Identification of Novel 1‑O-Substituted Aporphine Analogues as Potent 5‑HT_2C Receptor Agonists

The 5-HT_2C receptor has emerged as a promising target in the treatment of a variety of central nervous system disorders. We have first identified aporphines as a new class of 5-HT_2C receptor agonists. Structure–activity relationship results indicate that the aporphine core may be required for 5-HT_2C receptor activity, and substitutions at its C1 position are important for 5-HT_2C receptor activity. Our efforts to optimize our hit 15781 lead to the identification of the highly potent and selective 5-HT_2C agonist 18b (MQ02-439) with an EC₅₀ value of 104 nM and weak antagonism at the 5-HT_2A and 5-HT_2B receptors. The findings may serve as good starting points for the development of more potent and selective 5-HT_2C agonists as valuable pharmacological tools or potential drug candidates.