Actions of the prototypical 5-HT1A receptor agonist 8-OH-DPAT at human α2-adrenoceptors: (+)8-OH-DPAT, but not (−)8-OH-DPAT is an α2B subtype preferential agonist

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)α2-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 hα2B subtype (pKi about 7) over hα2A- and hα2C-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 hα2B- and the hα2A-adrenoceptor was found sensitive to GTPγS, a receptor/G protein-uncoupling agent, indicating agonist properties of the drug. Furthermore, using [35S]GTPγS binding determination at CHO-hα2B or CHO-hα2A cell membranes and G protein coupled inwardly rectifying potassium (GIRK) current recordings in Xenopus oocytes expressing hα2B, 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]GTPγS incorporation was lower at the hα2A- than at the hα2B-adrenoceptor, consistent with binding affinities. Thus, (+)8-OH-DPAT and, as a consequence, racemic (±)8-OH-DPAT are partial agonists at hα2-adrenoceptors with selectivity for the hα2B subtype, a property that might contribute to the effects of the compound described in native systems.