An imidazole based H-Phe-Phe-NH2 peptidomimetic with anti-allodynic effect in spared nerve injury mice

  • Bioorg Med Chem Lett. 2018 Aug 1;28(14):2446-2450. doi: 10.1016/j.bmcl.2018.06.009.
Anna Skogh  1 ,  Anna Lesniak  2 ,  Christian Sköld  1 ,  Maria Karlgren  3 ,  Fabienne Z Gaugaz  3 ,  Richard Svensson  3 ,  Shanti Diwakarla  2 ,  Anna Jonsson  2 ,  Rebecca Fransson  1 ,  Fred Nyberg  2 ,  Mathias Hallberg  2 ,  Anja Sandström  4
Affiliations
  • 1. Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
  • 2. The Beijer Laboratory, Department of Pharmaceutical Bioscience, Uppsala University, BMC, Box 591, SE-751 24 Uppsala, Sweden.
  • 3. 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.
  • 4. 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: [email protected].
PMID: 29929882 DOI: 10.1016/j.bmcl.2018.06.009
Abstract

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.

Keywords
Neuropathic pain; Peptidomimetics; Phenylalanine bioisostere; SNI mice; Substance P 1–7.
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