Novel 8-(furan-2-yl)-3-substituted Thiazolo [5,4-e][1,2,4] triazolo[1,5-c] pyrimidine-2(3H)-thione Derivatives as Potential Adenosine A(2A) Receptor Antagonists

Bioorg Med Chem. 2010 Apr 1;18(7):2491-500. doi: 10.1016/j.bmc.2010.02.048. Epub 2010 Mar 1.

Abstract

Novel thiazolotriazolopyrimidine derivatives (23-33) designed as potential adenosine A(2A) receptor (A(2A)R) antagonists were synthesized. Molecular docking studies revealed that all compounds (23-33) exhibited strong interaction with A(2A)R. The strong interaction of the compounds (23-33) with A(2A)R in silico was confirmed by their high binding affinity with human A(2A)R stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24-26 demonstrated substantial binding affinity and selectivity for A(2A)R as compared to SCH58261, a standard A(2A)R antagonist. Decrease in A(2A)R-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A(2A)R antagonist potential of the compounds 24-26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24-26 further supports their role in the alleviation of PD symptoms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Antipsychotic Agents / antagonists & inhibitors
  • Antipsychotic Agents / pharmacology
  • Catalepsy / chemically induced
  • Catalepsy / prevention & control
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Chromatography, Thin Layer
  • Computer Simulation
  • Crystallography, X-Ray
  • Cyclic AMP / metabolism
  • Drug Evaluation, Preclinical
  • Dyskinesia, Drug-Induced / prevention & control
  • Haloperidol / antagonists & inhibitors
  • Haloperidol / pharmacology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Models, Molecular
  • Motor Activity / drug effects
  • Protein Binding
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*
  • Radioligand Assay
  • Structure-Activity Relationship
  • Thiones / chemical synthesis*
  • Thiones / pharmacology*

Substances

  • 8-(furan-2-yl)-3-thiazolo (5,4-e)(1,2,4)triazolo(1,5-c)pyrimidine-2(3H)-thione
  • Adenosine A2 Receptor Antagonists
  • Antipsychotic Agents
  • Pyrimidines
  • Thiones
  • Cyclic AMP
  • Haloperidol