Investigating the Role of Serotonin 2A and 2C Receptors in Neurobiology

Drug addiction is a social problem in today’s society. In the drug addiction cycle, relapse is a crucial problem to overcome with impulsivity and cue reactivity as two important factors, shown to be linked to 5-HT2AR and 5-HT2CR. A synergistic effect has been discovered in that treatment of ineffective dose of the selective 5-HT2AR antagonist M100907 plus an ineffective dose of the selective 5-HT2CR agonist WAY163909 suppresses the impulsivity and cue reactivity. In view of this synergistic effect and the possibility of GPCR oligomers existence, bivalent ligands tethering M100907 and WAY163909 through click reaction have been developed. The proper site to tether the linker on M100907 molecule has been reported. In this dissertation, we reported various WAY163909 analogues to determine the amenable site for linker attachment without a significant change on the 5-HT2CR agonist activity. Replacement on bottom ring of WAY163909 with pipyridine or cyclohexanol resulted in loss of agonist activity for 5-HT2CR. It was eventually discovered that the methoxy substitution on the benzene ring of WAY163909 retained agonist activity toward 5-HT2CR. To construct the bivalent ligand, PEG chain was used as linker and the click reaction was employed to link two ligands. Bivalent ligands with various linker lengths (8-26 atoms) were synthesized. A pERK assay showed that the bivalent ligand with 17-atom linker gave distinct “U-shape” curve in cells expressing both 5-HT2AR and 5-HT2CR. We hypothesize M100907 is acting as an antagonist for 5-HT2CR. Replacement of fluoride with methoxy and nitro was made. However, the bivalent ligand with nitro group on M100907 exhibited no activity at the 5-HT2AR, while the one with methoxy group is currently under investigation. Chiral resolution of WAY163909 derivative was successfully achieved by using di-p-toluoyl-tartaric acid. Binding studies showed the (R, R)-enantiomer possessed high affinity to all three 5-HT2R, while the (S, S)-enantiomer showed high selectivity for 5-HT2CR over 5-HT2AR and 5-HT2BR. The calcium assay showed the EC50 of (R, R)-enantiomer is 1.2 ± 0.2 nM and the (S, S)-enantiomer is 60.1 ± 9.7 nM.Chemistry, Department o