Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D<sub>3</sub> (D<sub>3</sub>R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics
Alessandro Bonifazi, Elizabeth Saab, Julie Sanchez, Antonina L. Nazarova, Saheem A. Zaidi, Khorshada Jahan, Vsevolod Katritch, Meritxell Canals, J. Robert Lane, Amy Hauck Newman
Abstract
A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D 3 receptor (D 3 R) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and D 3 R, respectively, improving the dopamine receptor subtype selectivity (e.g., D 3 R over D 2 R) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood–brain barrier permeability. We identified the substituted trans -(2 S,4 R )-pyrrolidine and trans -phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists TRV130 ( 3 ) or loperamide ( 6 ). The lead compounds 46, 84, 114, and 121 have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via D 3 R antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.