Skogh A, Lesniak A, Sköld C, Karlgren M, Gaugaz FZ, Svensson R, Diwakarla S, Jonsson A, Fransson R, Nyberg F, Hallberg M, Sandström A
Bioorg. Med. Chem. Lett. 28 (14) 2446-2450 [2018-08-01; online 2018-06-15]
The dipeptide amide H-Phe-Phe-NH 2 (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.
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