PhD Scientific Days 2018

Budapest, April 19–20, 2018

Synthesis of novel 6-oxomorphinan derived pyrazolo- and isoxazolomorphinans: Potential compounds with mixed opioid receptor binding profile.

Vajda, Máté

Máté J. Vajda1
1 Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre u., 9. H-1092 Budapest, Hungary

Language of the presentation

Hungarian

Text of the abstract

INTRODUCTION: Opioids are generally used in medicine as the most potent analgesics. Besides their pain relief ability, they have serious side-effects which limit their clinical usage. It’s also known that the opioid system plays a key role in psychological responses and behavior. Thus, there’s increasing interest of other utilization possibilities of the system, mainly for the treatment of psychiatric disorders, along with the search for compounds which are potent analgesics with diminished side-effects. It’s been proven that selective kappa antagonists and/or delta agonists show potent antidepressant properties. DOR agonists can significantly increase the efficacy of MOR agonists, and DOR antagonists can prevent or diminish the development of tolerance and physical dependence by MOR agonists. Based on previous reports of heterocycle-fused morphinan compounds (emphasizing oxymorphazole, an oxymorphone derived 6,7:3’,4’-pyrazolomorphinan), a great number of them shows the desired binding profiles as described.
AIMS: Synthesis of a series of substituted oxycodone, oxymorphone derived pyrazolo- and isoxazolomorphinans, structural characterization with NMR spectroscopy and in vitro biological evaluation.
METHOD: For unsubstituted pyrazolo- and isoxazolomorphinans, we utilized N,N-dimethylformamide dimethyl acetal to synthesize 7-(N,N-dimethylaminomethylene)morphinan intermediates. For substituted compounds we synthetized 14-O-acylated compounds using the appropriate anhydrides, and used the 14-O → 7-C acyl migration method reported by Nagase and Portoghese (1990) to create the 1,3-dioxo intermediates. The initial purity examination was carried out with thin-layer chromatography, for detailed structural confirmation NMR and mass spectroscopy was used.
RESULTS: By the date of the abstract submission 12 end product have been synthesized with high purity out of the planed 16.
CONCLUSION: Since it’s an ongoing work, biological data is not yet available about the compounds, although based on similar structural moieties of previously reported compounds it is likely that some of our molecules exhibit the desired receptor binding profile and may be valuable compounds for the design of opioids with better side-effect profile.

Data of the presenter

Doctoral School: Pharmaceutical Sciences
Program: Experimental and Clinical Pharmacology
Supervisor: Sándor Hosztafi
E-mail address: vajdamatthew@gmail.com