A prior study reported on hydroxy substituted 2-benzylidene-1-indanone derivatives as A₁ and/or A_2A antagonists for the potential treatment of neurological conditions. A lead compound (1a) was identified with both A₁ and A_2A affinity in the micromolar range. The current study explored the structurally related methoxy substituted 2-benzylidene-1-indanone derivatives with various substitutions on ring A and B of the benzylidene indanone scaffold in order to enhance A₁ and A_2A affinity. This led to compounds with both A₁ and A_2A affinity in the nanomolar range, namely 2c (A₁K_i (rat) = 41 nM; A_2AK_i (rat) = 97 nM) with C4-OCH₃ substitution on ring A together with meta (3′) hydroxy substitution on ring B and 2e (A₁K_i (rat) = 42 nM; A_2AK_i (rat) = 78 nM) with C4-OCH₃ substitution on ring A together with meta (3′) and para (4′) dihydroxy substitution on ring B. Additionally, 2c is an A₁ antagonist. Consequently, the methoxy substituted 2-benzylidene-1-indanone scaffold is highly promising for the design of novel A₁ and A_2A antagonists.