New fused pyrroles with rA1/A2A antagonistic activity as potential therapeutics for neurodegenerative disorders

In a pilot study, eleven pyrrolopyridine and pyrrolopyrimidine derivatives (specifically, 7-azaindole and 7-deazapurine derivatives) were synthesised by Suzuki cross-coupling reactions and evaluated via radioligand binding assays as potential adenosine receptor (AR) antagonists in order to further investigate the structure-activity relationships of these compounds. 6-Chloro-4-phenyl-1H-pyrrolo[2,3-b]pyridine, with a 7-azaindole scaffold, was identified as a selective A₁ AR antagonist with a rA₁K_i value of 0.16 µM, and interestingly, the addition of a N-atom to the aforementioned fused heterocyclic ring system, creating corresponding 7-deazapurines, led to a dual A₁/A_2A AR ligand (2-chloro-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine: rA₁K_i: 0.19 ± 0.02 µM; rA_2AK_i: 0.43 ± 0.01 µM). Introducing an additional N-atom into the heterocyclic ring system was tolerable for rA₁ AR affinity and also led to rA_2A AR affinity. This pilot study concluded that new 7-azaindole and 7-deazapurine derivatives represent interesting scaffolds for design of A₁ and/or A_2A AR antagonists.