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Papers of the Week

Papers: 22 Jul 2023 - 28 Jul 2023

Basic Science

In Silico Studies, In Vitro Studies, Molecular/Cellular, Pharmacology/Drug Development

Inflammation/Inflammatory, Neuropathic Pain

2023 Jul 19

J Med Chem


Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D (DR) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics.


Bonifazi A, Saab E, Sanchez J, Nazarova AL, Zaidi SA, Jahan K, Katritch V, Canals M, Lane JR, Newman AH


A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D receptor (DR) 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 DR, respectively, improving the dopamine receptor subtype selectivity (e.g., DR over DR) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted -(2,4)-pyrrolidine and -phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists () or loperamide (). The lead compounds , , and have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via DR antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.