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Constrained H-Phe-Phe-NH2 Analogues With High Affinity to the Substance P 1-7 Binding Site and With Improved Metabolic Stability and Cell Permeability
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 Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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.
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2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 12, 4953-4965 p.Article in journal (Refereed) Published
Abstract [en]

We recently reported the discovery of H-Phe-Phe-NH2 as a small and high affinity ligand for the substance P 1-7 (SP1-7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) specific binding site and its intriguing ability to reduce neuropathic pain. With the overall aim to develop stable and orally bioavailable SP1-7 mimetics, the dipeptide was chosen as a lead compound. Herein the structure-activity relationship (SAR) of a set of modified H-Phe-Phe-NH2 analogues is presented together with their potential active uptake by PEPT1 transporter, intestinal permeability, and metabolic stability. Local constraints via peptide backbone methylation or preparation of cyclized analogues based on pyrrolidine were evaluated and were shown to significantly improve the in vitro pharmacokinetic properties. The SAR was rationalized by deriving a plausible binding pose for the high affinity ligands. Rigidification using a 3-phenylpyrrolidine moiety in the C-terminal of H-Phe-Phe-NH2 resulted in high affinity and improved intrinsic clearance and intestinal epithelial permeability.

Place, publisher, year, edition, pages
2013. Vol. 56, no 12, 4953-4965 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-149482DOI: 10.1021/jm400209hISI: 000321237100011PubMedID: 23735006OAI: oai:DiVA.org:uu-149482DiVA: diva2:406150
Available from: 2011-03-24 Created: 2011-03-20 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Discovery of Small Peptides and Peptidomimetics Targeting the Substance P 1-7 Binding Site: Focus on Design, Synthesis, Structure-Activity Relationships and Drug-Like Properties
Open this publication in new window or tab >>Discovery of Small Peptides and Peptidomimetics Targeting the Substance P 1-7 Binding Site: Focus on Design, Synthesis, Structure-Activity Relationships and Drug-Like Properties
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Biologically active peptides are important for many physiological functions in the human body and therefore serve as interesting starting points in drug discovery processes. In this work the neuropeptide substance P 1–7 (SP1–7, H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), which has been demonstrated to reduce neuropathic pain and attenuate opioid withdrawal symptoms in animal models, has been addressed in a medicinal chemistry program with the overall aim of transforming this bioactive peptide into more drug-like compounds. Specific binding sites for this neuropeptide have been detected in the brain and the spinal cord. Interestingly, the smaller neuropeptide endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) also interacts with these binding sites, although 10-fold less efficient.

In this work the structure–activity relationship of SP1–7 and EM-2, regarding their affinity to the SP1–7 binding site was elucidated using alanine scans, truncation, and terminal modifications. The C-terminal part of both peptides, and especially the C-terminal phenylalanine, was crucial for binding affinity. Moreover, the C-terminal functional group should preferably be a primary amide. The truncation studies finally resulted in the remarkable discovery of H-Phe-Phe-NH2 as an equally good binder as the heptapeptide SP1–7. This dipeptide amide served as a lead compound for further studies. In order to improve the drug-like properties and to find a plausible bioactive conformation, a set of rigidified and methylated dipeptides of different stereochemistry, and analogs with reduced peptide character, were synthesized and evaluated regarding binding, metabolic stability and absorption. Small SP1–7 analogs with retained affinity and substantially improved permeability and metabolic stability were identified.

Beside peptide chemistry the synthetic work included the development of a fast and convenient microwave-assisted protocol for direct arylation of imidazoles. Furthermore, microwave-assisted aminocarbonylation using Mo(CO)6 as a solid carbon monoxide source was investigated in the synthesis of MAP amides and for coupling of imidazoles with amino acids.

In a future perspective the present findings, together with the fact that some of the SP1–7 analogs discovered herein have been shown to reproduce the biological effects of SP1-7 in animal studies related to neuropathic pain and opioid dependence, can ultimately have an impact on drug discovery in these two areas.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 88 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 143
Keyword
substance P 1-7, peptidomimetics, structure-activity relationship, drug-like properties, phenylalanine, imidazole, MAP aryl amides, carbonylation
National Category
Medicinal Chemistry
Research subject
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-149480 (URN)978-91-554-8040-0 (ISBN)
Public defence
2011-05-06, B42, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2011-04-15 Created: 2011-03-20 Last updated: 2011-05-05Bibliographically approved

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Fransson, RebeccaSköld, ChristianSvensson, RichardArtursson, PerNyberg, FredHallberg, MathiasSandström, Anja

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