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N6-substituted adenosine receptor agonists: potential antihypertensive agents
B K Trivedi1, C J Blankley, J A Bristol
1Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Journal of Medicinal Chemistry
|March 1, 1991
Summary
Novel N6-substituted adenosine analogues were synthesized and tested for antihypertensive activity. Certain analogues demonstrated significant blood pressure reduction, suggesting a new class of antihypertensive agents targeting adenosine receptors.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Cardiovascular Research
Background:
- Adenosine is recognized for its diverse pharmacological actions, including hypotensive effects.
- This property suggests that modified adenosine analogues could serve as potential antihypertensive therapeutics.
Purpose of the Study:
- To synthesize and evaluate novel N6-benzocycloalkyladenosine analogues for their receptor binding and antihypertensive efficacy.
- To establish structure-activity relationships for these adenosine analogues concerning A1 and A2 receptor affinity and blood pressure regulation.
Main Methods:
- Synthesis of a series of N6-benzocycloalkyladenosine analogues.
- Assessment of adenosine receptor binding affinities (A1 and A2).
- Evaluation of antihypertensive activity in vitro and in vivo, including dose-dependency and duration of action.
Main Results:
- Adenosine analogues with a phenyl moiety two carbons from the C6-nitrogen exhibited superior A1 receptor affinity and selectivity.
- Many synthesized analogues displayed significant antihypertensive activity, with varying effects on heart rate.
- Compound 3 showed dose-dependent blood pressure reduction lasting over 20 hours and efficacy in a renal hypertensive rat model.
Conclusions:
- Appropriately modified N6-substituted adenosines represent a promising new class of antihypertensive agents.
- A1 receptor affinity is closely associated with the observed antihypertensive effects and bradycardic responses.
- Further investigation of these novel adenosine analogues is warranted for their therapeutic potential.