Deigin Vladislav, Korobov Nikolay, Volpina Olga, Linkova Natalia, Diatlova Anastasiia, Medvedev Dmitrii, Krasichkov Alexander, Polyakova Victoria
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16/10, 117997 Moscow, Russia.
Department of Pharmacology, Faculty of Fundamental Medicine, Lomonosov Moscow State University, GSP-1, Leninskie Gory, 119991 Moscow, Russia.
Int J Mol Sci. 2025 Aug 29;26(17):8437. doi: 10.3390/ijms26178437.
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 (). 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.
这种神经肽在神经内稳态的各个组成部分中的多方面参与会影响疼痛和行为调节。其中一种强效神经肽是从亚马逊青蛙皮肤中提取的皮啡肽（）。皮啡肽的独特之处在于其序列中的D - 丙氨酸残基，这激发了研究人员寻找用作药物的皮啡肽类似物。本研究的主要目的是合成几种新的线性和环状皮啡肽类似物，并将它们评估为潜在的非侵入性镇痛药。通过探索我们将线性肽转化为稳定肽结构的2,5 - 二酮哌嗪（2,5 - DKP）衍生物的方法，我们合成了几种新的皮啡肽线性肽和嵌合环肽模拟物。这些化合物在体外和体内进行了测试，以确定它们的生物活性和作为药物的潜在适用性。为了评估体外阿片样物质活性，使用了“豚鼠回肠”（GPI）试验。D2显示出最高活性，环肽D3和D4显示出高活性。我们可以假设皮啡肽类似物D2、D3和D4是μ型阿片受体的强效激动剂，并且具有高阿片样物质活性。然而，这需要在进一步研究中使用分子建模方法进行验证。皮啡肽的镇痛作用已在“热板”和“甩尾”试验中进行了评估。在大鼠中，D2皮啡肽类似物经鼻内给药后在“水甩尾”试验中表现出剂量依赖性镇痛作用。0.5μg / kg的较小剂量导致40％的镇痛作用和短期昏迷状态。在1.0μg / kg的剂量下观察到最大的长效镇痛作用，该剂量诱导完全昏迷。肽D2以5.0mg / kg的剂量腹腔内给药后的镇痛作用超过50％。 “旷场”试验表明，经鼻内给药后，肽D2对大鼠行为反应具有剂量依赖性（15、50、150μg / kg）抑制作用。基于胃内给药后小鼠镇痛作用评估的结果，结合2,5 - DKP支架（D3和D4）的线性肽新修饰物被证明有望用于口服。
