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Synthesis of alamandine glycoside analogs as new drug candidates to antagonize the MrgD receptor for pain relief

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Abstract

Two series of putatively brain-penetrant alamandine glycosides have been prepared for screening against the MrgD receptor. The first series retains the initial six residues of the alamandine sequence (ARVYIHP) as the “peptide message,” replacing the C-terminal proline (P) with several serine (S) glycosides at the C-terminus to produce “glycoside addresses”. In the second series, steric bulk was altered to modify the “peptide message”– the N-terminal alanine (A) residue was substituted with glycine (G); D-alanine (a); nor-valine (norV); D-nor-valine (D-norV); valine (V); and D-nor-valine (v), keeping the C-terminal serine-beta-D-glucoside (S-Glc) “glycoside address” constant. All the peptides and glycopeptides were synthesized as their C-terminal amides. The purity of native alamandine and its eleven selected derivatives were each confirmed using analytical HPLC. Also, the molecular weight and chemical composition were confirmed using mass spectroscopy. The MrgD receptor expression was evaluated in rationally chosen human cell lines, A549 and HEK 293. Both cell lines showed the presence of the MrgD receptor around 35 kDa, as confirmed by western blot analysis. The effect of varying concentrations of some alamandine derivatives on cell viability was evaluated on HEK 293 and A549 cell lines.

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Acknowledgements

This work was supported by NIH NIDA 5UG3DA047717 (HMM and RP), R01HL137282 (HMM), R21AG054766 (HMM), R21AI135935 (HMM), P01HL103453 (HMM), and a SEOS TRIF grant award (HMM). This research was partially supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under Award Number R01NS091238. We thank the Analytical & Biological Mass Spectrometry (ABMS) Core Facility, especially Yelena Feinstein and Krishna Parsawar, for their assistance with mass spectrometry analysis. The ABMS core facility is supported by the Research, Innovation, and Impact (RII), Technology and Research Initiative Fund (TRIF), and BIO5 Institute at the University of Arizona, Tucson, AZ. Finally, we wish to thank Prof. Laurence Hurley for his help and guidance at the University of Arizona, and particularly at the Dept. of Chemistry and Biochemistry, where he has been helpful in building bridges between chemistry and medicine since his arrival.

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Authors and Affiliations

  1. Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ, 85721, USA

    Wafaa Alabsi, Timothy Jaynes, Lajos Szabo & Robin Polt

  2. College of Pharmacy, Skaggs Pharmaceutical Sciences Center, The University of Arizona, Tucson, AZ, 85721-0207, USA

    Wafaa Alabsi & Heidi M. Mansour

  3. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA

    Tariq Alqahtani & Daekyu Sun

  4. Department of Pharmaceutical Sciences, College of Pharmacy, Ministry of National Guard Health Affairs, King Saud bin Abdulaziz University for Health Sciences, Riyadh, 11481, Saudi Arabia

    Tariq Alqahtani

  5. Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, 85726, USA

    Todd W. Vanderah

  6. College of Public Health & College of Medicine, FIU Center for Translational Science, Port St. Lucie, FL, 34987, USA

    Heidi M. Mansour

  7. Department of Chemistry & Biochemistry, BIO5, The University of Arizona, Tucson, AZ, 85721, USA

    Robin Polt

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  1. Wafaa Alabsi
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Correspondence to Robin Polt.

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Alabsi, W., Jaynes, T., Alqahtani, T. et al. Synthesis of alamandine glycoside analogs as new drug candidates to antagonize the MrgD receptor for pain relief. Med Chem Res 31, 1135–1146 (2022). https://doi.org/10.1007/s00044-022-02881-3

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