Adenosine applications inhibitors

As mentioned above, inhibition of adenosine kinase increases extracellular adenosine concentrations. Interest in enhancement of the neuroprotective, antinociceptive, and anti-inflammatory actions of adenosine has encouraged development of systemically applicable adenosine kinase inhibitor drugs. For example, it was found recently that the specific adenosine kinase inhibitor ABT-702, when given intraperitoneally, increases sleep and slow wave EEG activity of rats (Radek et al, 2004), a finding that encourages further research into the hypnogenic effect of this type of drug. 

L. M. Hansen and P.A. Kollman, Free energy perturbation calculations on models of active sites Applications to adenosine deaminase inhibitors, J. Comp. Chem. 11 994 (1990). 

Severe side-effects (hemorrhages in rats and dogs brain) have been reported after systemic application of several selected adenosine kinase inhibitors (Erion, 2000). Nevertheless, ABT-702 in particular is still reported to be in preclinical development. 

A pharmacophore model for new inhibitors was designed by Lee et al., although no inhibitory activity for the proposed inhibitors was determined experimentally.69 Long et al have designed adenosine kinase inhibitors to target Mycobacterium tuberculosis.70,71 Finally, a patent application from McMaster University disclosed phosphonates as millimolar adenosine kinase inhibitors.72... 

The short-acting cholinesterase inhibitor edrophonium was used to treat supraventricular tachyarrhythmias, particularly paroxysmal supraventricular tachycardia. In this application, edrophonium has been replaced by newer drugs (adenosine and the calcium channel blockers verapamil and diltiazem). 

A frequently cited mechanism of action for these agents is phosphodiesterase (PDE) inhibition and the associated antiplatelet effects that accompany increases in intracellular cyclic adenosine monophosphate (cAMP). In fact, the effects of these drugs go far beyond their direct effect on PDE inhibition or platelet function. This chapter discusses (/) cyclic nucleotides, PDE, and PDE inhibitors (if) the mechanisms of action of dipyridamole and cilostazol (Hi) drug issues and (iv) current clinical applications for dipyridamole and cilostazol, including recent clinical trials that may have changed our perception of the possible utility of these agents for percutaneous intervention. 

Thus, in comparing the binding of 1,6-dihydropurine ribonucleoside 3 (Fig. 20.2) and its 6-hydroxy derivative 4 to adenosine deaminase, they observed AT, values for these The initial application of the anchor principle described two inhibitors of 5.4 X 10 and3X 10 M respectively,... 

NATA, N-L-acetyltryptophanamide BSND, benzenesulfonamide BSFN, benzenesulfonate Sta, statine BZD, benzamidine CFM, coformycin MTX, methotrexate TMP, trimethoprim PT, pterin NPT, N5-deazapterin THP, tetrahydropyrrole Bz, benzene ADA, adenosine deaminase HCAIl, human carbonic anhydrase II TS, thymidyiate synifaase DHFR, dihydrofolate reductase MBP, mannose bindnig protein HEI, hydroxyethylene inhibitor HPR, (6R)-6-hydroxy-l,6 dihydropurine riboside (R),R configuration (S),S configuration NA, not available or not applicable. 

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