Az opioidkrízis egy lehetséges megoldása: új típusú fájdalomcsillapítók fejlesztése

Angyal, Péter and Varga, Szilárd and Soós, Tibor (2024) Az opioidkrízis egy lehetséges megoldása: új típusú fájdalomcsillapítók fejlesztése. SCIENTIA ET SECURITAS, 5 (2). pp. 108-115. ISSN 2732-2688

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Abstract

Az opioidválság hatására kiemelten fontos kutatási iránnyá vált az új fájdalomcsillapítók fejlesztése, amelyek a korábbiaknál kedvezőbb mellékhatásprofillal rendelkeznek. A probléma lehetséges megoldását ismét a természet inspirálta: a kratom növény egy metabolitja, a mitraginin-pszeudoindoxil, amelynek gyógyszeripari fejlesztését akadályozza a vegyülethez való korlátozott hozzáférhetőség. A Kooperatív Doktori Program keretében megvalósítottuk e természetes vegyület, majd számos származék első totálszintézisét. Ezzel lehetőség nyílt a szerkezet–hatás összefüggéseket feltérképező biológiai vizsgálatok és a célzott fejlesztés elvégzésére, továbbá felfedeztünk egy a farmakológiai hatást is befolyásoló izomerizációs jelenséget. Mindemellett egy olyan módszertani fejlesztést is végrehajtottunk, amely olefinek ipari szempontból jelentős vegyületekké (pl. Lobesia botrana szexferomonja) való átalakításában talált alkalmazást. | An ongoing public health emergency, the opioid crisis is characterized by the pervasive misuse and addiction to opioid substances, encompassing both prescription pain relievers and illicit drugs such as heroin. The alarming rise in overdose-related deaths is placing an overwhelming burden on healthcare infrastructure and communities worldwide. Tackling this crisis requires a holistic approach, including targeted education initiatives, the implementation of stricter prescription guidelines, widespread access to evidence-based addiction treatment, and, most importantly, intensified efforts to develop safer analgesics with more favorable side-effect profiles. Managing pain has been a longstanding challenge in the field of medicine, and its history is intricately linked with inspiration drawn from nature. While natural product derivatives such as opiates (e.g., morphine and its analogs) have been utilized for centuries to address both moderate-to-severe acute and chronic pain, their use is accompanied by a range of adverse effects and the risk of addiction. This concern is now propelling efforts to develop safer analgesic alternatives, with inspiration possibly derived from another natural source, kratom. Recently, there has been a growing interest in mitragynine pseudoindoxyl, identified as the most potent kratom metabolite to date, as a promising alternative for pain management with significantly reduced side effects. However, the pharmaceutical development involving this compound has been impeded by restricted access to both this compound and its unnatural analogues. In this context, we achieved the first enantioselective and scalable total synthesis of mitragynine pseudoindoxyl, along with its epimeric congener, speciogynine pseudoindoxyl. Additionally, our studies reveal that mitragynine pseudoindoxyl doesn’t function as a singular molecular entity but rather as a dynamic ensemble of stereoisomers in protic environments. Consequently, the insights gained from these synthetic, structural, and biological investigations laid the groundwork for the ongoing deliberate design of mitragynine pseudoindoxyl analogues, guiding the development of next-generation analgesics. Importantly, during this synthetic endeavour, we unearthed a previously unidentified reactivity that served as the foundation for a novel synthetic methodology. The crux of this approach lies in the unprecedented valorisation of an unactivated double bond into α,β-unsaturated carbonyls through alkenyl-thianthrenium intermediates, exhibiting remarkable chemo- and stereoselectivity in a metal-free environment. Given its applicability in the sustainable and cost-effective synthesis of pivotal industrial building blocks and strategic pheromones, such as the sex pheromone of the grapevine moth, Lobesia botrana, we have taken the step to secure this innovation through a patent application.

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