Conformationally Restrained, Chiral (Phenylisopropyl)amino-Substituted pyrazolo[3,4-d]pyrimidines and Purines With Selectivity for Adenosine A1 and A2 Receptors

J Med Chem. 1992 Aug 21;35(17):3263-9. doi: 10.1021/jm00095a024.

Abstract

Two modes of tethering a chiral (phenylisopropyl)amino substituent in pyrazolo[3,4-d]pyrimidines and purines have been explored. One mode gave (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5- propoxy-3H-imidazo[1,2-c]pyrazolo-[4,3-e]pyrimidine (12a) and its corresponding R-enantiomer 12b, which were selective for A2 and A1 adenosine receptors, respectively. The corresponding diimidazo[1,2-c:4',5'-e]pyrimidines 12e and 12f were analogously selective. This is the first example where a single chiral recognition unit provides enantiomers with opposite selectivities for adenosine receptors. The second mode gave (2S-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5- propoxy-3H-imidazo[1,2-c]-pyrazolo[4,3-e]pyrimidine (12c) and its corresponding R-enantiomer 12d. Compounds 12c and 12d were significantly less potent than 12a and 12b at A1 receptors, and were nonselective.

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism
  • Molecular Conformation
  • Molecular Structure
  • Purines / chemical synthesis*
  • Purines / metabolism
  • Purines / pharmacology
  • Pyrazoles / chemical synthesis
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Receptors, Purinergic / drug effects
  • Receptors, Purinergic / metabolism*
  • Stereoisomerism

Substances

  • Purines
  • Pyrazoles
  • Pyrimidines
  • Receptors, Purinergic
  • 2,7-dihydro-7-phenyl-2-(phenylmethyl)-5-propoxy-3H-imidazo(1,2-c)pyrazolo(4,3-e)pyrimidine