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C2,N6-disubstituted adenosines: synthesis and structure-activity relationships.
1Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Journal of Medicinal Chemistry
|August 1, 1989
Summary
Researchers explored modifying adenosine receptors (A1 and A2) to enhance A2 selectivity. They found that combining substitutions at C2 and N6 did not consistently improve A2 selectivity, with some modifications even reducing affinity.
Area of Science:
- Pharmacology
- Medicinal Chemistry
Background:
- Extracellular adenosine receptors are classified into two main subtypes: A1 and A2.
- Modifications at the C2 or N6 positions of adenosine can confer selectivity for the A2 receptor over the A1 receptor.
Purpose of the Study:
- To investigate the additive effects of substitutions at both C2 and N6 positions on the A2/A1 affinity ratio.
- To develop compounds with enhanced A2 receptor selectivity compared to existing agents.
Main Methods:
- Synthesized novel adenosine analogs with substitutions at C2 and N6 positions.
- Assessed the affinity and selectivity of these analogs for A1 and A2 adenosine receptors.
Main Results:
- Additivity of selectivity was observed only when an A1-selective group was present at the N6 position.
- Substitution at C2 of an A1-selective agonist (N6-cyclopentyladenosine) yielded a 70-fold shift favoring A2 selectivity.
- The same C2 substitution on an A2-selective agonist resulted in a 100-fold decrease in affinity without altering A2 selectivity.
Conclusions:
- Simultaneous C2 and N6 substitutions do not consistently yield additive effects for enhancing A2 receptor selectivity.
- The N6 substituent plays a critical role in determining the outcome of combined modifications on A2/A1 receptor affinity and selectivity.