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An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
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2018 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, nr 14, s. 2446-2450Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The dipeptide amide H-Phe-Phe-NH2 (1) that previously was identified as a ligand for the substance P 1-7 (SP1-7) binding site exerts intriguing results in animal models of neuropathic pain after central but not after peripheral administration. The dipeptide 1 is derived from stepwise modifications of the anti-nociceptive heptapeptide SP1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH2 peptidomimetic (4) comprising an imidazole ring as a bioisosteric element, in the spare nerve injury (SNI) mice model after peripheral administration. Peptidomimetic 4 was stable in plasma, displayed a fair membrane permeability and a favorable neurotoxic profile. Moreover, the effective dose (ED50) of 4 was superior as compared to gabapentin and morphine that are used in clinic.

Ort, förlag, år, upplaga, sidor
2018. Vol. 28, nr 14, s. 2446-2450
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
URN: urn:nbn:se:uu:diva-343682DOI: 10.1016/j.bmcl.2018.06.009ISI: 000438467200020PubMedID: 29929882OAI: oai:DiVA.org:uu-343682DiVA, id: diva2:1186566
Forskningsfinansiär
Vetenskapsrådet, 9459
Anmärkning

Title in dissertation reference list: An Imidazole-Based H-Phe-Phe-NH2 Peptidomimetic with Anti-Allodynic Effect in Spared Nerve Injury Mice and without Neurotoxic Liability

Tillgänglig från: 2018-02-28 Skapad: 2018-02-28 Senast uppdaterad: 2018-09-24Bibliografiskt granskad
Ingår i avhandling
1. Development of Substance P 1–7 Related Peptides and Peptidomimetics: Targeting Neuropathic Pain
Öppna denna publikation i ny flik eller fönster >>Development of Substance P 1–7 Related Peptides and Peptidomimetics: Targeting Neuropathic Pain
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 68
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 249
Nyckelord
Substance P 1–7, Peptidomimetics, Solid-phase Peptide Synthesis (SPPS), Palladium catalysis, Carbonylation, Imidazole, Bioisostere, Neuropathic pain, Allodynia, Structure-activity relationships
Nationell ämneskategori
Läkemedelskemi
Forskningsämne
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-343687 (URN)978-91-513-0254-6 (ISBN)
Disputation
2018-04-20, Hall B:41, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-03-28 Skapad: 2018-02-28 Senast uppdaterad: 2018-04-24

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Skogh, AnnaLesniak, AnnaSköld, ChristianKarlgren, MariaGaugaz, Fabienne Z.Svensson, RichardDiwakarla, ShantiFransson, RebeccaNyberg, FredHallberg, MathiasJohansson, Anja

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Skogh, AnnaLesniak, AnnaSköld, ChristianKarlgren, MariaGaugaz, Fabienne Z.Svensson, RichardDiwakarla, ShantiFransson, RebeccaNyberg, FredHallberg, MathiasJohansson, Anja
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Läkemedelsdesign och läkemedelsutvecklingInstitutionen för farmaceutisk biovetenskapInstitutionen för farmaciScience for Life Laboratory, SciLifeLabInstitutionen för läkemedelskemi
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