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Interactions of a boron-containing levodopa derivative on D2 dopamine receptor and its effects in a Parkinson disease model

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Abstract

Levodopa is a cornerstone in Parkinson’s disease treatment. Beneficial effects are mainly by binding on D2 receptors. Docking simulations of a set of compounds including well-known D2-ligands and a pool of Boron-Containing Compounds (BCC), particularly boroxazolidones with a tri/tetra-coordinated boron atom, were performed on the D2 Dopamine receptor (D2DR). Theoretical results yielded higher affinity of the compound DPBX, a Dopaboroxazolidone, than levodopa on D2DR. Essential interactions with residues in the third and sixth transmembrane domains of the D2DR appear to be crucial to induce and stabilize interactions in the active receptor state. Results from a motor performance evaluation of a murine model of Parkinson’s disease agree with theoretical results, as DPBX showed similar efficacy to that of levodopa for diminishing MPTP-induced parkinsonism. This beneficial effect was disrupted with prior Risperidone (D2DR antagonist) administration, supporting the role of D2DR in the biological effect of DPBX. In addition, DPBX limited neuronal loss in substantia nigra in a similar manner to that of levodopa administration.

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Acknowledgements

The authors thank Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional for allowing us to use their facilities during the theoretical evaluation.

Funding

The authors thank the Comisión de Operación y Fomento de Actividades Académicas, the Secretaría de Investigación y Posgrado del Instituto Politécnico Nacional (M2143), and the Consejo Nacional de Ciencia y Tecnología de México (CONACyT) for financial support and scholarships. ALO-N is the recipient of a post-doctoral fellowship at the current affiliation.

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Authors and Affiliations

  1. Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Diaz Mirón, s/n. Col. Casco de Santo Tomás, Del. Miguel Hidalgo, 11340, Mexico City, Mexico

    Antonio Abad-García, Eunice D. Farfán-García, Martiniano Bello, José G. Trujillo-Ferrara & Marvin A. Soriano-Ursúa

  2. Departamento de Nefrología, Hospital General de México “Dr. Eduardo Liceaga”, Dr. Balmis 148, Alc. Cuauhtémoc, 06720, Mexico City, Mexico

    A. Lilia Ocampo-Néstor

  3. Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, 11201-5497, USA

    Bhaskar C. Das

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  1. Antonio Abad-García
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Abad-García, A., Ocampo-Néstor, A.L., Das, B.C. et al. Interactions of a boron-containing levodopa derivative on D2 dopamine receptor and its effects in a Parkinson disease model. J Biol Inorg Chem 27, 121–131 (2022). https://doi.org/10.1007/s00775-021-01915-2

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