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Antiparkinson therapeutic potencies correlate with their affinities at dopamine D2 High receptors
Author(s) -
Seeman Philip
Publication year - 2007
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.20453
Subject(s) - bromocriptine , pergolide , chemistry , cabergoline , dopamine receptor d2 , pramipexole , dopamine agonist , agonist , quinpirole , dopamine receptor , pharmacology , dopamine , apomorphine , dopaminergic , medicine , endocrinology , receptor , parkinson's disease , biochemistry , disease , hormone , prolactin
To determine whether antiparkinson dopamine agonists preferentially act on the high‐affinity or the low‐affinity states of dopamine D1 and D2 receptors, the agonist potencies were obtained by competition against [ 3 H]SCH23390 for D1 High and D1 Low , and against [ 3 H]domperidone for D2 High and D2 Low . N ‐propylnorapomorphine and cabergoline were the most potent at D2 High , with dissociation constants of 0.18 and 0.36 nM, respectively. Other agonists had D2 High K i values of 0.52 nM for quinagolide, 0.6 nM for (+)PHNO, 0.9 for bromocriptine, 1.8 nM for apomorphine, 2.4 nM for pergolide, 3 nM for quinpirole, and 6.2 nM for lergotrile. There was a clear correlation between the K i values at D2 High and their therapeutic concentrations in the plasma water, as derived from the known concentrations after correction for the fraction bound to the human plasma proteins. The data suggest that D2 High is the primary and common target for the antiparkinson action of dopamine agonists. Bromocriptine, cabergoline, lergotrile, pergolide, and pramipexole had no affinity for D1 High , consistent with the clinical observations that the D2‐selective bromocriptine and pramipexole elicit low levels of dyskinesia. Synapse 61:1013–1018, 2007. © 2007 Wiley‐Liss, Inc.