Synthesis and In Silico Profile Modeling of 6-O-Fluoroalkyl-6-O-desmethyl-diprenorphine Analogs

Marton, János and Gombos, Dávid and Cumming, Paul and Fehér, Tamás and Milentyev, Alexander and Bauer, Beate and Willoch, Frode and Schoultz, Bent Wilhelm and Benyhe, Sándor and Ötvös, Ferenc (2025) Synthesis and In Silico Profile Modeling of 6-O-Fluoroalkyl-6-O-desmethyl-diprenorphine Analogs. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 26 (19). No. 9427. ISSN 1661-6596

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Abstract

We present the first preparation of novel 6-O-(fluoroalkyl)-6-O-desmethyl-diprenorphine analogs and 6-O-(tosyloxyalkyl)-6-O-desmethyl-3-O-trityl-diprenorphine-type precursors for the radiosynthesis of 6-O-([18F]fluoroalkyl)-6-O-desmethyl-diprenorphine radiotracers for molecular imaging by positron emission tomography (PET). The synthesis sequence to the new opioid receptor ligands consists of eleven steps starting from the poppy alkaloid thebaine. The precursor molecules were prepared in a three-step synthesis process from the «Luthra precursor» (TDDPN). We report the complete 1H- and 13C-NMR assignment of the new 6-O-(substituted)-6-O-desmethyl-diprenorphine derivatives, as well as the results of docking studies in silico for diverse novel opioid receptor ligands, including a new series of 6-O-(fluoroalkyl)- and 6-O-(hydroxyalkyl)-6-O-desmethyl-diprenorphine derivatives.

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