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Mol Pharmacol. 1994 Aug;46(2):299-312.

Molecular basis for the binding of 2-aminotetralins to human dopamine D2A and D3 receptors.

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CNS Preclinical R&D, Astra Arcus AB, Södertälje, Sweden.


The affinities of a series of stereochemically well defined 2-aminotetralin derivatives for cloned human dopamine D2A (443 amino acids) and D3 receptors expressed in mammalian cell lines have been determined using [3H]raclopride as radioligand. Several of the compounds tested showed high selectivity for the D3 receptor. Notably, (R)-7-hydroxy-2-dipropylaminotetralin displayed 70-fold selectivity for the D3 receptor and its cis-C1-methyl analog, (1S,2R)-AJ-148, displayed 38-fold selectivity. Large differences in receptor binding affinities between the compounds were obtained, despite the close structural relationship of the compounds. To better understand the receptor interactions of these compounds, we have constructed homology-based receptor models of the human D2A and D3 receptors by using bacteriorhodopsin as a template. The resulting model was used in conjunction with an indirect model. The indirect model describes a proposed active agonist conformation for dopaminergic 2-aminotetralins and related compounds and consists of a receptor excluded volume that was used to define the agonist binding site. We docked a number of ligands into the D2A and D3 binding sites by optimizing attractive interactions and minimizing repulsive interactions. In the binding site model of the D2A receptor, the protonated nitrogen of the ligands interacts with Asp-114 in transmembrane region (TM) 3 through a reinforced ionic bond. The aspartic acid is surrounded by aromatic residues that may stabilize the ion pair formed with the protonated ligands. In addition, a hydrogen bond is formed from the phenolic hydrogen of the agonist ligands to Ser-193 (TM 5). Aromatic edge-to-face interactions occur between Phe-390 (TM 6) and the aromatic ring of the agonists. 2-Aminotetralin-based dopaminergic antagonists [e.g., (1S,2R)-UH-232] structurally related to agonists have a different but partly overlapping mode of binding, with the aromatic ring located more extracellularly, compared with agonists. The structure-activity relationships that are apparent from this and previous studies are qualitatively rationalized by the binding site models.

[Indexed for MEDLINE]

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