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 EC(50) 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.