Adenosine Receptor Binding Compounds with Subtype and Functional Selectivity for Therapeutic Development

This technology includes adenosine receptor binding compounds which could potentially be used for development of more selective and safe treatment of cardiovascular, psychiatric and neurodegenerative disorders. Though adenosine has been extensively studied as a primary chemical scaffold for adenosine receptor agonists, very little structure activity data exist for C5' substitution. This technology presents novel rationally designed small molecule compounds capable of selective binding to adenosine receptor (subtypes A2a, A1, A2b and A3) and inducing effector-biased downstream signaling. High resolution crystal structure of Adenosine A2 receptor (AA2AR) in complex with agonist UK-432097 makes possible rational design of small molecules specifically targeting C5' substitutions of the agonist ribose ring, making possible more high affinity and subtype selective binding and potentially ligand specific modulation of adenosine receptor function. The final set of candidate compounds was selected by their synthetic feasibility and drug-likeness. The selected substitutions are expected to work by engaging new polar contacts with residues in TM helix 5, potentially changing signaling properties of new agonists.