This project continues tests of the hypothesis that adenosine is a physiological regulator of coronary blood flow and cardiac performance, focusing on the structure-activity relationships (SAR) of agonists and antagonists at the adenosine receptors of the cardiac atria and of coronary arteries. The research plan calls for the development of new systheses of novel 2-substituted and 2,6-disubstituted N-ethyl adenosine-5'-uronamides, some of which will be suitable for radiolabelling, photoaffinity radiolabelling and as ligands for affinity chromatography. Biological studies will use the SARs of adenosine analogs to map the cardiac atrial receptors which mediate the negative chronotropic and inotropic effects of adenosine and to compare these receptors with authentic A1 adenosine receptors. Other analgos serve to map the topography of the purine C-2 region and ribose domain of the A2 receptors in cultured cell lines and to see how well these in vitro systems predict coronary vasoactivity in vivo. Studies such as these provide the basis for the rational design of drugs that exploit the antiarrythmic, anticoagulant and vasodilatory properties of adenosine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL030391-04
Application #
3341411
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1984-02-01
Project End
1992-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Niiya, K; Uchida, S; Tsuji, T et al. (1994) Glibenclamide reduces the coronary vasoactivity of adenosine receptor agonists. J Pharmacol Exp Ther 271:14-9
Niiya, K; Jacobson, K A; Silvia, S K et al. (1993) Covalent binding of a selective agonist irreversibly activates guinea pig coronary artery A2 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 347:521-6
Niiya, K; Olsson, R A; Thompson, R D et al. (1992) 2-(N'-alkylidenehydrazino)adenosines: potent and selective coronary vasodilators. J Med Chem 35:4557-61
Ueeda, M; Silvia, S K; Olsson, R A (1992) Nitric oxide modulates coronary autoregulation in the guinea pig. Circ Res 70:1296-303
Niiya, K; Thompson, R D; Silvia, S K et al. (1992) 2-(N'-aralkylidenehydrazino)adenosines: potent and selective coronary vasodilators. J Med Chem 35:4562-6
Thompson, R D; Secunda, S; Daly, J W et al. (1991) Activity of N6-substituted 2-chloroadenosines at A1 and A2 adenosine receptors. J Med Chem 34:3388-90
Ueeda, M; Thompson, R D; Arroyo, L H et al. (1991) 2-Alkoxyadenosines: potent and selective agonists at the coronary artery A2 adenosine receptor. J Med Chem 34:1334-9
Thompson, R D; Secunda, S; Daly, J W et al. (1991) N6,9-disubstituted adenines: potent, selective antagonists at the A1 adenosine receptor. J Med Chem 34:2877-82
Olsson, R A; Pearson, J D (1990) Cardiovascular purinoceptors. Physiol Rev 70:761-845
Lohse, M J; Klotz, K N; Lindenborn-Fotinos, J et al. (1987) 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)--a selective high affinity antagonist radioligand for A1 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 336:204-10

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