The objectives of this PhD thesis have been the design, synthesis, and pharmacological evaluation of new small molecules as potential therapeutic agents for persistent pain management. The work was carried out at the Department of Drug and Health Sciences (University of Catania), and at the Institut für Pharmazeutische und Medizinische Chemie (Münster-Germany). The main objective was the synthesis of novel ligands able to bind opioid receptors and/or sigma receptors (σRs), both involved in pain modulation. Based upon SARs studies, different series of benzomorphan-based compounds have been obtained as derivatives of LP1 and LP2, ligands that are able to simultaneously bind MOR and DOR. The compounds have been evaluated for their affinity and selectivity with competitive radioligand binding assays on opioid and sigma receptors. Further pharmacological evaluation has been performed in pain animal models. Moreover, another two series of compounds, characterized by the benzomorphan scaffold in its destro configuration, were designed and synthesized in order to identify potential σ1R ligands. These compounds were also evaluated performing binding assay to investigate their affinity profile towards sigma receptors. In vivo evaluation was carried out to study the analgesic effect of most promising compounds in animal model of acute and chronic pain. Recently, the search for compounds with affinity for both MOR and σ1R is one of the innovative strategies to develop analgesics with reduced side effects. With this aim, two series of new fentanyl derivatives were synthesized, and their profile will be tested in vitro and in vivo. Finally, in the last part of this thesis the development of novel small molecules with potential opioid and/or σ1R ligands profile was described. The novel synthesized compounds are R-Carvone derivatives, and they were tested by competition binding assays to evaluate their affinity versus opioid and sigma receptors. These ligands are actually under investigation.
I principali obiettivi di questa tesi di dottorato sono stati la progettazione, sintesi e valutazione farmacologica di nuove molecole potenzialmente utili nel trattamento del dolore persistente. Il lavoro è stato svolto presso il Dipartimento di Scienze del Farmaco e della Salute (Università di Catania) e presso l’Institut für Pharmazeutische und Medizinische Chemie (Münster-Germania). Il principale obiettivo è stato sintetizzare nuovi ligandi capaci di legare i recettori oppioidi e/o i recettori sigma (σR), entrambi coinvolti nella modulazione del dolore. Sulla base di studi SAR, sono state ottenute diverse serie di composti a struttura benzomorfanica come derivati di LP1 e LP2, ligandi capaci di legare contemporaneamente il MOR e il DOR. L’affinità di questi composti verso i recettori oppiodi e sigma è stata valutata mediante saggi di radioligand competition binding. Una ulteriore valutazione farmacologica è stata eseguita in modelli animale di dolore. Inoltre, altre due serie di composti, caratterizzati dal nucleo benzomorfanico nella sua configurazione destro, sono state progettate e sintetizzate con lo scopo di indentificare potenziali ligandi σ1. Anche questi composti sono stati studiati mediante saggi di competition binding per valutarne il profilo di affinità verso i recettori sigma. L’effetto analgesico dei composti più promettenti è stato valutato in vivo in modelli animali di dolore acuto e cronico. Recentemente, la ricerca di composti che abbiano affinità sia per i recettori oppioidi che per i recettori sigma è considerata una strategia innovativa per lo sviluppo di analgesici con ridotti effetti avversi. Con questo obiettivo, sono state progettate e sintetizzate due serie di analoghi del Fentanyl il cui profilo sarà valutato in vitro e in vivo. In fine, nell’ultima parte di questa tesi viene descritta la sintesi di nuovi ligandi potenzialmente attivi sui recettori oppioidi e/sigma. I nuovi ligandi, derivati dall’R-Carvone, sono stati valutati mediante saggi di competition binding sui recettori oppioidi e sigma e attualmente sono ulteriormente in studio.
Progettazione, sintesi e valutazione biologica di nuovi ligandi come potenziali agenti terapeutici per il trattamento del dolore persistente / Costanzo, Giuliana. - (2024 Jun 14).
Progettazione, sintesi e valutazione biologica di nuovi ligandi come potenziali agenti terapeutici per il trattamento del dolore persistente
COSTANZO, GIULIANA
2024-06-14
Abstract
The objectives of this PhD thesis have been the design, synthesis, and pharmacological evaluation of new small molecules as potential therapeutic agents for persistent pain management. The work was carried out at the Department of Drug and Health Sciences (University of Catania), and at the Institut für Pharmazeutische und Medizinische Chemie (Münster-Germany). The main objective was the synthesis of novel ligands able to bind opioid receptors and/or sigma receptors (σRs), both involved in pain modulation. Based upon SARs studies, different series of benzomorphan-based compounds have been obtained as derivatives of LP1 and LP2, ligands that are able to simultaneously bind MOR and DOR. The compounds have been evaluated for their affinity and selectivity with competitive radioligand binding assays on opioid and sigma receptors. Further pharmacological evaluation has been performed in pain animal models. Moreover, another two series of compounds, characterized by the benzomorphan scaffold in its destro configuration, were designed and synthesized in order to identify potential σ1R ligands. These compounds were also evaluated performing binding assay to investigate their affinity profile towards sigma receptors. In vivo evaluation was carried out to study the analgesic effect of most promising compounds in animal model of acute and chronic pain. Recently, the search for compounds with affinity for both MOR and σ1R is one of the innovative strategies to develop analgesics with reduced side effects. With this aim, two series of new fentanyl derivatives were synthesized, and their profile will be tested in vitro and in vivo. Finally, in the last part of this thesis the development of novel small molecules with potential opioid and/or σ1R ligands profile was described. The novel synthesized compounds are R-Carvone derivatives, and they were tested by competition binding assays to evaluate their affinity versus opioid and sigma receptors. These ligands are actually under investigation.File | Dimensione | Formato | |
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