Functional potencies of dopamine agonists and antagonists at human dopamine D2 and D3 receptors

Abstract We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D 2 and D 3 receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D 2L and D 2S receptors (hD 2L -Low, hD 2L -High, hD 2S -Low and hD 2S -High, respectively) and human dopamine D 3 Ser-9 and D 3 Gly-9 receptors (hD 3 -Ser-9 and hD 3 -Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy- N , N -di- n -propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R -(+)- trans -3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D 2 and D 3 receptor full agonists and showed higher potencies in hD 2L -High and hD 2S -High compared to hD 2L -Low and hD 2S -Low. In hD 3 -Ser-9 and hD 3 -Gly-9 compared to hD 2L -Low and hD 2S -Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD 2L -Low; a low intrinsic activity partial agonist in hD 2S -Low; a moderate partial agonist in hD 3 -Ser-9 and hD 3 -Gly-9; a robust partial agonist in hD 2L -High; and a full agonist in hD 2S -High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD 2S -Low and hD 2S -High compared to hD 3 -Ser-9 and hD 3 -Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia.