title: Interactions of ligands with active and inactive conformations of the dopamine D2 receptor.
abstract: The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.
authors.affiliation: Department of Molecular Pharmacology, Preclinical R&D, Astra Arcus, Södertälje, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Malmberg
authors.forename: N
authors.initials: N
authors.lastname: Mohell
authors.forename: B
authors.initials: B
authors.lastname: Backlund Höök
authors.forename: A M
authors.initials: AM
authors.lastname: Johansson
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
authors.forename: G
authors.initials: G
authors.lastname: Nordvall
mesh_terms: D002478:Cells, Cultured; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D011487:Protein Conformation; D019257:Quinpirole / Q000494:pharmacology; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects*; D012457:Salicylamides / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D005576:Colforsin; D019257:Quinpirole; D020891:Raclopride; D000242:Cyclic AMP