An imidazole based H-Phe-Phe-NH 2 peptidomimetic with anti-allodynic effect in spared nerve injury mice.

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., Sköld C; Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden., Karlgren M; 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., 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., Diwakarla S; The Beijer Laboratory, Department of Pharmaceutical Bioscience, Uppsala University, BMC, Box 591, SE-751 24 Uppsala, Sweden., Jonsson A; The Beijer Laboratory, Department of Pharmaceutical Bioscience, Uppsala University, BMC, Box 591, SE-751 24 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; The Beijer Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden. Electronic address: anja.sandstrom@ilk.uu.se.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Aug 01; Vol. 28 (14), pp. 2446-2450. Date of Electronic Publication: 2018 Jun 15.
DOI: 10.1016/j.bmcl.2018.06.009
Abstrakt: The dipeptide amide H-Phe-Phe-NH 2 (1) that previously was identified as a ligand for the substance P 1-7 (SP 1-7 ) 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 SP 1-7 and the tetrapeptide endomorphin-2 that is also binding to the SP 1-7 site. We herein report a strong anti-allodynic effect of a new H-Phe-Phe-NH 2 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 (ED 50 ) of 4 was superior as compared to gabapentin and morphine that are used in clinic.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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