Abstract
Structure-activity relationships of 2-alkynyladenine derivatives were explored by varying substituents at the 9-, 8- and 2-positions of the purine moiety in order to optimize A2A adenosine receptor antagonist activity in vitro. A propargyl group at the 9-position was found to be important for A2A antagonist activity, and the introduction of a halogen, aryl, or heteroaryl at the 8-position further enhanced activity. A series of 8-substituted 2-alkynyl-N(9)-propargyladenine derivatives exhibited potent antagonist activity, with IC50 values in the low nM range. Compound 4a from this series was found to be orally active at a dose of 3 mg/kg in a mouse catalepsy model and a 6-hydroxydopamine-lesioned rat model of Parkinson's disease.
Keywords:
Adenosine receptor; Agonist; Antagonist; Parkinson’s disease; Structure–activity relationship.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives*
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Adenine / chemical synthesis
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Adenine / pharmacology
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Adenosine A2 Receptor Antagonists / chemical synthesis
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Adenosine A2 Receptor Antagonists / pharmacology*
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Animals
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Antiparkinson Agents / chemical synthesis
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Antiparkinson Agents / pharmacology*
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Antipsychotic Agents / chemical synthesis
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Antipsychotic Agents / pharmacology*
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Catalepsy / chemically induced
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Catalepsy / drug therapy
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Humans
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Male
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Mice
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Parkinson Disease / drug therapy
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Parkinson Disease / etiology
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Receptor, Adenosine A2A / chemistry*
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Structure-Activity Relationship
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Vasodilation / drug effects
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Vasodilator Agents / chemical synthesis
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Vasodilator Agents / pharmacology*
Substances
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8-bromo-2-(1-octyn-1-yl)-N9-propargyladenine
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Adenosine A2 Receptor Antagonists
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Antiparkinson Agents
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Antipsychotic Agents
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Receptor, Adenosine A2A
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Vasodilator Agents
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Adenine