Identification of Dmt-D-Lys-Phe-Phe-OH as a highly antinociceptive tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20
| Autor: | Engin Bojnik, Sándor Benyhe, Steven Ballet, Dirk Tourwé, Piotr Kosson, Lipkowski Andrzej W, Isabelle Van den Eynde, Patrycja Kleczkowska, Anna Leśniak |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Stereochemistry Metabolite Receptors Opioid mu Peptide Pharmacology Mice Radioligand Assay chemistry.chemical_compound Drug Stability GTP-Binding Proteins Receptors Opioid delta Opioid Receptor Binding Animals Receptor Opioid peptide Neurotensin Pain Measurement chemistry.chemical_classification Tetrapeptide Brain General Medicine Rats Analgesics Opioid DAMGO Opioid Peptides chemistry Peptides |
| Zdroj: | Pharmacological Reports. 65:836-846 |
| ISSN: | 1734-1140 |
| DOI: | 10.1016/s1734-1140(13)71064-8 |
| Popis: | Background Recently, we presented a novel compound (PK20, Dmt-D-Lys-Phe-Phe-Lys-Lys-Pro-Phe-Tle-Leu-OH) that targets single entity opioid and neurotensin pharmacophores. This endomorphin-2-like opioid peptide was introduced as a highly active analgesic because it elicited a strong dose- and time-dependent antinociceptive response when administered centrally and peripherally. Its pain-relieving activity was observed as rapidly as 5 min after drug injection. Such promising results led us to perform further studies, such as determining the resistance to enzymatic degradation, which resulted in obtaining a very stable opioid pharmacore PK20 metabolite. Methods The synthesis of PK20 and its N-terminal tetrapeptide fragment has been accomplished using solid phase peptide chemistry. The biological stability of peptides has been measured in human serum and analyzed by HPLC/MS. Peptides were pharmacologically characterized in in vitro MOP and DOP receptor binding as well as [ 35 S]GTPγS receptor binding assays. Antinociceptive properties of compounds were measured by in vivo assays in C 57 Bl 6 mice after intravenous or intrathecal applications. Results Dmt-D-Lys-Phe-Phe-OH (PK20M), an N -terminal tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20, is characterized by a long duration of action, as demonstrated by a preserved, long-lasting analgesic effect even 2 h post-injection (average % MPE = 69.33). In rat brain membranes, PK20M efficiently displaced both the MOP and DOP receptor selective radioprobes [ 3 H]DAMGO and [ 3 H]DIDI (pKi of 9.52 and 7.86, respectively) and potently stimulated [ 35 S]GTPγS binding, proving full agonism at both receptor types. In the [ 35 S]GTPγS assay, which measured the agonist-mediated G protein activation, PK20M together with PK20 and Met-enkephalin were potent stimulators of the regulatory G proteins. The relative affinities of PK20M for the μ and δ receptor subtypes revealed μ-receptor selectivity. Conclusion The novel MOP receptor selective metabolite has been shown to possess opioid subtype receptor selectivity, high potency, and effective analgesic activities as measured in various bioassays. |
| Databáze: | OpenAIRE |
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