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

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D2 and D3 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 D2L and D2S receptors (hD2L-Low, hD2L-High, hD2S-Low and hD2S-High, respectively) and human dopamine D3 Ser-9 and D3 Gly-9 receptors (hD3-Ser-9 and hD3-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 D2 and D3 receptor full agonists and showed higher potencies in hD2L-High and hD2S-High compared to hD2L-Low and hD2S-Low. In hD3-Ser-9 and hD3-Gly-9 compared to hD2L-Low and hD2S-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 hD2L-Low; a low intrinsic activity partial agonist in hD2S-Low; a moderate partial agonist in hD3-Ser-9 and hD3-Gly-9; a robust partial agonist in hD2L-High; and a full agonist in hD2S-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 hD2S-Low and hD2S-High compared to hD3-Ser-9 and hD3-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.