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Article

Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide

by
Alessia D’Aloia
1,†,
Federica Arrigoni
1,†,
Renata Tisi
1,2,
Alessandro Palmioli
1,2,
Michela Ceriani
1,
Valentina Artusa
1,
Cristina Airoldi
1,2,
Giuseppe Zampella
1,
Barbara Costa
1,* and
Laura Cipolla
1,*
1
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy
2
Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, P.zza dell’Ateneo Nuovo 1, 20126 Milano, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to the work.
Int. J. Mol. Sci. 2020, 21(23), 9074; https://doi.org/10.3390/ijms21239074
Submission received: 2 October 2020 / Revised: 23 November 2020 / Accepted: 26 November 2020 / Published: 28 November 2020
(This article belongs to the Special Issue Amides)
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Abstract

Palmitoylethanolamide (PEA) belongs to the class of N-acylethanolamine and is an endogenous lipid potentially useful in a wide range of therapeutic areas; products containing PEA are licensed for use in humans as a nutraceutical, a food supplement, or food for medical purposes for its analgesic and anti-inflammatory properties demonstrating efficacy and tolerability. However, the exogenously administered PEA is rapidly inactivated; in this process, fatty acid amide hydrolase (FAAH) plays a key role both in hepatic metabolism and in intracellular degradation. So, the aim of the present study was the design and synthesis of PEA analogues that are more resistant to FAAH-mediated hydrolysis. A small library of PEA analogues was designed and tested by molecular docking and density functional theory calculations to find the more stable analogue. The computational investigation identified RePEA as the best candidate in terms of both synthetic accessibility and metabolic stability to FAAH-mediated hydrolysis. The selected compound was synthesized and assayed ex vivo to monitor FAAH-mediated hydrolysis and to confirm its anti-inflammatory properties. 1H-NMR spectroscopy performed on membrane samples containing FAAH in integral membrane protein demonstrated that RePEA is not processed by FAAH, in contrast with PEA. Moreover, RePEA retains PEA’s ability to inhibit LPS-induced cytokine release in both murine N9 microglial cells and human PMA-THP-1 cells.
Keywords: palmitoylethanolamide; fatty acid amide hydrolase; inflammation; PPAR-α receptor; metabolism; PEA analogues palmitoylethanolamide; fatty acid amide hydrolase; inflammation; PPAR-α receptor; metabolism; PEA analogues

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MDPI and ACS Style

D’Aloia, A.; Arrigoni, F.; Tisi, R.; Palmioli, A.; Ceriani, M.; Artusa, V.; Airoldi, C.; Zampella, G.; Costa, B.; Cipolla, L. Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide. Int. J. Mol. Sci. 2020, 21, 9074. https://doi.org/10.3390/ijms21239074

AMA Style

D’Aloia A, Arrigoni F, Tisi R, Palmioli A, Ceriani M, Artusa V, Airoldi C, Zampella G, Costa B, Cipolla L. Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide. International Journal of Molecular Sciences. 2020; 21(23):9074. https://doi.org/10.3390/ijms21239074

Chicago/Turabian Style

D’Aloia, Alessia, Federica Arrigoni, Renata Tisi, Alessandro Palmioli, Michela Ceriani, Valentina Artusa, Cristina Airoldi, Giuseppe Zampella, Barbara Costa, and Laura Cipolla. 2020. "Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide" International Journal of Molecular Sciences 21, no. 23: 9074. https://doi.org/10.3390/ijms21239074

APA Style

D’Aloia, A., Arrigoni, F., Tisi, R., Palmioli, A., Ceriani, M., Artusa, V., Airoldi, C., Zampella, G., Costa, B., & Cipolla, L. (2020). Synthesis, Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide. International Journal of Molecular Sciences, 21(23), 9074. https://doi.org/10.3390/ijms21239074

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