Imidazo[1,2-α]pyridines possess adenosine A1 receptor affinity for the potential treatment of cognition in neurological disorders

Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A(1) receptor antagonistic activity. Prompted by this imidazo[1,2-alpha]pyridine analogues were synthesized and evaluated for their adenosine A(1) and A(2A) receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A(1) receptor agonistic or antagonistic functionality. Imidazo[1,2-alpha]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A(1) and A(2A) receptors. The influence of substitution on position C2 showed no improvement for either adenosine A(1) or A(2A) receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A(1) or A(2A) receptor affinity. Surprisingly para-substitution on the phenyl ring at position C2 in combination with a cyclohexylamino group at position C3 led to adenosine A(1) receptor affinity in the low micromolar range with compound 4d showing: (1) the highest affinity for the adenosine A(1) receptor with a K-i value of 2.06 mu M and (2) adenosine A(1) receptor antagonistic properties. This pilot study concludes that para-substituted 3-cyclohexylamino-2-phenyl-imidazo[1,2-alpha]pyridine analogues represent an interesting scaffold to investigate further structure-activity relationships in the design of novel imidazo[1,2-alpha]pyridine-based adenosine A(1) receptor antagonists for the treatment of neurodegenerative disorders. (C) 2017 Elsevier Ltd. All rights reserved.