Development of assay systems for characterisation of ligand binding properties to melanocortin 4 receptors
Date
2014-03-03
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Abstract
Käesolev doktoritöö „Uudsete meetodite arendamine ligandide sidumisomaduste uurimiseks melanokortiini 4 retseptorile“ käsitleb uuringutega, mille üheks eesmärgiks oli fluorestsentsil põhinevate katsesüsteemide väljatöötamine, mida saaks kasutada uute melanokortiini retseptorite spetsiifiliste ligandide avastamiseks. Melanokortiini retseptorid osalevad mitmete oluliste füsioloogiliste funktsioonide regulatsioonil nagu pigmentatsioon, seksuaal- ja toitumiskäitumine, energiatasakaalu reguleerimine, valu ja keha temperatuuri reguleerimine, immuunsed ja põletikuvastased reaktsioonid, jne. Seega on melanokortiini retseptoritele spetsiifilised ligandid perspektiivsed ravimikandidaadid selliste haiguste ravimiseks nagu rasvumine ja anoreksia, melanoom, erektsiooni ja seksuaalsuse häired, aga ka ärevushäired ning depressioon. Uute tõhusate ravimite leidmine sõltub suurel määral ka meie teadmistest retseptor-ligandide vastasmõju mehhanisme kohta ning oskusest kasutada neid teadmisi uudsete efektiivsete raviainete disainimiseks. Lisaks sellele, oleneb tihti ka meetodist, mis on antud juhul meie „silmadeks“ selles katsesüsteemis, millist toimeaine mõju me üldse näeme ja kui hästi me seda detekteerida ning iseloomustada suudame. Siin töös arendatud uudsed fluorestsentsil põhinevad kastesüsteemid võimaldavad loobuda radioaktiivsete ühendite kasutamisest ning jälgida retseptor-ligandi vastasmõjusid reaalajas. See võimaldab saada täiendavat informatsiooni melanokortiinse süsteemi funktsioneerimise kohta, aga ka luua automatiseeritud katsesüsteem uute aktiivsete ühendite leidmiseks.
Current PhD thesis “Development of assay systems for characterisation of ligand binding properties to melanocortin 4 receptors” describes our progress of melanocortin receptor studies connected with development of novel assay systems that would facilitate the discovery of novel receptor specific ligands. Melanocortin receptors are involved in regulation of wide variety of physiological functions like pigmentation, sexual behaviour, regulation of energy balance and feeding behaviours, temperature control and pain sense, inflammatory and immune responses and others. Thus, ligands for these receptors have a remarkable therapeutic potential for treatment of several human disorders like obesity and anorexia, melanoma, erectile dysfunction and sexual motivation, as well as anxiety and depression. Success in discovery of new drugs, in many aspects depends from our ability to understand the mechanisms of receptor-ligand interactions and use this to design novel, receptor subtype selective, potent and metabolically suitable drugs. Besides that, assay properties may play a very important role in interpretation of results, as the ability to see the effect of the drug depends on the “eyes” of the assay through which it is monitored. Fluorescence anisotropy-based assay systems we developed avoid the use of radioactive ligands and allow on-line monitoring of receptor-ligand interactions that would improve general understanding of the melanocortin system.
Current PhD thesis “Development of assay systems for characterisation of ligand binding properties to melanocortin 4 receptors” describes our progress of melanocortin receptor studies connected with development of novel assay systems that would facilitate the discovery of novel receptor specific ligands. Melanocortin receptors are involved in regulation of wide variety of physiological functions like pigmentation, sexual behaviour, regulation of energy balance and feeding behaviours, temperature control and pain sense, inflammatory and immune responses and others. Thus, ligands for these receptors have a remarkable therapeutic potential for treatment of several human disorders like obesity and anorexia, melanoma, erectile dysfunction and sexual motivation, as well as anxiety and depression. Success in discovery of new drugs, in many aspects depends from our ability to understand the mechanisms of receptor-ligand interactions and use this to design novel, receptor subtype selective, potent and metabolically suitable drugs. Besides that, assay properties may play a very important role in interpretation of results, as the ability to see the effect of the drug depends on the “eyes” of the assay through which it is monitored. Fluorescence anisotropy-based assay systems we developed avoid the use of radioactive ligands and allow on-line monitoring of receptor-ligand interactions that would improve general understanding of the melanocortin system.
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Keywords
melanokortiiniretseptorid, ligandid, interaktsioonid, ravimidisain, melanocortin receptors, ligands, interactions, drug design