Thebaine Derivatives as a New Regulator of Tumor Angiogenesis

Abstract

Cancer pain management is mostly done by opioids; however, they have further pharmacological effects apart from analgesia including angiogenesis. In this study, peripherally acting ligands of µ opioid receptor (MOR) were synthesized and evaluated as a tool to investigate peripheral effects of opioids in controlling angiogenesis. For this purpose, the designed compounds were synthesized from thebaine and N-(4-dimethylaminophenyl)maleimide under Diels-Alder and nucleophilic substitution (SN) reactions with different alkyl halides to form quaternary ammonium salts. In silico study conducted by docking these compounds on active (5C1M) and inactive (4DKL) form of MOR. Results of in silico study indicate that all compounds were more likely to be an antagonist of MOR based on their interaction patterns with MOR. For biological assessment, they were tested on human umbilical vein endothelial cells using a proliferation MTT test. Also, these compounds were studied by in vivo hot plate test to examine the ability of compounds to cross the blood-brain barrier (BBB). In biological tests, these compounds showed double-faced results with pro-angiogenic effect in lower doses and anti-angiogenic effect in higher doses. Their pro-angiogenic effect was comparable with VEGF. The in vivo study proved their peripherally acting nature. The contradictory effects of opioids on angiogenesis could be explained by its two different targets including MOR and opioid growth factor receptor. This gives a privilege to opioids for use as an angiogenesis controller. By developing more peripherally acting opioids with minimizing central effects, more research in this area is hoped.

KEYWORDS:

• Opioid
• angiogenesis
• HUVEC
• peripheral acting
• hot plate test
• MTT
• VEGF
• anti-angiogenesis

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

This research was supported by the National Instate for Medical Research and Development (NIMAD) [Grant number 943760] and the Research council of Tehran University of Medical Sciences [Grant number 95-04-33-33469].