2',3'-diesters to regenerate the parent compound in the presence of human blood was demonstrated. 2',3'-Dipropionate esters of 2b and 4a were readily cleaved in a two-step reaction to regenerate the parent drug, on a time scale of two hours. The cleavage of a 2',3'-dihexanoate ester occurred at a slower rate. This indicates that the prodrugs are suitable as masked forms of the biologically active A3AR agonists and antagonists for future evaluation in vivo.

scholarly journals Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

2011 ◽  
Vol 115 (6) ◽  
pp. 1251-1260 ◽  
Author(s):  
Sarah M. Brown ◽  
Michael Holtzman ◽  
Thomas Kim ◽  
Evan D. Kharasch
Keyword(s):  
Radioligand Binding ◽  
Competitive Inhibition ◽  
Antinociceptive Effect ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Biologically Active ◽  
Whole Body ◽  
Tail Flick ◽  
High Affinity

Background The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine. Methods Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.

scholarly journals Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy

2015 ◽  
Vol 6 (7) ◽  
pp. 804-808 ◽  
Author(s):  
Dilip K. Tosh ◽  
Steven Crane ◽  
Zhoumou Chen ◽  
Silvia Paoletta ◽  
Zhan-Guo Gao ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
In Vivo Efficacy ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
A3 Adenosine Receptor

scholarly journals Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A3 adenosine receptor agonists

MedChemComm ◽  
2015 ◽  
Vol 6 (4) ◽  
pp. 555-563 ◽  
Author(s):  
Dilip K. Tosh ◽  
Silvia Paoletta ◽  
Zhoumou Chen ◽  
Steven Crane ◽  
John Lloyd ◽  
...  
Keyword(s):  
Click Chemistry ◽  
Adenosine Receptor ◽  
Design Synthesis ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
A3 Adenosine Receptor ◽  
Dark Green ◽  
Light Green

C2-phenylethynyl (dark green) and C2-phenyl-triazolyl (light green) nucleosides in the A3AR.

Cardiac desensitization to adenosine analogues after prolonged R-PIA infusion in vivo

1993 ◽  
Vol 265 (6) ◽  
pp. H1916-H1927 ◽  
Author(s):  
H. T. Lee ◽  
C. I. Thompson ◽  
A. Hernandez ◽  
J. L. Lewy ◽  
F. L. Belloni
Keyword(s):  
G Proteins ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Radioligand Binding ◽  
Significant Loss ◽  
Binding Assays ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
A1 Receptor

To determine the effects of chronic in vivo stimulation of adenosine receptors, R-(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), a selective A1 receptor agonist, was administered to rats as a continuous 7-day infusion (200 nmol/h). Inotropic and chronotropic responses of isolated atria to adenosine receptor agonists were markedly desensitized compared with the responses of atria from age-matched control animals. Carbachol's negative chronotropic effect was also attenuated, indicating a heterologous mode of desensitization. Antagonist radioligand binding assays indicated a 52% reduction in A1 adenosine receptor maximum binding, and competition binding assays revealed a significant loss of G protein-coupled high-affinity A1 receptors in atria from R-PIA-treated rats. Inhibitory G proteins (Gi) were significantly reduced, as quantified by immunoblot analysis, with no change in the amount of stimulatory G proteins. Ventricular membranes from R-PIA rats showed loss of Gi and uncoupling of A1 receptors, without a significant change in A1 receptor density. Thus chronic R-PIA infusion desensitized rat atrial muscle to the effects of adenosine receptor agonists via several regulatory adaptations, including downregulation of A1 adenosine receptors, uncoupling of A1 receptors from their associated G proteins, and loss of Gi proteins.

The design, synthesis, pharmacokinetic and pharmacodynamic evaluation of acyloxyalkyl-substituted T705 prodrugs

2019 ◽  
Vol 15 ◽  
Author(s):  
Xingzhou Li ◽  
Tianhong Zhang ◽  
Wu Zhong
Keyword(s):  
Plasma Concentration ◽  
Development Strategy ◽  
Parent Compound ◽  
Systemic Exposure ◽  
Parent Drug ◽  
New Drugs ◽  
Structure Modification ◽  
Design Synthesis ◽  
Pharmacokinetic Properties

Background: The pharmacokinetic properties of T705 are not optimal for the development of new drugs. Objective: To improve the pharmacokinetic properties of T-705, structure modification of T-705 was conducted using a prodrug strategy. Method: The acidic amide H atom (N4-H) of T705 was attempted to be replaced with acyloxyalkyl groups following the prodrugs development strategy for carboxylic acids, and the resulting compounds were investigated whether could work as prodrugs and contribute to improving the pharmacokinetic properties of the parent compound T705 in vivo. Results: 4-acyloxyalkyl-T705 (4a–e), did act as prodrugs in vivo. 4-iso-butyryloxymethyl-T705 (4a) and 4-acetoxymethyl-T705 (4b) could significantly improve the plasma concentration and systemic exposure for T705, compound 4a displayed non inferior anti-influenza activities, compared with its parent drug T705. Conclusion: Our prodrugs development strategy for T705 is feasible, which may serves as a reference to prodrugs development of similar heterocyclic amides compounds.

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