{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:47:56Z","timestamp":1788922076130,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Higher Education","award":["FSEE-2025-0015"],"award-info":[{"award-number":["FSEE-2025-0015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The neuropeptide\u2019s 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 \u201cGuinea Pig Ileum\u201d (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 \u00b5-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 \u201cHot-Plate\u201d and \u201cTail-Flick\u201d tests. In rats, D2 dermorphin analogues demonstrated dose-dependent analgesic effect in the \u201cWater Tail-Flick\u201d test after intranasal administration. A smaller dose of 0.5 \u00b5g\/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 \u00b5g\/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 \u201cOpen-Field\u201d test demonstrated a dose-dependent (15, 50, 150 \u03bcg\/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.<\/jats:p>","DOI":"10.3390\/ijms26178437","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:42:21Z","timestamp":1756485741000},"page":"8437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Neurotropic Activity of Novel Dermorphin Analogs Active at Systemic and Noninvasive Administration"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1257-8697","authenticated-orcid":false,"given":"Vladislav","family":"Deigin","sequence":"first","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16\/10, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay","family":"Korobov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Fundamental Medicine, Lomonosov Moscow State University, GSP-1, Leninskie Gory, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0740-6110","authenticated-orcid":false,"given":"Olga","family":"Volpina","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16\/10, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5156-5421","authenticated-orcid":false,"given":"Natalia","family":"Linkova","sequence":"additional","affiliation":[{"name":"Departments of Hospital Surgery, Belgorod National Research University, 308015 Belgorod, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia","family":"Diatlova","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16\/10, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7401-258X","authenticated-orcid":false,"given":"Dmitrii","family":"Medvedev","sequence":"additional","affiliation":[{"name":"The Department of Social Rehabilitation and Occupational Therapy of the St. Petersburg Medical and Social Institute, 72A Kondratievsky St., 195271 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Krasichkov","sequence":"additional","affiliation":[{"name":"Department of Radio Engineering Systems of Electrotechnical University LETI, 5F Prof. Popova Str., 197022 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8682-9909","authenticated-orcid":false,"given":"Victoria","family":"Polyakova","sequence":"additional","affiliation":[{"name":"Departments of Hospital Surgery, Belgorod National Research University, 308015 Belgorod, Russia"},{"name":"The Department of Social Rehabilitation and Occupational Therapy of the St. Petersburg Medical and Social Institute, 72A Kondratievsky St., 195271 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mizusawa, K. 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