Hybrid design reveals a dopamine D3R ligand with promising in vitro ADME properties.

There is significant interest in identifying dopamine D3 receptor (D3R) antagonists and partial agonists with favorable drug-like properties as in vivo chemical tools and as experimental therapeutics for substance use disorders. We hypothesized that preserving the classical D3R antagonist pharmacophore while incorporating metabolically favorable structural features into the secondary pharmacophore ("tail") region would enable the discovery of selective D3R-targeted ligands with good ADME characteristics. Specifically, orthosteric binding site ("head") fragments known to confer D3R affinity were coupled with "tail" motifs inspired by non-catechol D1 receptor agonists, which have demonstrated enhanced pharmacokinetic stability. From this work, we have identified a new D3R ligand compound 8o. Compound 8o exhibits high affinity for D3R (2.7 nM) with >30-fold binding preference versus other dopamine receptors. Preliminary functional activity studies suggest that compound 8o is a D3R partial agonist. Docking studies indicate that 8o exhibits D3R interactions that are consistent with a bitopic mode of binding. Compound 8o also shows favorable in vitro ADME properties, that are predictive of good drug-like behavior, making it a promising lead molecule for future D3R in vivo probe and therapeutic optimization.