Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D 3 (D 3 R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics.

Autor: Bonifazi A; Medicinal 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., Saab E; Medicinal 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., Sanchez J; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, U.K.; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, U.K., Nazarova AL; Department of Quantitative and Computational Biology, Department of Chemistry, Dornsife Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, California 90089, United States., Zaidi SA; Department of Quantitative and Computational Biology, Department of Chemistry, Dornsife Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, California 90089, United States., Jahan K; Medicinal 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., Katritch V; Department of Quantitative and Computational Biology, Department of Chemistry, Dornsife Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, California 90089, United States., Canals M; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, U.K.; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, U.K., Lane JR; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, U.K.; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, U.K., Newman AH; Medicinal 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.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2023 Aug 10; Vol. 66 (15), pp. 10304-10341. Date of Electronic Publication: 2023 Jul 19.
DOI: 10.1021/acs.jmedchem.3c00417
Abstrakt: 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.
Databáze: MEDLINE