title: Mechanisms of ligand binding and efficacy at the human D2(short) dopamine receptor.
abstract: Mechanisms of ligand binding and receptor activation for the human D2(short) dopamine receptor have been probed using two homologous series of monohydroxylated and dihydroxylated agonists (phenylethylamines and 2-dipropylaminotetralins). In ligand binding studies, the majority of compounds exhibited competition curves versus [3H]spiperone that were best fitted using a two site binding model. The compounds had different abilities (potencies and maximal effects) to stimulate [35S]GTPgammaS binding and to inhibit forskolin-stimulated cAMP accumulation. From the data it can be concluded that: (i) the ability of an agonist to stabilize receptor/G protein coupling can be used to predict agonist efficacy for some groups of compounds (2-dipropylaminotetralins) but not for others (phenylethylamines); (ii) the receptor may be activated by unhydroxylated compounds; (iii) single hydroxyl groups or pairs of hydroxyl groups on the agonist may contribute to binding affinity, potency and efficacy; and (iv) for the 2-dipropylaminotetralin series two modes of agonist/receptor interaction have been identified associated with different relative efficacy.
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology*; D016466:CHO Cells; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D010627:Phenethylamines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D018491:Dopamine Agonists; D008024:Ligands; D010627:Phenethylamines; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; C113776:dopamine D2L receptor; D005576:Colforsin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP