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An Imidazole-Based H-Phe-Phe-NH2 Peptidomimetic with Anti-Allodynic Effect in Spared Nerve Injury Mice and without Neurotoxic Liability
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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(English)Manuscript (preprint) (Other academic)
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-343682OAI: oai:DiVA.org:uu-343682DiVA, id: diva2:1186566
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-02-28
In thesis
1. Development of Substance P 1–7 Related Peptides and Peptidomimetics: Targeting Neuropathic Pain
Open this publication in new window or tab >>Development of Substance P 1–7 Related Peptides and Peptidomimetics: Targeting Neuropathic Pain
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The neuropeptide substance P 1–7 (SP1–7, H-Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-OH) and its amidated analogue SP1–7 amide, have displayed intriguing effects in experimental models for neuropathic pain acting on a specific, yet unknown SP1–7 target. The aim of this thesis was to design and synthesise SP1–7 related peptides and peptidomimetics, to be used as research tools to study the SP1–7 system, and to serve as drug leads in the neuropathic pain area.

The in vivo structure activity relationship (SAR) of the SP1–7 amide was elucidated using Ala-substituted, N-terminally truncated and N-methylated variants. By evaluation of the anti-allodynic effect in spared nerve injury (SNI) mice and the pharmacokinetic properties it is suggested that Phe7 acts as a message residue and Arg1 as an address residue, both important for the overall anti-allodynic activity. In contrast, Lys3 could be substituted by alanine, and the Pro2-Lys3 and Pro4-Gln5 bond could be N-methylated with retained anti-allodynic effect. The Pro2-Lys3 bond was found most sensitive towards proteolysis and indeed, N-methylation of this bond delivered peptides completely inert in plasma. Conversely, prolonged plasma stability did not improve the overall in vivo activity for these peptides. Instead, the SP1–7 amide remained the most potent peptide in vivo, despite fast degradation in plasma.    

Besides peptide synthesis, the synthetic work included development of a Pd-catalysed aminocarbonylation protocol using an amino acid nucleophile, which was used for the synthesis of an imidazole-based peptidomimetic. This peptidomimetic was equipotent to the SP1–7 amide, and more potent than the drug gabapentin, in regard to its anti-allodynic effect in SNI mice, and it is a promising drug lead for further development. The Pd-catalysed aminocarbonylation protocol was refined further, in regards to reaction scope and requirements for solid-phase peptide synthesis and has proven useful for N-capping, isotopic labelling, and intramolecular cyclisation of peptides.

In summary, the work presented herein resulted in an in vivo SAR for SP1–7 related peptides, a novel small molecule SP1–7 peptidomimetic, and methods expanding the toolbox for synthesising modified peptides and peptidomimetics – a field in drug discovery that presently gaining increasing attention.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 249
Keywords
Substance P 1–7, Peptidomimetics, Solid-phase Peptide Synthesis (SPPS), Palladium catalysis, Carbonylation, Imidazole, Bioisostere, Neuropathic pain, Allodynia, Structure-activity relationships
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343687 (URN)978-91-513-0254-6 (ISBN)
Public defence
2018-04-20, Hall B:41, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2018-03-28 Created: 2018-02-28 Last updated: 2018-04-24

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