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Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis
Published on: July 3, 2015
Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR)
Alessandro Bonifazi1, Elizabeth Saab1, Julie Sanchez2,3
1Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse─Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, Maryland 21224, United States.
Abstract:
A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D3 receptor (D3R) 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 D3R, respectively, improving the dopamine receptor subtype selectivity (e.g., D3R over D2R) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted trans-(2S,4R)-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 D3R antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.
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