RESUMEN
Opioids represent the most extensive category of abused substances in the United States, and the number of fatalities caused by these drugs exceeds those associated with all other drug overdoses combined. The administration of naltrexone, a potent pan-opioid receptor antagonist, to an individual dependent on opioids can trigger opioid withdrawal and induce severe side effects. There is a pressing demand for opioid antagonists free of opioid withdrawal effects. In our laboratory, we have identified a compound with affinity to mu, delta, and kappa opioid receptors in the range of 150-250 nM. This blood-brain barrier (BBB)-permeant compound was metabolically stable in vitro and in vivo. Our in vivo work demonstrated that 1-10 mg/kg intraperitoneal administration of our compound produces moderate efficacy in antagonizing morphine-induced antiallodynia effects in the chemotherapy-induced peripheral neuropathy (CIPN) model. The treatment was well-tolerated and did not cause behavioral changes. We have observed a fast elimination rate of this metabolically stable molecule. Furthermore, no organ toxicity was observed during the chronic administration of the compound over a 14-day period. Overall, we report a novel functional opioid antagonist holds promise for developing an opioid withdrawal therapeutic.
RESUMEN
Triple-negative breast cancer (TNBC) poses significant challenges due to its aggressive nature and limited treatment options. In this study, we investigated the impact of urea-based compounds on TNBC cells to uncover their mechanisms of action and therapeutic potential. Notably, polypharmacology urea analogues were found to work via p53-related pathways, and their cytotoxic effects were amplified by the modulation of oxidative phosphorylation pathways in the mitochondria of cancer cells. Specifically, compound 1 demonstrated an uncoupling effect on adenosine triphosphate (ATP) synthesis, leading to a time- and concentration-dependent shift toward glycolysis-based ATP production in MDA-MB-231 cells. At the same time, no significant changes in ATP synthesis were observed in noncancerous MCF10A cells. Moreover, the unique combination of mitochondrial- and p53-related effects leads to a higher cytotoxicity of urea analogues in cancer cells. Notably, the majority of tested clinical agents, but sorafenib, showed significantly higher toxicity in MCF10A cells. To test our hypothesis of sensitizing cancer cells to the treatment via modulation of mitochondrial health, we explored the combinatorial effects of urea-based analogues with established chemotherapeutic agents commonly used in TNBC treatment. Synergistic effects were evident in most tested combinations in TNBC cell lines, while noncancerous MCF10A cells exhibited higher resistance to these combination treatments. The combination of compound 1 with SN38 displayed nearly 60-fold selectivity toward TNBC cells over MCF10A cells. Encouragingly, combinations involving compound 1 restored the sensitivity of TNBC cells to cisplatin. In conclusion, our study provides valuable insights into the mechanisms of action of urea-based compounds in TNBC cells. The observed induction of mitochondrial membrane depolarization, inhibition of superoxide dismutase activity, disruption of ATP synthesis, and cell-line-specific responses contribute to their cytotoxic effects. Additionally, we demonstrated the synergistic potential of compound 1 to enhance the efficacy of existing TNBC treatments. However, the therapeutic potential and underlying molecular mechanisms of urea-based analogues in TNBC cell lines require further exploration.
RESUMEN
Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist. Multiple reports suggest that modulation of KOR signaling is a promising therapeutic strategy in treating neuropathic pain (NP). As a proof-of-concept study, we tested compound 2 in a rat model of NP and recorded its ability to modulate sensory and emotional pain-related behaviors. Observed in vitro and in vivo results suggest that these ligands can be used to develop compounds with potential application as pain therapeutics.