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

Abstract

Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A1 receptor antagonistic activity. Prompted by this imidazo[1,2-α]pyridine analogues were synthesized and evaluated for their adenosine A1 and A2A receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A1 receptor agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A1 and A2A receptors. The influence of substitution on position C2 showed no improvement for either adenosine A1 or A2A receptor affinity. The addition of an amino or a cyclohexylamino group to position C3 also showed no improvement of adenosine A1 or A2A receptor affinity. Surprisingly para-substitution on the phenyl ring at position C2 in combination with a cyclohexylamino group at position C3 led to adenosine A1 receptor affinity in the low micromolar range with compound 4d showing: (1) the highest affinity for the adenosine A1 receptor with a Ki value of 2.06µM and (2) adenosine A1 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 A1 receptor antagonists for the treatment of neurodegenerative disorders.

• Authors: Roslyn Lefin, Mietha M van der Walt, Pieter J Milne, Gisella Terre'Blanche
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 27 Issue 17 Pg. 3963-3967 (09 01 2017) ISSN: 1464-3405 [Electronic] England
• PMID: 28789895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Adenosine A1 Receptor Antagonists
• Pyridines
• Receptor, Adenosine A1
• imidazo(1,2-a)pyridine

Topics

• Adenosine A1 Receptor Antagonists (chemical synthesis, chemistry, pharmacology)
• Cognition (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Nervous System Diseases (drug therapy)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Receptor, Adenosine A1 (metabolism)
• Structure-Activity Relationship