title: Actions of the prototypical 5-HT1A receptor agonist 8-OH-DPAT at human alpha2-adrenoceptors: (+)8-OH-DPAT, but not (-)8-OH-DPAT is an alpha2B subtype preferential agonist.
abstract: 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] is the prototypical agonist at serotonin 5-HT1A receptors; however, activity at other targets contributes to the functional effects of the compound as well. We examined the properties of 8-OH-DPAT and its enantiomers at recombinant human (h)alpha2-adrenoceptor subtypes, using a panel of radioligand binding and functional tests. In competition binding experiments using [3H]-RX821002, about 10-fold selectivity of (+)8-OH-DPAT for the halpha2B subtype (pKi about 7) over halpha2A- and halpha2C-adrenoceptors was observed. In contrast, the S(-) enantiomer of 8-OH-DPAT showed similar weak affinities for the three receptor subtypes (pKis<6). The binding affinity of (+)8-OH-DPAT at the halpha2B- and the halpha2A-adrenoceptor was found sensitive to GTPgammaS, a receptor/G protein-uncoupling agent, indicating agonist properties of the drug. Furthermore, using [35S]GTPgammaS binding determination at CHO-halpha2B or CHO-halpha2A cell membranes and G protein coupled inwardly rectifying potassium (GIRK) current recordings in Xenopus oocytes expressing halpha2B, partial agonist activity of (+)8-OH-DPAT at the respective receptors was confirmed in these two different functional assays. Potency of (+)8-OH-DPAT for stimulation of [35S]GTPgammaS incorporation was lower at the halpha2A- than at the halpha2B-adrenoceptor, consistent with binding affinities. Thus, (+)8-OH-DPAT and, as a consequence, racemic (+/-)8-OH-DPAT are partial agonists at halpha2-adrenoceptors with selectivity for the halpha2B subtype, a property that might contribute to the effects of the compound described in native systems.
authors.affiliation: Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, F-81106 Castres Cedex, France. peter.heusler@pierre-fabre.com
authors.forename: Peter
authors.initials: P
authors.lastname: Heusler
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rauly-Lestienne
authors.forename: Amélie
authors.initials: A
authors.lastname: Tourette
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Tardif
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Ailhaud
authors.forename: Guillaume
authors.initials: G
authors.lastname: Croville
authors.forename: Didier
authors.initials: D
authors.lastname: Cussac
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000737:chemistry* / Q000494:pharmacology*; D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004553:Electric Conductivity; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D058825:Serotonin 5-HT1 Receptor Agonists; D013237:Stereoisomerism
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D058825:Serotonin 5-HT1 Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017371:8-Hydroxy-2-(di-n-propylamino)tetralin