The discovery of N-substituted-pyridoindolines and their binding affinities at the 5-HT2A, 5-HT2C and D2 receptors, and in vivo efficacy as 5-HT2A antagonists is described. The structure–activity relationship of a series of core tetracyclic derivatives with varying butyrophenone sidechains is also discussed. This study has led to the identification of potent, orally bioavailable 5-HT2A/D2 receptor dual antagonists as potential atypical antipsychotics.