Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists

Abstract

The adenosine A_2A receptor (A_2AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A_2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 (K_i (hA_2AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound 5m showed a high affinity for hA_2AR with a K_i value of 5 nM and demonstrated antagonist activity with an IC₅₀ of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (9x, K_i = 21 nM; 10d, K_i = 15 nM) and functional antagonist activities (9x, IC₅₀ = 9 µM; 10d, IC₅₀ = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A_2AR antagonists for therapeutic applications.

Keywords: A2A receptor antagonist; cAMP assay; fluorescence polarization; quinazoline.