Methoxy substituted 2-benzylidene-1-indanone derivatives as A1 and/or A2A AR antagonists for the potential treatment of neurological conditions

Abstract

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 (A₁ K _i (rat) = 41 nM; A_2A K _i (rat) = 97 nM) with C4-OCH₃ substitution on ring A together with meta (3') hydroxy substitution on ring B and 2e (A₁ K _i (rat) = 42 nM; A_2A K _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.

Fig. 1. The structures of ASP-5854 and JNJ-40255293.

Fig. 2. The structures and K_i values of compounds structurally related to benzylidene indanones and the structural modifications to lead compound 1a to determine features essential for dual A₁/A_2A AR affinity.

Scheme 1. Synthesis of 2a–g, 2i, 2k & 2m. Reagents and conditions: a) acetone, K₂CO₃, MeI, 50 °C (18 h); b) MeOH, HCl (32%), 120 °C (24 h).

Fig. 3. Structural requirements of the 2-benzylidene-1-indanone scaffold for dual A₁/A_2A affinity.

Fig. 4. The binding curves of compounds 2c and CPA (reference compound) are examples of A₁ AR antagonistic action (A) and A₁ AR agonistic action (B), respectively, determined via a GTP shift assays (with and without 100 μM GTP) in rat whole brain membranes expressing A₁ ARs with [³H]DPCPX as radioligand. (A) GTP shift of 1.46 calculated for compound 2c, (B) GTP shift of 15 calculated for compound CPA.