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-HTIA 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)alpha(2)-adrenoceptor subtypes, using a panel of radioligand binding and functional tests. In competition binding experiments using [H-3]-RX821002, about 10-fold selectivity of (+)8-OH-DPAT for the ham subtype (pK(i) about 7) over h alpha(2A)- and h alpha(2C)-adrenoceptors was observed. In contrast, the S() enantiomer of 8-0H-DPAT showed similar weak affinities for the three receptor subtypes (pKis <6). The binding affinity of ( +)8-0H-DPAT at the h alpha(2B)- and the h alpha(2A)-adrenoceptor was found sensitive to GTP gamma S, a receptor/G protein-uncoupling agent, indicating agonist properties of the drug. Furthermore, using [S-35]GTP gamma S binding determination at CHO-h alpha(28) or CHO-h alpha(2A) cell membranes and G protein coupled inwardly rectifying potassium (GIRK) current recordings in Xenopus oocytes expressing h alpha(28), partial agonist activity of (+)8-0H-DPAT at the respective receptors was confirmed in these two different functional assays. Potency of (+)8-0H-DPAT for stimulation of [S-35]GTPyS incorporation was lower at the h alpha(2A)- than at the h alpha(2B)-adrenoceptor, consistent with binding affinities. Thus, ( +)8-0H-DPAT and, as a consequence, racemic (+/-)8-OH-DPAT are partial agonists at h alpha(2)-drenoceptors with selectivity for the ha28 subtype, a property that might contribute to the effects of the compound described in native systems. (C) 2010 Elsevier B.V. All rights reserved.