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Antiparkinson concentrations of pramipexole and PHNO occupy dopamine D2high and D3high receptors

2005; Wiley; Volume: 58; Issue: 2 Linguagem: Inglês

10.1002/syn.20193

1098-2396

Philip Seeman, Françoise Ko, Matthäus Willeit, Patrick N. McCormick, Nathalie Ginovart,

Neurological disorders and treatments

Because the high-affinity state of dopamine D2 receptors, D2High, is the functional state of D2, and because the proportion of D2 receptors in the high-affinity state correlates with dopamine behavioral supersensitivity, the present study was designed to determine the affinities of antiparkinson dopamine agonists at the D2High site by means of competition with [3H]domperidone. In contrast to [125I]iodosulpride or [3H]spiperone, which are not sensitive to low concentrations of dopamine agonists, [3H]domperidone readily reveals dissociation constants (Ki) for antiparkinson agonists at D2High and D3High receptors. The Ki values for the human cloned D2High and D3High receptors, respectively, were 19 and 9 nM for pramipexole, 0.24 and 0.6 nM for (+)PHNO, 0.7 and 1.3 nM for bromocriptine, 0.5 and 2.6 nM for apomorphine, and 0.09 and 0.25 nM for (−)N-propylnorapomorphine. After correcting for the fraction of drug bound to plasma proteins, the known clinical concentrations in plasma or plasma water of these drugs, including pramipexole and (+)PHNO, are sufficient to occupy and activate the high-affinity state of D2, D2High, in treating Parkinson's disease. The D3High receptors are less selectively occupied by (+)PHNO, bromocriptine, apomorphine, and (−)NPA. Synapse 58:122–128, 2005. © 2005 Wiley-Liss, Inc.