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.
Copyright 2010 Elsevier Ltd. All rights reserved.
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