Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 15; p. 3429
• Main Authors: Dyniewicz, Jolanta, Lipiński, Piotr F. J., Kosson, Piotr, Bochyńska-Czyż, Marta, Matalińska, Joanna, Misicka, Aleksandra
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.07.2020; MDPI
• Subjects: Acids; Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Cell Line, Tumor; cytotoxic activity; Cytotoxicity; Cytotoxins - chemical synthesis; Cytotoxins - chemistry; Cytotoxins - pharmacology; diacylhydrazine; Humans; Hydrazones - chemistry; Male; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Molecular Docking Simulation; multitarget compounds; Narcotics; N′-acylhydrazide; Opioid Peptides - chemical synthesis; Opioid Peptides - chemistry; Opioid Peptides - pharmacology; Peptides; Rats; Rats, Wistar; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; µ-opioid receptor; diacylhydrazine; opioid peptides; N’-acylhydrazide; privileged structures; analgesics; peptidomimetics; µ-opioid receptor; cytotoxic activity; N-acylhydrazone; multitarget compounds; structure activity relationships
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25153429

In the present contribution, we analyze the influence that C-terminal extension of short opioid peptide sequences by organic fragments has on receptor affinity, in vivo analgesic activity, and antimelanoma properties. The considered fragments were based on either N-acylhydrazone (NAH) or N′-acylhydrazide motifs combined with the 3,5-bis(trifluoromethyl)phenyl moiety. Eleven novel compounds were synthesized and subject to biological evaluation. The analyzed compounds exhibit a diversified range of affinities for the µ opioid receptor (MOR), rather low δ opioid receptor (DOR) affinities, and no appreciable neurokinin-1 receptor binding. In three out of four pairs, N-acylhydrazone-based derivatives bind MOR better than their N’-acylhydrazide counterparts. The best of the novel derivatives have similar low nanomolar MOR binding affinity as the reference opioids, such as morphine and biphalin. The obtained order of MOR affinities was compared to the results of molecular docking. In vivo, four tested compounds turned out to be relatively strong analgesics. Finally, the NAH-based analogues reduce the number of melanoma cells in cell culture, while their N′-acylhydrazide counterparts do not. The antimelanoma properties are roughly correlated to the lipophilicity of the compounds.