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Small constrained SP1-7 analogues bind to a unique site and promote anti-allodynic effects following systemic injection in mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Biologisk beroendeforskning)
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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2015 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 298, 112-119 p.Article in journal (Refereed) Published
Abstract [en]

Previous results have shown that the substance P (SP) N-terminal fragment SP1–7 may attenuate hyperalgesia and produce anti-allodynia in animals using various experimental models for neuropathic pain. The heptapeptide was found to induce its effects through binding to and activating specific sites apart from any known neurokinin or opioid receptor. Furthermore, we have applied a medicinal chemistry program to develop lead compounds mimicking the effect of SP1–7. The present study was designed to evaluate the pharmacological effect of these compounds using the mouse spared nerve injury (SNI) model of chronic neuropathic pain. Also, as no comprehensive screen with the aim to identify the SP1–7 target has yet been performed we screened our lead compound H-Phe-Phe-NH2 toward a panel of drug targets. The extensive target screen, including 111 targets, did not reveal any hit for the binding site among a number of known receptors or enzymes involved in pain modulation. Our animal studies confirmed that SP1–7, but also synthetic analogs thereof, possesses anti-allodynic effects in the mouse SNI model of neuropathic pain. One of the lead compounds, a constrained H-Phe-Phe-NH2 analog, was shown to exhibit a significant anti-allodynic effect.

Place, publisher, year, edition, pages
2015. Vol. 298, 112-119 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-247270DOI: 10.1016/j.neuroscience.2015.04.002ISI: 000354783300011PubMedID: 25862586OAI: oai:DiVA.org:uu-247270DiVA: diva2:795532
Available from: 2015-03-16 Created: 2015-03-16 Last updated: 2017-12-04Bibliographically approved
In thesis
1. The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain
Open this publication in new window or tab >>The Impact of the Neuropeptide Substance P (SP) Fragment SP1-7 on Chronic Neuropathic Pain
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is an unmet medical need for the efficient treatment of neuropathic pain, a condition that affects approximately 10% of the population worldwide. Current therapies need to be improved due to the associated side effects and lack of response in many patients. Moreover, neuropathic pain causes great suffering to patients and puts an economical burden on society.

The work presented in this thesis addresses SP1-7, (Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), a major metabolite of the pronociceptive neuropeptide Substance P (SP). SP is released in the spinal cord following a noxious stimulus and binds to the NK1 receptor. In contrast to SP, the degradation fragment SP1-7 is antinociceptive through binding to specific binding sites distinct from the NK1 receptor.

The aim of this thesis was to investigate the impact of SP1-7 on neuropathic pain. To understand how SP1-7 exerts its effect, a series of N-truncated forms of the heptapeptide were biologically evaluated. A set of small high-affinity ligands was evaluated in animal models of neuropathic pain. To confirm a clinical relevance the levels of SP1-7 in human neuropathic pain were assessed incerebrospinal fluid (CSF) collected from neuropathic pain patients.

The results showed that SP1-7 could alleviate thermal as well as mechanical hypersensitivity in three different animal models of neuropathic pain. C-terminal amidation was connected with increased efficacy. N-terminal truncation of SP1-7 indicated a necessity of five amino acids in order to retain biological effect. One small high-affinity ligand showed a significant anti-allodynic effect. CSF levels of SP1-7 in neuropathic pain patients were lower compared to controls. Taken together, these findings demonstrate that the formation of SP1-7 may be attenuated in neuropathic pain. C-terminal amidation and a majority of its amino acids are necessary for stability and permeability. Clearly, SP1-7 and SP1-7 mimetics with high affinity to the SP1-7 binding site ameliorate neuropathic pain-like behaviors in animal models of neuropathic pain. Overall, the findings presented in this thesis contribute to new knowledge regarding the role of SP1-7 and related analogues and fragments in neuropathic pain. In a future perspective, this could be essential for the development of efficient strategies for managing patients with neuropathic pain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 198
Keyword
neuropathic pain; substance P (SP); SP1-7; bioactive fragments; spared nerve injury; spinal cord injury; streptozotocin-induced diabetes; allodynia; hyperalgesia; peptidomimetics; cerebrospinal fluid; spinal cord stimulation, radioimmunoassay
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-241637 (URN)978-91-554-9206-9 (ISBN)
Public defence
2015-05-08, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2015-04-17 Created: 2015-01-14 Last updated: 2015-07-07

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Jonsson, AnnaSkogh, AnnaBrolin, ErikaWatanabe, HiroyukiHallberg, MathiasSandström, AnjaNyberg, Fred

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