Nucleosides and Nucleotides. 103. 2-Alkynyladenosines: A Novel Class of Selective Adenosine A2 Receptor Agonists With Potent Antihypertensive Effects

J Med Chem. 1992 Jan 24;35(2):241-52. doi: 10.1021/jm00080a007.

Abstract

The synthesis and receptor-binding activities at A1 and A2 adenosine receptors for a series of 2-alkynyladenosines are described. The palladium-catalyzed cross-coupling reaction of 2-iodoadenosine (4a) with various terminal alkynes in the presence of bis(triphenylphosphine)palladium dichloride and cuprous iodide in N,N-dimethylformamide containing triethylamine gives 2-alkynyladenosines (5a-r). An economical synthetic method for the preparation of 9-(2,3,5-tri-O-acetyl-1-beta-D-ribofuranosyl)-6-chloro-2-iodopurine++ + (2), which is a precursor of 4a, is also included. Several transformation reactions of 2-(1-octyn-1-yl)adenosine (5e) and 2-(1-ethyn-1-yl)adenosine (9) and a similar cross-coupling reaction of 6-chloropurine derivative 11 and 8-bromoadenosine (13) with 1-octyne are also reported. Many of these 2-alkynyladenosines tested for A1 and A2 adenosine receptor binding activities in rat brain are selective for the A2 adenosine receptor. Among them, 2-(1-hexyn-1-yl)adenosine (5c) has the highest affinity for both A1 and A2 receptors with Ki values of 126.5 and 2.8 nM, respectively. The structure-activity relationship of this series of compounds including 6- or 8-alkynylpurine nucleosides and 2-alkyl- and 2-alkenyladenosines is discussed in terms of potency at both receptor subtypes. Additionally, we describe how hypotensive activity and heart rate decrease brought on by 5 and some other compounds with spontaneously hypertensive rats are proportional to the order of the potency to both A1 and A2 binding affinities. Thus, 2-alkynyladenosines are interesting and promising as antihypertensive agents that should be considered for further detailed preclinical evaluation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / metabolism
  • Adenosine / pharmacology
  • Adenosine Deaminase / metabolism
  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / metabolism
  • Antihypertensive Agents / pharmacology
  • Blood Pressure / drug effects
  • Brain / metabolism
  • Female
  • Heart Rate / drug effects
  • In Vitro Techniques
  • Male
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred Strains
  • Receptors, Purinergic / drug effects*
  • Receptors, Purinergic / metabolism
  • Structure-Activity Relationship

Substances

  • Antihypertensive Agents
  • Receptors, Purinergic
  • Adenosine Deaminase
  • Adenosine