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The dopamine D2-like receptors (D2R, D3R, and D4R), which belong to class A G protein-coupled receptors, are important targets for antipsychotics. In the development of novel antipsychotics to avoid adverse side effects, subtype-selective dopamine receptor ligands that bind divergent secondary binding pockets (SBP) in addition to the conserved orthosteric binding site (OBS) have been discovered. SB269652, an allosteric modulator of D2R, consists of a tetrahydroisoquinoline pharmacophore bound in the OBS and an indole-2-carboxamide moiety bound in a SBP between TM2 and TM7. This ligand was recently characterized to act allosterically by a novel mechanism involving a D2R homodimer whereby the bitopic binding mode of SB269652 in one protomer negatively modulates the binding of an orthosteric ligand, either an agonist or an inverse agonist, to the second protomer (Lane et al., Nature Chemical Biology, 2014).To characterize the structural basis for the allosteric effect of SB269652, we combined ligand modifications, complementary receptor mutagenesis, and computational analysis, to identify the key interactions between SB269652 and D2R and the correspondingly induced conformational changes that are critical to propagate the allosteric impact across the dimer interface. We specifically considered three pairs of SB269652 derivatives that are modified in the orthosteric or secondary pharmacophore, or the linker region - in each pair, the modifications either retain/improve or eliminate the allosteric property. Using molecular docking and dynamics simulations, we characterized the binding modes of these derivatives in D2R, either in a protomer alone or in a dimer context with an orthosteric ligand bound in the other protomer. The results of our comparative modeling and analysis highlight the importance of the receptor-ligand interaction formed in the SBP between Glu95(2.65) and the indole-2-carboxamide moiety, in modulating the conformational rearrangements of the dimer interface(s).