The relatively high affinity of (R)-3 for 5-HT7 receptors provided an opportunity to derive potent and selective 5-HT7 receptor ligands by structural modification of (R)-3. Therefore, we initiated a synthetic program targeting analogues of (R)-3, initially focusing on variations of the substitution pattern in the C11-phenyl ring, specifically the introduction of substituents in the ortho positions of the C11-phenyl group. We prepared stable atropisomeric biaryl derivatives of (R)-aporphine, which are structurally well-characterized and interact in a stereoselective fashion with 5-HT7, 5-HT1A, and D2A receptors. These novel derivatives show a preference for the 5-HT7 receptor subtype and have been characterized as 5-HT7 receptor antagonists. The 2′-CN,6′-Me-substituted analogue (6aR,aS)-14 is the most interesting of the novel derivatives as it is a potent 5-HT7 receptor antagonist which exhibits selectivity versus 5-HT1A and D2A receptors. Furthermore, the stable atropisomers (6aR,aS)- and (6aR,aR)-14 display pharmacological stereoselectivity, representing one of the few instances in which stereoisomers with axial chirality have been demonstrated to interact in a stereoselective fashion with G-protein-coupled receptors. (6aR,aS)-14 will be useful as a pharmacological tool in 5-HT research.