MOLECULAR-BASIS FOR THE BINDING OF 2-AMINOTETRALINS TO HUMAN DOPAMINED-2A AND D-3 RECEPTORS

The affinities of a series of stereochemically well defined 2-aminotet ralin derivatives for cloned human dopamine D-2A (443 amino acids) and D-3 receptors expressed in mammalian cell lines have been determined using [H-3]raclopride as radioligand. Several of the compounds tested showed high selectivity for the D-3 receptor. Notably, (R)-7-hydroxy-2 -dipropylaminotetralin displayed 70-fold selectivity for the D-3 recep tor and its cis-C1-methyl analog, (1S,2R)-AJ-148, displayed 38-foId se lectivity. Large differences in receptor binding affinities between th e compounds were obtained, despite the close structural relationship o f the compounds. To better understand the receptor interactions of the se compounds, we have constructed homology-based receptor models of th e human D-2A and D-3 receptors by using bacteriorhodopsin as a templat e. The resulting model was used in conjunction with an indirect model. The indirect model describes a proposed active agonist conformation f or dopaminergic 2-aminotetralins and related compounds and consists of a receptor excluded volume that was used to define the agonist bindin g site. We docked a number of ligands into the D-2A and D-3 binding si tes by optimizing attractive interactions and minimizing repulsive int eractions. In the binding site model of the DPA receptor, the protonat ed nitrogen of the ligands interacts with Asp-114 in transmembrane reg ion (TM)3 through a reinforced ionic bond. The aspartic acid is surrou nded by aromatic residues that may stabilize the ion pair formed with the protonated ligands. In addition, a hydrogen bond is formed from th e phenolic hydrogen of the agonist ligands to Ser-193 (TM 5). Aromatic edge-to-face interactions occur between Phe-390 (TM 6) and the aromat ic ring of the agonists. 2-Aminotetralin-based dopaminergic antagonist s [e.g., (1S,2R)-UH-232] structurally related to agonists have a diffe rent but partly overlapping mode of binding, with the aromatic ring lo cated more extracellularly, compared with agonists. The structure-acti vity relationships that are apparent from this and previous studies ar e qualitatively rationalized by the binding site models.