Methoxy substituted 2-benzylidene-1-indanone derivatives as A(1) and/or A(2A) AR antagonists for the potential treatment of neurological conditions.

A prior study reported on hydroxy substituted 2-benzylidene-1-indanone derivatives as A(1) and/or A(2A) antagonists for the potential treatment of neurological conditions. A lead compound (1a) was identified with both A(1) 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 A(1) and A(2A) affinity. This led to compounds with both A(1) and A(2A) affinity in the nanomolar range, namely 2c (A(1) K (i) (rat) = 41 nM; A(2A) K (i) (rat) = 97 nM) with C4-OCH(3) substitution on ring A together with meta (3') hydroxy substitution on ring B and 2e (A(1) K (i) (rat) = 42 nM; A(2A) K (i) (rat) = 78 nM) with C4-OCH(3) substitution on ring A together with meta (3') and para (4') dihydroxy substitution on ring B. Additionally, 2c is an A(1) antagonist. Consequently, the methoxy substituted 2-benzylidene-1-indanone scaffold is highly promising for the design of novel A(1) and A(2A) antagonists.