Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists

J Med Chem. 2016 Apr 14;59(7):3249-63. doi: 10.1021/acs.jmedchem.5b01998. Epub 2016 Feb 18.

Abstract

Purine (N)-methanocarba-5'-N-alkyluronamidoriboside A3 adenosine receptor (A3AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A3AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A3AR binding site.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine A3 Receptor Agonists / administration & dosage
  • Adenosine A3 Receptor Agonists / chemistry
  • Adenosine A3 Receptor Agonists / pharmacology*
  • Administration, Oral
  • Animals
  • CHO Cells
  • Carbohydrates / chemistry*
  • Cricetinae
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Molecular
  • Nucleosides / chemistry*
  • Pain / drug therapy*
  • Purines / chemistry*
  • Receptor, Adenosine A3 / chemistry*
  • Structure-Activity Relationship

Substances

  • Adenosine A3 Receptor Agonists
  • Carbohydrates
  • Nucleosides
  • Purines
  • Receptor, Adenosine A3