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Ribose-modified adenosine analogues as potential partial agonists for the adenosine receptor
E M van der Wenden1, J K von Frijtag Drabbe Künzel, R A Mathôt
1Leiden-Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, The Netherlands.
Journal of Medicinal Chemistry
|September 29, 1995
Summary
Researchers synthesized deoxy adenosine analogues to find partial agonists for adenosine receptors. Hydroxyl groups on adenosine significantly impact receptor affinity and activity, with varying effects based on their position.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Organic Synthesis
Background:
- Adenosine receptors (A1 and A2a) are crucial drug targets.
- N6-substituted adenosine analogues are investigated for therapeutic potential.
- Understanding the role of hydroxyl groups in adenosine analogue activity is important.
Purpose of the Study:
- To develop a practical synthesis for 2'- and 3'-deoxy analogues of N6-substituted adenosines.
- To evaluate the synthesized deoxy analogues as partial agonists for adenosine A1 and A2a receptors.
- To elucidate the structure-activity relationships concerning hydroxyl group modifications.
Main Methods:
- A three-step synthetic route involving hydroxyl protection, leaving group replacement, and deprotection/amination.
- Synthesis of deoxy analogues of CPA, CHA, and R-/S-PIA.
- In vitro assessment using GTP shift assay to measure intrinsic activity at adenosine receptors.
- In vivo evaluation of deoxy analogues of CPA and R-PIA in the rat cardiovascular system.
Main Results:
- Successfully synthesized 2'- and 3'-deoxy analogues of N6-substituted adenosines.
- Demonstrated that hydroxyl groups are critical determinants of affinity and intrinsic activity.
- Removal of 2'- and 3'-hydroxyl groups altered both affinity and intrinsic activity.
- Removal of the 5'-hydroxyl group primarily decreased receptor affinity.
Conclusions:
- The developed three-step synthesis is effective for creating deoxy adenosine analogues.
- The presence and position of hydroxyl groups significantly modulate adenosine receptor interactions.
- These findings provide valuable insights for designing novel adenosine receptor modulators.