Impact of N-methylation of the substance P 1-7 amide on anti-allodynic effect in mice after peripheral administration.

Autor: Skogh A; Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden., Lesniak A; The Beijer Laboratory, Department of Pharmaceutical Bioscience, Uppsala University, BMC, Box 591, SE-751 24 Uppsala, Sweden., Gaugaz FZ; Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Science for Life Laboratory Drug Discovery and Development Platform, Department of Pharmacy, Uppsala University, BMC, Box 580, SE-751 23 Uppsala, Sweden., Svensson R; Uppsala Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Science for Life Laboratory Drug Discovery and Development Platform, Department of Pharmacy, Uppsala University, BMC, Box 580, SE-751 23 Uppsala, Sweden., Lindeberg G; Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden., Fransson R; Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden., Nyberg F; The Beijer Laboratory, Department of Pharmaceutical Bioscience, Uppsala University, BMC, Box 591, SE-751 24 Uppsala, Sweden., Hallberg M; The Beijer Laboratory, Department of Pharmaceutical Bioscience, Uppsala University, BMC, Box 591, SE-751 24 Uppsala, Sweden., Sandström A; Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: anja.sandstrom@orgfarm.uu.se.
Jazyk: angličtina
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences [Eur J Pharm Sci] 2017 Nov 15; Vol. 109, pp. 533-540. Date of Electronic Publication: 2017 Sep 05.
DOI: 10.1016/j.ejps.2017.09.007
Abstrakt: Substance P 1-7 (SP 1-7 , Arg 1 -Pro 2 -Lys 3 -Pro 4 -Gln 5 -Gln 6 -Phe 7 ) 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, SP 1-7 is having anti-inflammatory, anti-nociceptive and anti-hyperalgesic effects in experimental models. Despite all encouraging properties of SP 1-7 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 SP 1-7 acts through an unknown target that is distinct from all known opioid and tachykinin receptors. The SP 1-7 amide 1 (Arg 1 -Pro 2 -Lys 3 -Pro 4 -Gln 5 -Gln 6 -Phe 7 -NH 2 ) was previously shown to be superior to the endogenous SP 1-7 in all experimental pain models where the two compounds were compared. Herein, we report that N-methylation scan of the backbone of the SP 1-7 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 [MeLys 3 ]SP 1-7 amide (3) and the [MeGln 5 ]SP 1-7 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 Arg 1 and C-terminal Phe 7 , anticipated to serve as address and message residues, respectively, for achieving the anti-allodynic effect is emphasized. Notably, the three heptapeptides: the SP 1-7 amide (1), the [MeLys 3 ]SP 1-7 amide (3) amide and the [MeGln 5 ]SP 1-7 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.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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