Linker Functionalization of a Bivalent Ligand for the Study of the 5-HT2AR/ 5-HT2CR Heterodimer



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G-protein-coupled receptors (GPCRs) are important pharmaceutical targets. In recent years, it has been found that GPCRs can function as homo- and hetero- dimers. The serotonin receptors 5-HT2AR and 5-HT2CR have been shown to form a heterodimer. These two receptors regulate impulsivity and cue reactivity, two factors that can lead to drug addiction relapse. A synergistic effect of the 5-HT2AR antagonist M100907 and the 5-HT2CR agonist WAY163909 in the suppression of impulsivity and cue reactivity has been reported. A bivalent ligand containing these two pharmacophores, linked by a polyethylene glycol chain and a triazole, has been developed. In this thesis, attempts to functionalize the linker portion of the bivalent ligand for the addition of a fluorophore are reported. The first approach was to functionalize the triazole portion of the linker via the iodoalkyne-azide cycloaddition reaction; however, it was determined that this method was unsuitable due to challenges with purity and yield. The second approach was to functionalize the polyethylene glycol portion of the linker by replacing an oxygen atom with a nitrogen atom, allowing for tertiary substitution at the nitrogen. A linker was synthesized containing a tertiary amine in which an ester side-chain was included. This ester serves as a handle for incorporation of a fluorophore via amide coupling. A fluorophore-tagged bivalent ligand will open the door to cellular imaging of the 5-HT2AR/5-HT2CR GPCR heterodimer.



Serotonin, Bivalent ligand, 5-HT2AR antagonist, 5-HT2CR agonist, Fluorophores