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

Abstract

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.

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

“…At MOR, the most populated cluster (with respect to the positioning of the opioid part) closely resembles the experimental positioning of DAMGO in this receptor. Similar binding poses were also proposed based on molecular modelling results for the opioid fragment of other opioid/antitachykinin hybrids [17] or some Tyr-d-Ala-Phe-Phe (TAPP) derivatives [66]. Aromatic rings of BU72 (experiment [67]), fentanyl (modelling [68]) cyclic opioid derivatives (modelling [69]), or linear peptide opioids (modelling [70]) were found to be located similarly as the Phe 4 ring in MOR-1 pose.…”

“…These include our previous contribution on AA3266 [29] and the above mentioned AWL3020 [44]. Recently Dyniewicz et al reported a series of hybrid compounds in which various opioid sequences were appended (at the C-terminus) with the 3,5-bis(trifluoromethyl)phenyl moiety characteristic for neurokinin-1 antagonists [17]. The compounds turned out to have very low or negligible rat NK1R affinity.…”

“…Working in the paradigm of multi-functional analgesics, researchers have investigated molecules designed by joining pharmacophores of various molecular targets and functional activities. The considered combinations are as diverse as MOR agonist/DOR agonist [6,7] MOR agonist/DOR antagonist [8,9], MOR agonist/cholecystokinin CCK2 receptor antagonist [10,11], MOR agonist/ neurotensin agonist [12,13], MOR agonist/ melanocortin-4 antagonist [14], MOR agonist/σ1-receptor antagonist [15,16], MOR agonist/voltage gated calcium channel (VGCC) blocker [17], MOR agonist/cannabinoid-1 receptors agonist [18] or MOR agonist/neuropeptide FF receptor agonist [19].…”

“…With this in mind, we synthesized compound AA3266 (Figure 1, disclosed previously [29]) that consists of an enkephalin-like fragment (Tyr-d-Ala-Gly-Phe-) and N-carboxybenzyl-d-tryptophan (Z-d-Trp) fragment joined by N -acylhydrazide bridge [17]. The latter fragment can be considered to form the NK1R antagonist pharmacophore.…”

Biphalin—A Potent Opioid Agonist—As a Panacea for Opioid System-Dependent Pathophysiological Diseases?

“…Further studies have shown that only one tetrapeptide with a hydrazide bridge and phenylalanine residue from the other tetrapeptide is responsible for the biological properties of biphalin [ 19 ]. The results were used to design and then synthesize a series of truncated biphalin analogs with a shortened second arm or with its replacement with another pharmacophore [ 25 , 26 , 27 , 28 ]. It was shown that even the hydrazide of tetrapeptide (H-Tyr-D-Ala-Gly-Phe-NH-NH 2 ) exhibited a good affinity for MOR, similar to the affinity of biphalin, but this compound had a 100 times lower affinity for DOR.…”