Design of (N)-methanocarba Adenosine 5'-uronamides as Species-Independent A3 Receptor-Selective Agonists

Bioorg Med Chem Lett. 2008 May 1;18(9):2813-9. doi: 10.1016/j.bmcl.2008.04.001. Epub 2008 Apr 4.

Abstract

2-Chloro-5'-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0]hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A(3) adenosine receptor (AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A(1)AR. Therefore, we varied substituents at the N(6) and C2 positions in search of compounds that have improved A(3)AR selectivity and are species independent. An N(6)-methyl analogue was balanced in affinity at mouse A(1)/A(3)ARs, with high selectivity in comparison to the A(2A)AR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A(3)AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A(3)AR selectivity more effectively than similar chains attached at the 3-position of the N(6)-benzyl group.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / chemical synthesis
  • Adenosine / pharmacology*
  • Adenosine A3 Receptor Agonists*
  • Alkanes / chemistry
  • Animals
  • Binding Sites
  • Drug Design*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Models, Chemical
  • Nucleosides / chemical synthesis
  • Nucleosides / pharmacology*
  • Ribose / chemistry
  • Structure-Activity Relationship

Substances

  • Adenosine A3 Receptor Agonists
  • Alkanes
  • Nucleosides
  • Ribose
  • Adenosine