The 5-HT7 receptor is the last member of the serotonin receptors family. This receptor, cloned and identified in 1993, belongs to the G protein-coupled receptor family and is positively coupled with adenylyl cyclase. Different isoforms, which differ only in the length and amino acid composition of their C-terminal tail, are generated by alternative splicing of the 5-HT7 receptor gene and are namely: 5-HT7(a), (b), (c) in rat and 5-HT7(a), (b), (d) in human. These isoforms do not show significant differences in their pharmacological profile, signal transduction or tissue distribution and the 5-HT7(a) is the most abundant in human. Since its identification, 5-HT7 receptor has been the subject of intense research efforts due to its presence in functionally relevant regions of the brain. For this reason, 5-HT7 receptor has been suggested to have a role in a wide range of physiological functions such as nociception, sleep, locomotor activity regulation, learning and memory. Also, it seems to be involved in some pathologies like anxiety, depression, epilepsy, and Fragile X syndrome. After the cloning of 5-HT7 receptor, a number of non-selective ligands, belonging to different chemical classes and showing high affinity toward this receptor, were identified; however, these compounds display multi-receptor affinity. In the last decade, there have been many efforts to discover selective agents for the 5-HT7 receptor. Examples of such molecules are characterized as long-chain arylpiperazine compounds, which are categorized as 5-HT7R ligands because they indicate high affinity and good selectivity for the receptor. Due to the high drug potential of long-chain arylpiperazines, with a number of successfully developed drugs or pharmacological tools, various structure-affinity relationships studies have been done. Furthermore, given the therapeutic potential of 5-HT7 receptor agents in central nervous system disorders, we recently worked on the development of new selective 5-HT7 receptor ligands to gain a comprehensive insight about their structure-affinity relationships and the functional properties. In this thesis, novel series of long-chain arylpiperazines were designed, synthesized, and tested to evaluate their affinity for the 5-HT7 and 5-HT1A receptors. Moreover, molecular modeling studies were performed in order to investigate these new ligands interactions with the 5-HT7 receptor.
Il recettore 5-HT7 è l’ultimo membro della famiglia dei recettori della serotonina, fu clonato e identificato per la prima volta nel 1993 e appartiene alla superfamiglia dei recettori accoppiati a proteina G. Lo splicing alternativo del gene che codifica per il recettore 5-HT7 genera isoforme differenti: 5-HT7(a), (b), (c) nel ratto e 5-HT7(a), (b), (d) nell’uomo, che differiscono soltanto nella lunghezza e composizione amminoacidica dell’estremità carbossi-terminale. Queste isoforme non mostrano differenze significative nel loro profilo farmacologico, nella modalità di trasduzione del segnale o nella distribuzione tissutale e nell’uomo l’isoforma più abbondante del recettore è la 5-HT7(a). Sin dalla sua caratterizzazione questo recettore è stato oggetto di numerosi studi riguardo il ruolo sul sistema nervoso centrale, dov’è particolarmente abbondante e per questo motivo è stato possibile ipotizzare che è implicato in una varietà di funzioni fisiologiche tra cui: nocicezione, apprendimento e memoria, ritmo sonno-veglia, regolazione dell'attività locomotoria; in aggiunta, evidenze sperimentali definiscono il suo coinvolgimento in alcune patologie come ansia, depressione, epilessia e sindrome dell’X fragile. Dopo la clonazione e la caratterizzazione del recettore 5-HT7, sono state identificate differenti classi di ligandi ad alta affinità ma non selettivi. Nell’ultima decade, notevoli sforzi sono stati fatti per scoprire nuovi agenti selettivi e i derivati long-chain aril-piperazininici rappresentano una fra le classi più promettenti, in quanto mostrano elevata affinità e buona selettività per il recettore 5-HT7. Pertanto visti i numerosi studi di correlazione struttura affinità che riguardano questa classe di agenti serotoninergici e l elevato potenziale terapeutico, da parecchi anni il gruppo di ricerca in cui ho sviluppato il mio progetto di dottorato, si occupa della progettazione e sintesi di nuovi derivati alchilpiperazinici quali ligandi per il recettore 5-HT7. In questa tesi nuove serie di derivati long-chain aril-piperazininici sono stati progettati, sintetizzati e testati in modo da valutare l’affinità e la selettività per il recettore 5-HT7 nei confronti del recettore 5-HT1A. Inoltre sono stati effettuati studi di molecular modeling al fine di valutare le specifiche interazioni dei nuovi ligandi con il recettore 5-HT7.
New alkylpiperazines as 5-HT7R ligands / Intagliata, Sebastiano. - (2015 Dec 08).
New alkylpiperazines as 5-HT7R ligands
INTAGLIATA, SEBASTIANO
2015-12-08
Abstract
The 5-HT7 receptor is the last member of the serotonin receptors family. This receptor, cloned and identified in 1993, belongs to the G protein-coupled receptor family and is positively coupled with adenylyl cyclase. Different isoforms, which differ only in the length and amino acid composition of their C-terminal tail, are generated by alternative splicing of the 5-HT7 receptor gene and are namely: 5-HT7(a), (b), (c) in rat and 5-HT7(a), (b), (d) in human. These isoforms do not show significant differences in their pharmacological profile, signal transduction or tissue distribution and the 5-HT7(a) is the most abundant in human. Since its identification, 5-HT7 receptor has been the subject of intense research efforts due to its presence in functionally relevant regions of the brain. For this reason, 5-HT7 receptor has been suggested to have a role in a wide range of physiological functions such as nociception, sleep, locomotor activity regulation, learning and memory. Also, it seems to be involved in some pathologies like anxiety, depression, epilepsy, and Fragile X syndrome. After the cloning of 5-HT7 receptor, a number of non-selective ligands, belonging to different chemical classes and showing high affinity toward this receptor, were identified; however, these compounds display multi-receptor affinity. In the last decade, there have been many efforts to discover selective agents for the 5-HT7 receptor. Examples of such molecules are characterized as long-chain arylpiperazine compounds, which are categorized as 5-HT7R ligands because they indicate high affinity and good selectivity for the receptor. Due to the high drug potential of long-chain arylpiperazines, with a number of successfully developed drugs or pharmacological tools, various structure-affinity relationships studies have been done. Furthermore, given the therapeutic potential of 5-HT7 receptor agents in central nervous system disorders, we recently worked on the development of new selective 5-HT7 receptor ligands to gain a comprehensive insight about their structure-affinity relationships and the functional properties. In this thesis, novel series of long-chain arylpiperazines were designed, synthesized, and tested to evaluate their affinity for the 5-HT7 and 5-HT1A receptors. Moreover, molecular modeling studies were performed in order to investigate these new ligands interactions with the 5-HT7 receptor.File | Dimensione | Formato | |
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Doctoral Thesis Sebastiano Intagliata.pdf
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