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Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and µ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics.
Bonifazi, Alessandro; Saab, Elizabeth; Sanchez, Julie; Nazarova, Antonina L; Zaidi, Saheem A; Jahan, Khorshada; Katritch, Vsevolod; Canals, Meritxell; Lane, J Robert; Newman, Amy Hauck.
Afiliación
  • 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.
  • Nazarova AL; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, U.K.
  • 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; 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.
  • Katritch V; 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.
  • Canals M; 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.
  • Lane JR; Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, U.K.
  • Newman AH; Centre of Membrane Protein and Receptors, Universities of Birmingham and Nottingham, Midlands NG2 7AG, U.K.
J Med Chem ; 66(15): 10304-10341, 2023 08 10.
Article en En | MEDLINE | ID: mdl-37467430
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Analgésicos Opioides / Trastornos Relacionados con Opioides Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Analgésicos Opioides / Trastornos Relacionados con Opioides Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos