Imidazo[1,2-α]pyridines possess adenosine A 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 receptor antagonistic activity. Prompted by this imidazo[1,2-α]pyridine analogues were synthesized and evaluated for their adenosine A and A receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A receptor agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A and A receptors. The influence of substitution on position C2 showed no improvement for either adenosine A or A receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A or A 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 receptor affinity in the low micromolar range with compound 4d showing: (1) the highest affinity for the adenosine A receptor with a K value of 2.06µM and (2) adenosine A receptor antagonistic properties. This pilot study concludes that para-substituted 3-cyclohexylamino-2-phenyl-imidazo[1,2-α]pyridine analogues represent an interesting scaffold to investigate further structure-activity relationships in the design of novel imidazo[1,2-α]pyridine-based adenosine A receptor antagonists for the treatment of neurodegenerative disorders.