New alkylpiperazines as 5-HT7R ligands

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.