Design of GalR2 subtype specific ligands: their role in depression-like behavior and feeding regulation
Date
2013-03-05
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Abstract
Galaniin on 29 aminohappe pikkune neuropeptiid, mis avastati ligi 30 aastat tagasi Stockholmis, Karolinska Instituudis Viktor Muti ja tema kolleegide poolt. Galaniin reguleerib kolme spetsiifilise G-valguga seotud retseptori (GPCR) alatüüpide (GalR1-GalR3) interaktsioonide abil mitmeid bioloogilisi funkt¬sioone nagu depressioon, ärevus, alkoholisõltuvus, ainevahetuse häired ja valu. Kõik kolm retseptori alatüüpi on galaniini suhtes kõrge afiinsusega, omades seejuures erinevaid funktsionaalseid omadusi ja signaaliülekande radasid. Seetõttu on neil täita erinevad ülesanded mitmesuguste haiguste ja pato¬loogi¬liste seisundite reguleerimisel, muutes galaniini ja tema spetsiifilised retseptorid olulisteks farmakoloogia märklaudadeks ning uurimisobjektideks neuro¬teaduses. Hoolimata sellest on retseptorite alatüüpide seotus erinevate haigus¬tega senini täielikult määratlemata, mis on suurel määral põhjustatud galaniini retseptorite alatüüp-spetsiifiliste ligandide puuduse tõttu.
Käesoleva doktoritöö peamiseks eesmärgiks on galaniini alatüübile 2 (GalR2) spetsiifiliste ligandide disainimine, süntees ja omaduste uurimine nii in vitro kui ka in vivo tingimustes.
Galanin is a 29 amino acid long neuropeptide. Through interactions with its three G-protein coupled receptors, GalR1-GalR3, galanin is involved in several functions in the central nervous system, including the regulation of depression-like behavior and food consumption. As all the three receptor subtypes have somewhat different functional binding properties and signaling pathways it has been suggested that they have distinct roles in the regulation of various human diseases and pathological conditions. This makes GalR1-GalR3 unique pharmacological targets. However, due to the lack of subtype specific ligands in the galanin field the involvement of different galanin receptors in various diseases remains to be determined. This thesis is therefore devoted to the development of novel GalR2 subtype specific ligands. Additionally, these novel compounds and the functions of GalR2 have been investigated in two different behavioral models, namely depression-like behavior and feeding regulation.
Galanin is a 29 amino acid long neuropeptide. Through interactions with its three G-protein coupled receptors, GalR1-GalR3, galanin is involved in several functions in the central nervous system, including the regulation of depression-like behavior and food consumption. As all the three receptor subtypes have somewhat different functional binding properties and signaling pathways it has been suggested that they have distinct roles in the regulation of various human diseases and pathological conditions. This makes GalR1-GalR3 unique pharmacological targets. However, due to the lack of subtype specific ligands in the galanin field the involvement of different galanin receptors in various diseases remains to be determined. This thesis is therefore devoted to the development of novel GalR2 subtype specific ligands. Additionally, these novel compounds and the functions of GalR2 have been investigated in two different behavioral models, namely depression-like behavior and feeding regulation.
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Keywords
galaniin, ligandid, toitumine, depressioon, galanin, ligands, G-valgud, G-proteins, nutrition, depression (psychology)