Depressive disorders are a series of psychiatric pathologies, characterized by depressed mood, anhedonia, and other physical symptoms that can compromise the subject's quality of life. Some of these physical symptoms may include headaches, chronic pain, sleep disturbances, and weight loss or gain. It is often a disabling condition that affects the emotional and cognitive sphere of the individual. According to the WHO, the illness affects more than 280 million people worldwide. The treatment of depressive disorders involves psychotherapy sessions often accompanied by the administration of antidepressant medications. The most commonly used medications are based on the regulation of certain neurotransmitters such as serotonin, norepinephrine, and dopamine. These treatments may lead to an improvement in symptoms weeks or months after starting therapy, but they have a low efficacy rate and serious side effects. Following recent studies, a new theory regarding the pathogenesis of depressive disorders has emerged: the glutamatergic theory. The NMDA (N-methyl-D-aspartate) receptor is an ionotropic receptor for glutamate, linked to the activation of certain brain pathways such as synaptogenesis, memory, and learning. It has been observed that excessive stimulation of NMDA receptors, caused in turn by high synaptic concentrations of glutamate, leads to unregulated increases in intracellular Ca2+ concentrations, which can predispose to proapoptotic events. Recently, a drug acting as a non-competitive antagonist of the NMDA receptor has been approved: (S)-ketamine or esketamine, sold under the trade name Spravato®. This medication induces a faster onset of therapeutic effects and is effective in the case of treatment-resistant depression. However, its use is limited due to the risk of psychotomimetic effects and potential for abuse. So, there is a need for molecules that consistently act as non-competitive antagonists of the NMDA receptor, but with lower binding affinity, in order to avoid the psychotomimetic and dissociative effects typical of ketamine. This thesis project focuses on the synthesis of the two enantiomers of picenadol, and a small library of structural analogs that may have similar pharmacological activity. Picenadol have been developed in the past as an opioid analgesic, but obsolete and imprecise evidences show that the two enantiomers of picenadol act also as NMDA antagonists. The two enantiomers of picenadol, along with the structural analogues, will be initially tested in vitro to assess their mode of interaction with the NMDA and other relevant CNS receptors.
I disturbi depressivi sono una serie di patologie psichiatriche caratterizzate da umore depresso, anedonia, e altri sintomi fisici che possono compromettere la qualità di vita del soggetto. Alcuni di questi sintomi fisici possono essere: mal di testa, dolore cronico, disturbi del sonno, perdita o aumento di peso. È spesso una malattia invalidante che compromette la sfera emotiva e cognitiva della persona. Secondo l’OMS la malattia colpisce più di 280 milioni di persone in tutto il mondo. Per il trattamento dei disturbi depressivi si interviene con sedute di psicoterapia, spesso accompagnate dalla somministrazione di farmaci antidepressivi. I farmaci maggiormente utilizzati si basano sulla regolazione di alcuni neurotrasmettitori: serotonina, noradrenalina e dopamina. Questi trattamenti possono portare a un miglioramento della sintomatologia dopo settimane o mesi dall’inizio della terapia, ma hanno un basso tasso di efficacia e gravi effetti collaterali. A seguito di recenti studi, si è sviluppata una nuova teoria riguardante la patogenesi dei disturbi depressivi: la teoria glutammatergica. Il recettore NMDA (N-metil-D-aspartato) è un recettore ionotropico per il glutammato, coinvolto in alcuni pathway cerebrali, come la sinaptogenesi, la memoria e l’apprendimento. Si è visto che un’eccessiva stimolazione dei recettori NMDA, causata a sua volta da elevate concentrazioni sinaptiche di glutammato, provoca un aumento disregolato della concentrazione di Ca2+ intracellulare che può evolvere in eventi proapoptotici. Recentemente è stato approvato un farmaco che agisce come antagonista non competitivo del recettore NMDA: (S)-ketamina o esketamina, commercializzato con il nome Spravato®. Questo farmaco induce una più rapida manifestazione degli effetti terapeutici rispetto alle terapie standard, ed è efficace anche nei casi di depressione resistente. Il suo utilizzo è però limitato a causa del rischio di effetti psicotomimetici e del potenziale di abuso. Si stanno dunque cercando delle molecole che agiscano sempre come antagonisti non competitivi del recettore NMDA, che però abbiano una minor affinità di binding con il suddetto recettore, in modo tale da evitare l’effetto psicotomimetico e dissociativo tipico della ketamina. Questo progetto di tesi verte sull’ottimizzazione di una strategia sintetica per l’ottenimento dei due enantiomeri otticamente puri del picenadolo, e di una piccola libreria di analoghi strutturali, allo scopo di valutarne il profilo farmacologico. Il picenadolo è stato sviluppato in passato come farmaco analgesico oppioide, ma le datate ed imprecise evidenze mostrano come entrambi gli enantiomeri si comportino da antagonisti NMDA. I due enantiomeri del picenadolo, e gli analoghi strutturali sintetizzati, saranno testati in vitro per valutare la loro attività nei confronti del recettore NMDA e altri recettori rilevanti del SNC.
Sintesi e caratterizzazione di (+)- e (-)-picenadolo, ed analoghi otticamente puri, come potenziali antagonisti non competitivi del recettore NMDA
SCUSSAT, DAMIANO LUPO
2023/2024
Abstract
Depressive disorders are a series of psychiatric pathologies, characterized by depressed mood, anhedonia, and other physical symptoms that can compromise the subject's quality of life. Some of these physical symptoms may include headaches, chronic pain, sleep disturbances, and weight loss or gain. It is often a disabling condition that affects the emotional and cognitive sphere of the individual. According to the WHO, the illness affects more than 280 million people worldwide. The treatment of depressive disorders involves psychotherapy sessions often accompanied by the administration of antidepressant medications. The most commonly used medications are based on the regulation of certain neurotransmitters such as serotonin, norepinephrine, and dopamine. These treatments may lead to an improvement in symptoms weeks or months after starting therapy, but they have a low efficacy rate and serious side effects. Following recent studies, a new theory regarding the pathogenesis of depressive disorders has emerged: the glutamatergic theory. The NMDA (N-methyl-D-aspartate) receptor is an ionotropic receptor for glutamate, linked to the activation of certain brain pathways such as synaptogenesis, memory, and learning. It has been observed that excessive stimulation of NMDA receptors, caused in turn by high synaptic concentrations of glutamate, leads to unregulated increases in intracellular Ca2+ concentrations, which can predispose to proapoptotic events. Recently, a drug acting as a non-competitive antagonist of the NMDA receptor has been approved: (S)-ketamine or esketamine, sold under the trade name Spravato®. This medication induces a faster onset of therapeutic effects and is effective in the case of treatment-resistant depression. However, its use is limited due to the risk of psychotomimetic effects and potential for abuse. So, there is a need for molecules that consistently act as non-competitive antagonists of the NMDA receptor, but with lower binding affinity, in order to avoid the psychotomimetic and dissociative effects typical of ketamine. This thesis project focuses on the synthesis of the two enantiomers of picenadol, and a small library of structural analogs that may have similar pharmacological activity. Picenadol have been developed in the past as an opioid analgesic, but obsolete and imprecise evidences show that the two enantiomers of picenadol act also as NMDA antagonists. The two enantiomers of picenadol, along with the structural analogues, will be initially tested in vitro to assess their mode of interaction with the NMDA and other relevant CNS receptors.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/68652