Dermorphin Analogs D2(Russian Academy of Sciences)

The neuropeptide’s multifaceted involvement in various components of neural homeostasis impacts pain and behavioral regulation. One of the highly potent neuropeptides is dermorphin, extracted from the skin of the Amazon frog (Phyllomedusa sauvagei). The unique feature of dermorphin is the D-Ala residue in its sequence, which has inspired researchers to search for dermorphin analogs for use as pharmaceuticals. The primary objective of this study is to synthesize several new linear and cyclic dermorphin analogs and evaluate them as potential non-invasive analgesics. By exploring our method for converting linear peptides into 2,5-diketopiperazine(2,5-DKP) derivatives, which stabilize peptide structures, we synthesize several new dermorphin linear peptides and chimeric cyclopeptidomimetics. These compounds were tested in vitro and in vivo to determine their biological activities and potential applicability as pharmaceuticals. For the evaluation of in vitro opioid activity, the “Guinea Pig Ileum” (GPI) test was used. D2 showed the highest activity, and cyclopeptides D3 and D4 showed high activity. We can assume that dermorphin analogues D2, D3, and D4 are potent agonists of µ-type opioid receptors and have high opioid activity. However, this needs to be verified using molecular modeling methods in further research. The analgesic effects of dermorphins have been evaluated in the “Hot-Plate” and “Tail-Flick” tests. In rats, D2 dermorphin analogues demonstrated dose-dependent analgesic effect in the “Water Tail-Flick” test after intranasal administration. A smaller dose of 0.5 µg/kg resulted in 40% analgesia and a short-term state of stupor. The maximum long-lasting analgesia was observed at a dose of 1.0 µg/kg, which induced complete stupor. The analgesic effect of peptide D2 after intraperitoneal administration at a 5.0 mg/kg dose was over 50%. The “Open-Field” test demonstrated a dose-dependent (15, 50, 150 μg/kg) peptide D2 suppression effect on behavioural reactions in rats following intranasal administration. A new modification of linear peptides, combined with a 2,5-DKP scaffold (D3 and D4), proved promising for oral use based on the results of analgesic effect evaluation in mice following intragastric administration.