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Bioorg Med Chem. 2014 Jun 15;22(12):3072-82. doi: 10.1016/j.bmc.2014.04.041. Epub 2014 Apr 28.

8-Substituted 2-alkynyl-N(9)-propargyladenines as A2A adenosine receptor antagonists.

Author information

1
Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan.
2
Biochemicals Division, Yamasa Corporation, 2-10-1 Araoicho, Choshi, Chiba 288-0056, Japan. Electronic address: k_yamada@yamasa.com.

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

PMID:
24815000
DOI:
10.1016/j.bmc.2014.04.041
[Indexed for MEDLINE]

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