Synthesis and structure-activity relationships of 4-cycloalkylamino-1, 2, 4-triazolo[4, 3-a]quinoxalin-1- one derivatives as A1 and A3 adenosine receptor antagonists

Arch Pharm (Weinheim). 2004 Jan;337(1):35-41. doi: 10.1002/ardp.200300816.

Abstract

In a previous paper we reported the synthesis and binding activity of 4-cycloalkylamino-1, 2, 4-triazolo[4, 3-a]quinoxalin-1-one derivatives, differently substituted on the appended 2-phenyl ring, some of which were potent and selective A(1) adenosine receptor (AR) antagonists. In the present paper several 4-cycloalkylamino-2-phenyl-1, 2, 4-triazolo[4, 3-a]quinoxalin-1-one derivatives (1-11), bearing simple substituents on the benzofused moiety, are reported. The binding data of bovine A(1) and A(2A) and human A(3) AR show that we have obtained highly potent A(1) AR antagonists. In particular, the 4-cyclohexylamino derivatives 1-5 show higher A(1) vs A(2A) selectivity than the parent compound A, which lacks substituents on the benzofused moiety. Moreover, compounds 1-11 display, in general, good A(3) AR affinity. Finally, SAR studies provide some new insights about the steric requirements of the A(3) receptor pocket, which accommodates the benzofused moiety of our 4-amino-triazoloquinoxalin-1-one derivatives.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / antagonists & inhibitors
  • Adenosine / metabolism
  • Adenosine / pharmacokinetics
  • Alkanes / chemical synthesis*
  • Alkanes / pharmacokinetics*
  • Animals
  • Binding Sites
  • Binding, Competitive
  • CHO Cells
  • Cattle
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Humans
  • Iodine Isotopes
  • Membranes
  • Neostriatum / cytology
  • Neostriatum / metabolism
  • Phenethylamines / antagonists & inhibitors
  • Phenethylamines / metabolism
  • Phenethylamines / pharmacokinetics
  • Purinergic Antagonists*
  • Quantitative Structure-Activity Relationship*
  • Quinoxalines / administration & dosage
  • Quinoxalines / chemical synthesis*
  • Quinoxalines / pharmacokinetics*
  • Receptors, Purinergic / drug effects
  • Triazoles / administration & dosage
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacokinetics*
  • Tritium

Substances

  • Alkanes
  • Iodine Isotopes
  • Phenethylamines
  • Purinergic Antagonists
  • Quinoxalines
  • Receptors, Purinergic
  • Triazoles
  • Tritium
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • N(6)-cyclohexyladenosine
  • N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide
  • Adenosine