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Importance of N-and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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. 106, p. 345-351Article in journal (Refereed) Published
Abstract [en]

The heptapeptide SP1-7 (1, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)) is the major bioactive metabolite formed after proteolytic processing of the neuropeptide substance P (SP, Arg(1)-Pro(2)-Lys(3)-Pro(4)-GIn(5)-Gln(6)-Phe(7)-Phe(8)-Gly(9)-Leu(10)-Meti(11)-NH2). The heptapeptide 1 frequently exhibits opposite effects to those induced by SP, such as exerting antinociception, or attenuating thermal hyperalgesia and mechanical allodynia. The heptapeptide SP1-7 amide (2, Arg(1)-Pro(2)-Lys(3)-Pro(4)-Gln(5)-Gln(6)-Phe(7)-NH2 ) is often more efficacious than 1 in experimental pain models. We have now assessed the anti-allodynic outcome after systemic administration of 2 and a series of Ala substituted and truncated analogues of 2, in the spared nerve injury (SNI) mice model and the results obtained were correlated with in vitro plasma stability and permeability measurements. It is herein demonstrated that an intact Arg(1) in SP1-7 amide analogues is fundamental for retaining a potent in vivo effect, while Lys(3) of 2 is less important. A displacement with Ala(1) or truncation rendered the peptide analogues either inactive or with a significantly attenuated in vivo activity. Thus, the pentapeptide SP3-7 amide (7, t(1/2) = 11.1 min) proven to be the major metabolite of 2, demonstrated an in vivo effect itself although considerably less significant than 2 in the SNI model. Intraperitoneal administration of 2 in a low dose furnished the most powerful anti-allodynic effect in the SNI model of all the analogous evaluated, despite a fast proteolysis of 2 in plasma (t(1/2) = 6.4 min). It is concluded that not only the C-terminal residue, that we previously demonstrated, but also the N-terminal with its basic side chain, are important for achieving effective pain relief. This information is of value for the further design process aimed at identifying more drug-like SP1-7 amide related peptidomimetics with pronounced antiallodynic effects.

Place, publisher, year, edition, pages
Elsevier, 2017. Vol. 106, p. 345-351
Keyword [en]
Neuropathic pain, Spared nerve injury (SNI), SP1-7, Neuropeptides, Plasma stability, Structure-activity relationship, Message-address concept
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-334033DOI: 10.1016/j.ejps.2017.06.004ISI: 000406988600036PubMedID: 28587787OAI: oai:DiVA.org:uu-334033DiVA, id: diva2:1159686
Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2018-02-28Bibliographically approved
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
Keyword
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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Organic Pharmaceutical ChemistryDepartment of Pharmaceutical BiosciencesScience for Life Laboratory, SciLifeLabDepartment of Pharmacy
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