Highly Selective Adenosine A2 Receptor Agonists in a Series of N-alkylated 2-aminoadenosines

J Med Chem. 1991 Aug;34(8):2570-9. doi: 10.1021/jm00112a035.

Abstract

A wide variety of 2-substituted aminoadenosines were prepared for comparison with the moderately A2 receptor selective adenosine agonist 2-anilinoadenosine (CV-1808). High selectivity combined with significant affinity at the A2 receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A2 selective compound, was modified by introduction of a variety of substituents in the benzene ring and the side chain. Some of these changes led to improved A2 affinity and increased selectivity. Replacement of the phenyl moiety by cyclohexenyl produced a 210-fold selective agonist 3ag (CGS 22989) whereas the cyclohexanyl analogue 3af (CGS 22492) was 530-fold selective at the A2 site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / chemistry
  • Adenosine / metabolism
  • Adenosine / pharmacology
  • Adenosine / therapeutic use
  • Alkylation
  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use
  • Blood Pressure / drug effects
  • Chemical Phenomena
  • Chemistry
  • Cyclohexanes / chemical synthesis
  • Cyclohexanes / pharmacology
  • Cyclohexanes / therapeutic use
  • Heart Rate / drug effects
  • Hypertension / drug therapy
  • Male
  • Molecular Structure
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred Strains
  • Receptors, Purinergic / drug effects*
  • Receptors, Purinergic / physiology

Substances

  • Antihypertensive Agents
  • Cyclohexanes
  • Receptors, Purinergic
  • 2-((2-cyclohexylethyl)amino)adenosine
  • 2-aminoadenosine
  • 2-phenylaminoadenosine
  • Adenosine