Adenosine and analogues

Q. Deng, I. German, D. Buchanan, and R. T. Kennedy, Retention and Separation of Adenosine and Analogues by Affinity Chromatography with an Aptamer Stationary Phase, Anal. Chem. 2001, 73, 5415. 

Deng Q, German I, Buchanan D, Kennedy RT (2001) Retention and separation of adenosine and analogues by affinity chromatography with an aptamer stationary phase, Anal Chem, 73 5415—5421... 

Fig. 7. Adenosine and guanosine analogues with both RNA and DNA antiviral effectiveness.

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

There is evidence that in cerebral ischaemia adenosine may have protective effects, since it inhibits the release of many excitatory neurotransmitters, such as glutamate, and it also stabilises the membrane potential. Unfortunately, adenosine has an extremely short half-life, but recently nucleoside (adenosine) transport inhibitors, e.g. draflazine, have been developed that prevent the endothelial uptake and breakdown of adenosine and prolong its beneficial effects. Nucleoside transport inhibitors also have myocardial protective properties and may have a role in organ preservation prior to transplantation. Adenosine also has an antinociceptive function and various adenosine analogues have antinociceptive activity, which correlates with their affinity for the A1 receptors (Lipkowski and co-workers 1996). 

Fig. 12. A method for converting an alcohol, R—CH2OH, into the arsonomethyl analogue of its phosphate. This was used to make the arsonomethyl analogue of AMP. R—CH2OH represents adenosine, and R —CH2OH its 2, 3 -isopropylidene derivative.

Subtypes of adenosine receptors exist - A, Aj and A3 -which have differential sensitivities to adenosine nucleoside analogues, including 2-methylthio-AMP, 2-thioadenosine, DPMA. IB-MECA, NECA, CPA. CCPA and DPCPX. These receptors, and subtypes within A2, have all been cloned. They have structures typical of the seven-transmembrane G-protein-coupled superfamily of receptors, but have amongst the shortest sequences known (A3 has only 318 amino acids), and a lack of sequence similarity with any other receptors appears to put them in a class of their own. Adenosine receptors are not sensitive to nucleotides such as ADP (adenosine diphosphate) and ATP (adenosine triphosphate), which instead act as P2 receptor agonists that are nucleotide-... 

Several novel diadenosine 5, 5" -P-l,P-4-tetraphosphate (AppppA) analogues (94 95) and an adenosine tetraphosphate analogue (%) have been prepared as competitive inhibitors of ADP-induced platelet aggregation. Among the various analogues, the P-2, P-3-monochloromethylene AppCHClppA was found to be particularly active. 

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