2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives

Abstract

A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A₁, A_2A, A_2B, and A₃ adenosine receptor subtypes. Eleven purines showed potent antagonism at A₁, A₃, dual A₁/A_2A, A₁/A_2B, or A₁/A₃ adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.

Keywords: 2-arylpurine derivatives; G protein-coupled receptors; adenine derivatives; adenosine receptor antagonists; structure-activity relationship.

Figure 1

The adenosine receptor antagonists scaffold identified in our previous work.

Scheme 1

Synthetic approach to 2-aryl-adenine derivatives 3a–x.

Figure 2

Structure-activity relationship of 2-aryl-9-substituted-6-morpholino purine derivatives for the adenosine receptor antagonists.

Figure 3

(a) Competition binding curve for compound 3x at A₁ receptors. (b) Concentration-response curve of compound 3x in the presence of 10 µM of NECA at human A₁ receptor expressed in CHO cells. Points represent the mean ± standard deviation (vertical bars) of duplicate measurements.

Figure 4

Predicted binding mode of compound 3x in the orthosteric site of the A₁ receptor. The receptor is depicted as a grey cartoon, with the ligand and key side chains represented as sticks. Hydrogen bonds are shown as black dashed lines.