In summary, we report the synthesis and biological activity of substituted 1-(3-pyridylcarbamoyl)indolines which illustrates the use of 5,6-disubstitution as a replacement for a fused 5-membered ring in the context of 5-HT2C/2B receptor antagonists. Although compounds such as 3 and 4 were found to be potent and selective 5-HT2C/2B receptor antagonists, they were also very potent inhibitors of a number of human cytochrome P450 enzymes which precluded their development as potential anxiolytic agents. Elaboration of the left hand side pyridyl ring abolished the inhibitory activity, leading to bipyridyl ethers such as 5, which is the first reported brain penetrant, 5-HT2C receptor antagonist with selectivity over both the 5-HT2A and 5-HT2B receptor subtypes. Furthermore, 5 was found to exert marked anxiolytic-like responses in rat models, confirming that these responses are mediated by 5-HT2C receptor blockade.