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Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration
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 Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 109, p. 533-540, article id S0928-0987(17)30497-9Article in journal (Refereed) Published
Abstract [en]

Substance P 1-7 (SP1-7, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7) is the major bioactive metabolite formed after proteolytic degradation of the tachykinin substance P (SP). This heptapeptide often opposes the effects of the mother peptide. Hence, SP1-7 is having anti-inflammatory, anti-nociceptive and anti-hyperalgesic effects in experimental models. Despite all encouraging properties of SP1-7 its exact mode of action has not yet been elucidated which has hampered further development of this heptapeptide in drug discovery. Contrary to SP that mediates its biological activity via the NK-1 receptor, the N-terminal fragment SP1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP1-7 amide 1 (Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-NH2) was previously shown to be superior to the endogenous SP1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N-methylation scan of the backbone of the SP1-7 amide (1) results in peptides that are significantly less prone to undergo proteolysis in plasma from both mouse and human. However, with the two exceptions of the [MeLys3]SP1-7 amide (3) and the [MeGln5]SP1-7 amide (4), the peptides with a methyl group attached to the backbone are devoid of significant anti-allodynic effects after peripheral administration in the spared nerve injury (SNI) mouse model of neuropathic pain. It is suggested that the N-methylation does not allow these peptides to form the accurate bioactive conformations or interactions required for efficient binding to the macromolecular target. The importance of intact N-terminal Arg1 and C-terminal Phe7, anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP1-7 amide (1), the [MeLys3]SP1-7 amide (3) amide and the [MeGln5]SP1-7 amide (4) are all considerably more effective in the SNI mouse model than gabapentin that is widely used in the clinic for treatment of neuropathic pain.

Place, publisher, year, edition, pages
2017. Vol. 109, p. 533-540, article id S0928-0987(17)30497-9
Keywords [en]
Anti-allodynia, N-methylation, SP(1–7) amide, Solid phase peptide synthesis (SPPS), Spared nerve injury (SNI), Substance P (SP)
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-335651DOI: 10.1016/j.ejps.2017.09.007ISI: 000413325000055PubMedID: 28887235OAI: oai:DiVA.org:uu-335651DiVA, id: diva2:1163636
Funder
Swedish Research Council, 9459The Swedish Brain FoundationBerzelii Centre EXSELENTAvailable from: 2017-12-07 Created: 2017-12-07 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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Skogh, AnnaLesniak, AnnaGaugaz, Fabienne Z.Svensson, RichardLindeberg, GunnarFransson, RebeccaNyberg, FredHallberg, MathiasSandström, Anja

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Skogh, AnnaLesniak, AnnaGaugaz, Fabienne Z.Svensson, RichardLindeberg, GunnarFransson, RebeccaNyberg, FredHallberg, MathiasSandström, Anja
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Department of Medicinal ChemistryDepartment of Pharmaceutical BiosciencesDepartment of PharmacyScience for Life Laboratory, SciLifeLab
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