adenosine-5--(n-ethylcarboxamide) and Dyskinesia--Drug-Induced

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.

Topics: Adenosine A2 Receptor Antagonists; Animals; Antipsychotic Agents; Catalepsy; Cell Line; Cell Membrane; Chromatography, Thin Layer; Computer Simulation; Crystallography, X-Ray; Cyclic AMP; Drug Evaluation, Preclinical; Dyskinesia, Drug-Induced; Haloperidol; Humans; Magnetic Resonance Spectroscopy; Male; Mice; Models, Molecular; Motor Activity; Protein Binding; Pyrimidines; Radioligand Assay; Structure-Activity Relationship; Thiones

A pattern of perioral dyskinesia was induced in adult male rabbits by concomitant stimulation of dopamine D1 receptors (SKF 38393) and blockade of dopamine D2 receptors (sulpiride). Rabbits treated with sulpiride (6 and 12.5 mg/kg i.v.) then, 90 min thereafter, with SKF 38393 (0.1, 1 and 10 mg/kg i.v.) showed a pattern of perioral dyskinesia characterized by compulsive and repetitive sniffing, licking and vacuous chewing. These effects were completely prevented by the administration of N-ethylcarboxamide adenosine (NECA), an A2 > A1 adenosine receptor agonist. The present results confirm that perioral dyskinesia is dependent on the activation of dopamine D1 receptors. They also show that, in order to induce perioral dyskinesia in rabbits, a concomitant blockade of dopamine D2 receptors is required. Finally, the antagonistic effect of NECA on the appearance of perioral movements confirms that adenosine receptors play a key role in the control of dopamine-mediated effects.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Behavior, Animal; Dyskinesia, Drug-Induced; Male; Rabbits; Sulpiride