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Antiparkinson concentrations of pramipexole and PHNO occupy dopamine D2 high and D3 high receptors
Author(s) -
Seeman Philip,
Ko Françoise,
Willeit Matthäus,
McCormick Patrick,
Ginovart Nathalie
Publication year - 2005
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20193
Subject(s) - pramipexole , apomorphine , dopamine receptor d3 , dopamine receptor d2 , dopamine receptor , chemistry , bromocriptine , dopamine , spiperone , pharmacology , receptor , dopaminergic , domperidone , dopamine agonist , endocrinology , medicine , parkinson's disease , biochemistry , hormone , disease , prolactin
Because the high‐affinity state of dopamine D2 receptors, D2 High , 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 D2 High site by means of competition with [ 3 H]domperidone. In contrast to [ 125 I]iodosulpride or [ 3 H]spiperone, which are not sensitive to low concentrations of dopamine agonists, [ 3 H]domperidone readily reveals dissociation constants ( K i ) for antiparkinson agonists at D2 High and D3 High receptors. The K i values for the human cloned D2 High and D3 High 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, D2 High , in treating Parkinson's disease. The D3 High receptors are less selectively occupied by (+)PHNO, bromocriptine, apomorphine, and (−)NPA. Synapse 58:122–128, 2005. © 2005 Wiley‐Liss, Inc.