Novel 3-aralkyl-7-(amino-substituted)-1,2,3-triazolo[4,5-d]pyrimidines with high affinity toward A1 adenosine receptors

J Med Chem. 1998 Feb 26;41(5):668-73. doi: 10.1021/jm9701334.

Abstract

Three series of several 1,2,3-triazolo[4,5-d]pyrimidine derivatives bearing various amino substituents at the 7 position and one of three lipophilic substituents at the 3 position (benzyl, phenethyl, or 2-chlorobenzyl) were prepared starting from the corresponding 7-chloro compounds, by nucleophilic substitution by the appropriate amine. Radioligand binding assays at bovine brain adenosine A1 and A2A receptors showed that some compounds possessed a high affinity and selectivity for the A1 receptor subtype. In particular the biological results suggested the compounds bearing cycloalkylamino (cyclopentyl- and cyclohexylamino) or aralkylamino (alpha-methylbenzyl- and 1-methyl-2-phenylethylamino or amphetamino) substituents at the 7 position were the most active derivatives. The best lipophilic substituent at the 3 position was the 2-chlorobenzyl (A1 affinity Ki < 50 nM) followed by the benzyl and then the phenethyl groups. This pattern of structure-activity relationship (SAR) was similar to that previously reported for analogous 1,2,3-triazolopyridazino derivatives (Biagi et al., 1994, 1995, 1996) except for the compounds bearing substituted aromatic amines which presented a generalized and strong decrease of the A1 receptor affinity. These facts allowed us to attribute to these molecules a binding mode within the A1 adenosine receptor analogous to that of the corresponding triazolopyridazines.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Animals
  • Brain / metabolism
  • Cattle
  • Cell Membrane / metabolism
  • Cerebral Cortex / metabolism
  • Corpus Striatum / metabolism
  • Phenethylamines / metabolism
  • Pyridazines / metabolism
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / metabolism
  • Radioligand Assay
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1 / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazoles / chemistry*

Substances

  • Phenethylamines
  • Pyridazines
  • Pyrimidines
  • Receptor, Adenosine A2A
  • Receptors, Purinergic P1
  • Triazoles
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • N-(1-methyl-2-phenylethyl)adenosine
  • Adenosine